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Role of Inflammation in Disease

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Inflamed  

The debate over the latest cure-all craze.

BY

Medical Dispatch NOVEMBER 30, 2015 ISSUE     http://www.newyorker.com/magazine/2015/11/30/inflamed

 

The National Institutes of Health recently designated inflammation a priority.

 

The National Institutes of Health recently designated inflammation a priority.
CREDIT ILLUSTRATION BY CHAD HAGEN

 

Several years ago, I fell at the gym and ripped two tendons in my wrist. The pain was excruciating, and within minutes my hand had swollen grotesquely and become hot to the touch. I was reminded of a patient I’d seen early in medical school, whose bacterial infection extended from his knee to his toes. Latin was long absent from the teaching curriculum, but, as my instructor examined the leg, he cited the four classic symptoms of inflammation articulated by the Roman medical writer Celsus in the first century: rubor, redness; tumor, swelling; calor, heat; and dolor, pain. In Latin, inflammatio means “setting on fire,” and as I considered the searing pain in my injured hand I understood how the condition earned its name.

Inflammation occurs when the body rallies to defend itself against invading microbes or to heal damaged tissue. The walls of the capillaries dilate and grow more porous, enabling white blood cells to flood the damaged site. As blood flows in and fluid leaks out, the region swells, which can put pressure on surrounding nerves, causing pain; inflammatory molecules may also activate pain fibres. The heat most likely results from the increase in blood flow.
The key white blood cell in inflammation is called a macrophage, and for decades it has been a subject of study in my hematology laboratory and in many others. Macrophages were once cast as humble handmaidens of the immune system, responsible for recognizing microbes or debris and gobbling them up. But in recent years researchers have come to understand that macrophages are able to assemble, within themselves, specialized platforms that pump out the dozens of molecules that promote inflammation. These platforms, called inflammasomes, are like pop-up factories—quickly assembled when needed and quickly dismantled when the crisis has passed.

For centuries, scientists have debated whether inflammation is good or bad for us. Now we believe that it’s both: too little, and microbes fester and spread in the body, or wounds fail to heal; too much, and nearby healthy tissue can be degraded or destroyed. The fire of inflammation must be tightly controlled—turned on at the right moment and, just as critically, turned off. Lately, however, several lines of research have revealed that low-level inflammation can simmer quietly in the body, in the absence of overt trauma or infection, with profound implications for our health. Using advanced technologies, scientists have discovered that heart attacks, diabetes, and Alzheimer’s disease may be linked to smoldering inflammation, and some researchers have even speculated about its role in psychiatric conditions.

As a result, understanding and controlling inflammation has become a central goal of modern medical investigation. The internal research arm of the National Institutes of Health recently designated inflammation a priority, mobilizing several hundred scientists and hundreds of millions of dollars to better define its role in health and disease; in 2013, the journal Science devoted an entire issue to the subject. This explosion in activity has captured the public imagination. In best-selling books and on television and radio talk shows, threads of research are woven into cure-all tales in which inflammation is responsible for nearly every malady, and its defeat is the secret to health and longevity. New diets will counter the inflammation simmering in your gut and restore your mental equilibrium. Anti-inflammatory supplements will lift your depression and ameliorate autism. Certain drugs will tamp down the silent inflammation that degrades your tissues, improving your health and extending your life. Everything, and everyone, is inflamed.

Such claims aside, there is genuine evidence that inflammation plays a role in certain health conditions. In atherosclerosis, blood flow to the heart or the brain is blocked, resulting in a heart attack or a stroke. For a long time, atherosclerosis was thought to result mainly from eating fatty foods, which clogged the arteries. “Atherosclerosis was all about fats and grease,” Peter Libby, a professor at Harvard Medical School and a cardiologist at Brigham and Women’s Hospital, in Boston, told me recently. “Most physicians saw atherosclerosis as a straight plumbing problem.”

During his cardiology training, Libby studied immunology, and he became fascinated with the work of Rudolf Virchow, a nineteenth-century German pathologist. Virchow speculated that atherosclerosis might be an active process, caused by inflamed blood vessels, not one caused simply by the accumulation of fat. In the mid-nineteen-nineties, in studies with mice, Libby, working in parallel with other groups of scientists, found that low-density lipoproteins—LDLs, those particles of “bad” cholesterol—can work their way into the lining of arteries. There, they sometimes trigger an inflammatory response, which can cause blood clots that block the artery. Libby and others began to understand that atherosclerosis wasn’t a mere plumbing problem but also an immune disease—“our body’s defenses turned against ourselves,” he told me.

Paul Ridker, a cardiovascular expert and a colleague of Libby’s at Harvard and Brigham and Women’s, moved the research beyond the laboratory. He found that many patients who’d had heart attacks, despite lacking factors such as high blood pressure, high cholesterol, and a history of smoking, had an elevated level of C-reactive protein, a molecule produced in response to inflammation, in their blood. After demonstrating, in a separate study, that cholesterol-reducing statins could also reduce C-reactive-protein levels, Ridker launched the Jupiter trial, in which people with elevated levels of C-reactive protein but normal cholesterol levels were given a placebo or a statin medication. In 2008, the published results showed that the subjects who received the statin saw their levels of C-reactive protein drop and were less likely three and a half years later to suffer a heart attack. This suggested that elevated cholesterol isn’t the only factor at work in cardiovascular disease, and that in some cases statins, acting as anti-inflammatory agents, could be used to treat the condition.
The benefit was modest: the statin treatment reduced the risk of heart attack in only about one per cent of the patients. Still, that figure is statistically significant, and for one in every hundred patients—a hundred in every ten thousand—it’s meaningful. An independent safety-monitoring board ended the study early, saying that it was unethical to continue once it was clear that statins provided a benefit not available to the subjects on the placebo. (Critics argue that shortening the trial, which was funded by a drug company, exaggerated the potential benefits and underestimated long-term harm, but the researchers strongly disagree.) The N.I.H. and other scientific groups are funding new studies to further explore whether anti-inflammatory drugs—for example, low doses of immunomodulatory agents that are used for treating severe arthritis—can help prevent cardiovascular disease.
Another chronic condition that has been linked to inflammation is Type II diabetes. People with this condition can’t adequately use insulin, a molecule that enables the body’s cells to take glucose out of the bloodstream and derive energy from it. Their organs fail and glucose builds to dangerous levels in the blood. Recently, researchers have found macrophages in the pancreases of people with Type II diabetes. The macrophages release inflammatory molecules that are thought to impair insulin activity. One of these inflammatory molecules is called interleukin-1, and in 2007 the New England Journal of Medicine reported on a clinical trial in which an interleukin-1 blocker proved to be modestly effective at lowering blood-sugar levels in Type II diabetics. This suggests that, by blocking inflammation, it might be possible to restore insulin activity and alleviate some of the symptoms of diabetes.

Alzheimer’s disease, too, seems to show a link to inflammation. Alzheimer’s results from the buildup of amyloid and tau proteins in the brain; specialized cells called glial cells, which are related to macrophages, recognize these proteins as debris and release inflammatory molecules to get rid of them. This inflammation is thought to further impair the working of neurons, worsening Alzheimer’s. The connection is tantalizing, but it’s important to note that it doesn’t mean that inflammation causes Alzheimer’s. Nor is there strong evidence that inflammation contributes to other forms of dementia where the brain isn’t filled with protein debris. And in clinical trials anti-inflammatory drugs like naproxen and ibuprofen have failed to ameliorate or prevent Alzheimer’s.

 

On September 18, 2015, scientists at the N.I.H. convened a meeting to publicly present their research priorities, one of which is to decipher the consequences of inflammation. It’s increasingly apparent that inflammation plays some role in many health conditions, but scientists are far from grasping the nature of that relationship, the mechanisms involved, or the extent to which treating inflammation is helpful.

“We really don’t know how much inflammation contributes to diabetes, Alzheimer’s, depression, and other disorders,” Michael Gottesman, a director of research at the N.I.H., told me. “We know a lot about the mouse and its immune response. Much, much less is understood in humans. As we learn more, we see how much more we need to learn.” Gottesman pointed out that, of the thousand or so proteins circulating in our bloodstream, about a third are involved in inflammation and in our immune response, so simply detecting their presence doesn’t reveal much about their potential involvement in any particular disease. “Correlation is not causation,” he emphasized. “Because you find an inflammatory protein in a certain disorder, it doesn’t mean that it is causing that disorder.”
This lack of certainty hasn’t dampened the enthusiasm of a growing number of doctors who believe that inflammation is the source of a wide range of conditions, including dementia, depression, autism, A.D.H.D., and even aging. One of the most prominent such voices is that of Mark Hyman, whose books—including “The Blood Sugar Solution 10-Day Detox Diet”—are best-sellers. Hyman serves as a personal health adviser to Bill and Hillary Clinton and to the King and Queen of Jordan. Recently, he was recruited by the Cleveland Clinic with millions of dollars in funding to establish a center based on his ideas. Trained in family medicine, Hyman told me that he considers himself a new type of doctor. “I am a doctor who treats root causes and addresses the body as a dynamic system,” he wrote in an e-mail. “Being an inflammalogist is part of that.”

Studies with human subjects clearly indicate that, in cases where inflammation underlies a chronic condition, the inflammation is local: in the arteries (heart disease); or in the brain (Alzheimer’s); or in the pancreas (diabetes). And though there are associations between various forms of inflammatory disease—for example, people with psoriasis or periodontal disease have a somewhat higher risk of heart disease—it has not been proved that there is a causal connection. Hyman and other doctors, such as the neurologist David Perlmutter, promote a more radical idea: that certain foods and environmental toxins cause smoldering inflammation, which somehow spreads to other areas of the body, including the brain, degrading one’s health, mental acuity, and life span.

The notion of a gut-brain connection seems to derive from studies with mice, including one that showed that introducing a bacterium into a mouse’s gastrointestinal tract led to behavioral changes, such as a reluctance to navigate mazes. But there’s scant evidence that anything similar happens in people, or any rigorous study to show that “anti-inflammatory diets” reduce depression. Earlier this year, the journal Brain, Behavior, and Immunity published a meta-analysis of more than fifty clinical studies that found inflammatory molecules in patients with depression. The paper revealed that there was little consistency from study to study about which molecules correlated to the condition. Steven Hyman, a former director of the National Institute of Mental Health and now the head of the Stanley Center at the Broad Institute (and no relation to Mark Hyman), in Cambridge, Massachusetts, noted that depression is “one of those topics where exuberant theorization vastly outstrips the data.”

Nonetheless, Mark Hyman holds fast to his view. “Inflammation is the final common pathway for pretty much all chronic diseases,” he told me. His recommended solution is an “anti-inflammatory diet”—omitting sugar, caffeine, beans, dairy, gluten, and processed foods, as well as taking a variety of supplements, including probiotics, fish oil, Vitamins C and D, and curcumin, a key molecule in turmeric. Hyman introduced me to one of the patients he had treated with his anti-inflammatory diet and supplements, a forty-seven-year-old hedge-fund manager in Cambridge named Jim Silverman. Two decades ago, Silverman began noticing blood in his stool. A colonoscopy resulted in a diagnosis of ulcerative colitis. In the ensuing years, Silverman was treated by gastroenterologists with aspirin-based medication, anti-inflammatory suppositories, and even corticosteroids, but the problem persisted. Then, five years ago, on a flight home from a business conference, he happened to sit next to Hyman, who told him that he could cure colitis.
“I thought, What a bullshitter,” Silverman said. He travelled anyway to Hyman’s UltraWellness Center, in Lenox, Massachusetts, to consult with him. Hyman told him that dairy was inflaming his bowel. Silverman was skeptical, but he kept track of his diet and bleeding episodes, and ultimately concluded that restricting dairy products resulted in long periods without bleeding. He now thinks that he could be suffering from a dairy allergy. In addition to avoiding dairy products, he continues to follow the anti-inflammatory regimen of supplements prescribed by Hyman. “I’m just taking it because I’m doing well,” he said. “I have no idea if it’s doing anything, but I don’t want to rock the boat.”

I asked Gary Wu, a professor of gastroenterology at the Perelman School of Medicine, at the University of Pennsylvania, and one of the world’s experts on the gut microbiome, about the alleged value of treating inflammatory bowel disease by restricting specific foods. Recently, in the journal Gastroenterology, Wu and his colleagues published a comprehensive review of scientific studies on diet and inflammatory bowel disease. They found only two dietary interventions that had been proved to reduce inflammation: an “elemental diet,” which is a liquid mixture of amino acids, simple sugars, and triglycerides, and a slightly more complex liquid diet. The liquid mixtures are typically administered with a tube placed through the nose. “The diet is not palatable,” Wu said. “And you don’t eat during the day. There is no intake of whole foods at all.”

David Agus, a cancer specialist and a professor of medicine and engineering at the University of Southern California, is equally skeptical of Hyman’s claims for the anti-inflammation diet. Agus, who is perhaps best known for being the doctor on “CBS This Morning,” recently received a multimillion-dollar grant from the National Cancer Institute to study how inflammation may spur the growth of tumors. “This notion that foods cause inflammation and foods can block inflammation, there’s zero data that it changes clinical outcomes,” he told me. “If the idea gets people to eat fruits and vegetables, I love it, but it’s not real.” Agus noted that vitamins don’t counter inflammation, and that it’s been shown, in rigorous clinical trials, that they may increase one’s risk of developing cancer.
Still, Agus views inflammation as a component not only of cancer but also of chronic diseases like diabetes and dementia. Rather than special diets, he supports preventively taking approved anti-inflammatory medications, such as aspirin and statins, and scrupulously scheduling the standard vaccinations in order to prevent infections. In “The End of Illness,” Agus encourages the reader to “reduce your daily dose of inflammation” by, among other things, not wearing high heels, since these can inflame your feet and the inflammation could possibly affect your vital organs. When I pressed him on that suggestion, he told me, “What I meant is that if your feet hurt all day it’s probably not a good thing. The downside is you just wear a different pair of shoes. The upside is it gave you an understanding of inflammation and its role in disease.”

Mark Hyman, at times, acknowledges the possible limits of his paradigm. When I asked him about the alleged link among gut inflammation, diet, and psychological disorders, he conceded that some of his evidence was anecdotal, derived from his own clinical practice. He mentioned the case of a child with asthma, eczema, and A.D.H.D., whom he treated with “an elimination diet, taking him off processed foods, and giving him supplements.” The child’s allergic problems improved and his behavior was markedly better, Hyman said: “It was a light-bulb moment. I saw secondary effects on the brain that came out of treating physical problems.”

He also cited studies of patients with rheumatoid arthritis, a painful and debilitating auto-immune condition that inflames and erodes the joints, who became less depressed after being treated with inflammatory blockers. But had the anti-inflammatory treatment directly lifted their depression, or had their mood improved simply because they were more mobile and in less pain? I told Hyman that it was hard to connect the dots. “For sure,” he said.

 

Connecting the dots is a challenge even for scientists who are actively involved in inflammation research. One afternoon, I visited Ramnik Xavier, the chair of gastroenterology at Massachusetts General Hospital and an expert in Crohn’s disease and ulcerative colitis. The bowel is inflamed in both conditions: ulcerative colitis affects the colon, whereas Crohn’s disease can affect any part of the digestive system. But the nature of inflammation varies almost from person to person and involves interactions among DNA, many kinds of gastrointestinal cells, and the peculiarities of the gut microbiome. “Lots of cells, lots of genes, lots of bugs,” Xavier said.

Xavier, a compact man with a laconic manner and thick black hair marked by streaks of gray, initially studied the role of specialized white blood cells, known as T-cells and B-cells, in defending the body against the development of colitis. Eventually, with Mark Daly, a geneticist at the Broad Institute, Xavier began to search for genes that predispose people to inflammatory bowel disease and for genes that might protect them against it. The two scientists, as part of an international consortium, have identified at least a hundred and sixty areas of DNA that are associated with an increased risk of inflammatory bowel disease; Xavier’s lab has zeroed in on about two dozen genes within these regions of DNA.
One of the frustrations of treating inflammation is that our weapons against it are so imprecise. Drugs like naproxen and ibuprofen are the equivalent of peashooters. At the other extreme, cannon-like steroids shut down the immune system, raising the risk of infection, eroding the bones, predisposing the patient to diabetes, and causing mood swings. Even the peashooters can cause collateral damage: aspirin may help to protect against colon cancer, heart attack, and stroke, but it also raises the risk of gastrointestinal bleeding. Ibuprofen, naproxen, and similar drugs were labelled by the F.D.A. as increasing the risk of heart attack and stroke in people who’ve never suffered either condition, and clinical trials failed to show that they prevent or ameliorate dementia. (Although these drugs reduce inflammation, they may also alter the lining of blood vessels and increase the risk of clots.) Statins lower the chance of a heart attack, but there is growing concern not only about the side effect of muscle pain but also about increasing the likelihood of diabetes. And the absolute benefits of these preventive medications is slight, measured in single digits.

In the lab at the Broad Institute, Xavier and his team were trying to discover new treatments that can block inflammation in a targeted manner. The day I visited, they were assessing molecules associated with colitis, especially one called interleukin-10, or IL-10, which is known to decrease inflammation. In a cavernous room, I watched as a robotic arm moved among racks of plastic plates, each containing hundreds of small wells in which chemical compounds were being tested. Some people with Crohn’s disease have genetic mutations that disable the salubrious effects of IL-10. Xavier is trying to identify molecules that can compensate for this deficiency, in the hope that such molecules might eventually be turned into drugs to treat this subset of patients.

But other patients suffer from a different manifestation of Crohn’s—they can’t fully clear debris from cells in their gut, so it builds up, triggering inflammation. In a neighboring lab, members of Xavier’s research team were trying to develop drugs for that condition, too. A robotic arm was handling plates that contained genetically engineered cells and moving them under a fluorescent microscope. The images appeared on a computer screen—fields of cells studded with yellow and green dots, like the sky in van Gogh’s “Starry Night.”

On another visit, Xavier took me to his clinic at Mass General. Patients, ranging from the very young to the elderly, were reclining in Barcaloungers as nurses and physicians intravenously administered potent anti-inflammatory drugs. Later, I spoke by phone to one of Xavier’s patients, a forty-nine-year-old woman named Maria Ray, who received a diagnosis of colitis in 1998. She was treated with sulfa drugs and corticosteroids, which controlled the problem for several years, but in 2004, after a series of flare-ups, she underwent surgery to remove her colon. Soon after, she developed ulcers on her skin, arthritis of her knees and elbows, and inflammation in both eyes. Xavier prescribed other drugs, and for two years her condition improved, but lately her skin lesions and eye inflammation have returned. “We hoped surgery would cure her ulcerative colitis,” Xavier said. “But we don’t really understand why there is such an overactive immune system now inflaming these other parts of her body.”
At the very least, the fact that Ray has symptoms in many organs, despite the removal of her colon, complicates the simplistic view that treating the gut will suppress inflammation elsewhere. Moreover, there’s no evidence that patients with Crohn’s or colitis are more likely than average to develop dementia and other cognitive disorders. “What we see in mice is not always reproduced in people,” Xavier said.

 

Perhaps no aspect of inflammation is more compelling, or illusory, than the idea that it may be responsible for aging. An internist friend in Manhattan told me that healthy patients occasionally come in to her office carrying Mark Hyman’s books, eager to live longer by following his anti-inflammation life style. When I asked Hyman if he could introduce me to someone who follows his longevity regimen, he readily offered himself. “I’m aiming to live to a hundred and twenty,” he said.

The notion stems from grains of evidence, such as studies that have shown an increase in inflammation with age. The genesis of aging is still a mystery. It may occur for a host of reasons—a waning of the energy generated by the mitochondria within cells, the tendency of DNA to grow fragile and more mutation-prone over time—and it’s much too simplistic to attribute the process to inflammation alone. Luigi Ferrucci, the scientific director of the National Institute on Aging, conducted some of the early research on inflammation and aging, and for a while, he told me, he believed the avenue held promise. On the morning we spoke, he had just finished his daily six-mile run. Sixty-one years old, born in Livorno, on the coast of Tuscany, Ferrucci is an animated man with a stubbly beard who favors crew-neck sweaters. In the past four decades, he has studied thousands of people in order to identify the biological processes that result in aging. He measured scores of molecules in the blood, hoping to find clues that would lead him to the cause of aging’s hallmarks, particularly sarcopenia, or loss of muscle mass, and cognitive decline.

His most illuminating studies involved people in late middle age who showed no sign of heart disease, diabetes, dementia, or other conditions that might be associated with inflammation. He found that a single inflammatory molecule, called interleukin-6, was the most powerful predictor of who would eventually become disabled. Healthy patients with high levels of the IL-6 molecule aged more quickly and grew sicker than those without the inflammatory molecule. “I thought I had discovered the cause of aging and was going to win the Nobel Prize,” Ferrucci said, laughing.
But then he found other subjects with no evidence of inflammation, and without elevated levels of IL-6 or other inflammatory molecules, whose bodies nevertheless began to decline. “We are looking at the layer, not at the core of the problem,” he said. “Inflammation may accelerate aging in some people—but it is a manifestation of something that is occurring underneath.” He reiterated the point that correlation is not causation. “If you have the curiosity of the scientist, you can’t stop there, because you want to know why,” he said. “You want to break the toy so you can see how it’s working inside.”

Toward that end, Ferrucci recently organized a large team of collaborators and launched a new clinical study, GESTALT, which stands for Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing. Groups of healthy people will be studied intensively as they age, with detailed analyses of their DNA, RNA, proteins, metabolic capacity, and other sophisticated parameters, every two years for at least a decade. “Then we can say what mechanisms account for increased inflammation with aging, and the loss of muscle mass, or the loss of memory, or the loss of energy capacity or fitness,” Ferrucci said. “These have never really been addressed on a deep level in humans.”

In the meantime, he sticks to a Mediterranean diet, mainly out of fealty to his heritage. (Ferrucci is known among his N.I.H. colleagues as a gourmet Italian cook.) The media recently gave much attention to a study, published in 2013 in the New England Journal of Medicine, on the benefits of a Mediterranean diet in preventing heart attack or stroke. But, as Ferrucci noted, the benefits weren’t clearly related to inflammation and they accrued to a very small percentage of the subjects on the diet. “Believe me, if there were a diet that prevented aging, I would be on it,” he said.

We’d all like a simple solution for complex medical problems. We’re desperate to feel in command of our lives, particularly as we age and see friends and family afflicted by Alzheimer’s, stroke, and heart failure. “My patients, understandably, are very focussed on the foods they eat, wanting control, hoping they won’t have to take immune-suppressive treatments,” Gary Wu, the University of Pennsylvania gastroenterologist, told me.

Some years ago, I became obsessed with a restrictive diet—no bread, cheese, ice cream, cookies—in an attempt to lower my cholesterol levels. (My father died of a heart attack in his fifties, and I was haunted by his fate.) After nearly six months, I’d lost some fifteen pounds, but my cholesterol level had hardly budged, and I’d become so vigilant about everything I ate that I stopped enjoying meals. Gradually, I resumed a balanced and more reasonable diet and regained an appreciation for one of life’s fundamental pleasures.

Scientists may yet discover that inflammation contributes to disease in unexpected ways. But it’s important to remember, too, that inflammation serves a vital role in the body. “We are playing with one of the primary mechanisms selected by nature to maintain the integrity of our body against the thousand environmental attacks that we receive every day,” Ferrucci said. “Inflammation is part of our maintenance and repair system. Without it, we can’t heal.”

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Obesity Issues

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

The Changing Face of Obesity

Science tells us obesity is a chronic disease. Why does the outmoded and injurious notion that it is a problem of willpower persist?

By Joseph Proietto | November 1, 2015   http://www.the-scientist.com//?articles.view/articleNo/44288/title/The-Changing-Face-of-Obesity/

In Dante Alighieri’s Divine Comedy the narrator meets a man named Ciacco who had been sent to Hell for the “Damning sin of Gluttony.” According to Catholic theology, in order to end up in Hell one must willfully commit a serious sin. So Dante believed that fat people chose to be fat. This antiquated view of the cause of obesity is still widespread, even among medical professionals. The consequences of this misconception are significant, because it forms the basis for the discrimination suffered by the obese; for the wasting of scarce resources in attempts to change lifestyle habits by public education; and for the limited availability of subsidized obesity treatments.

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While obesity is often labeled a lifestyle disease, poor lifestyle choices alone account for only a 6 to 8 kg weight gain. The body has a powerful negative feedback system to prevent excessive weight gain. The strongest inhibitor of hunger, the hormone leptin, is made by fat cells. A period of increased energy intake will result in fat deposition, which will increase leptin production. Leptin suppresses hunger and increases energy expenditure. This slows down weight gain. To become obese, it may be necessary to harbor a genetic difference that makes the individual resistant to the action of leptin.

Evidence from twin and adoption studies suggests that obesity has a genetic basis, and over the past two decades a number of genes associated with obesity have been described. The most common genetic defect in European populations leading to severe obesity is due to mutations in the gene coding for the melanocortin 4 receptor (MCR4). Still, this defect can explain severe obesity in only approximately 6 percent to 7 percent of cases (J Clin Invest, 106:271-79, 2000). Other genes have been discovered that can cause milder increases in weight; for example, variants of just one gene (FTO) can explain up to 3 kg of weight variation between individuals (Science, 316:889-94, 2007).

Genes do not directly cause weight gain. Rather, genes influence the desire for food and the feeling of satiety. In an environment with either poor access to food or access to only low-calorie food, obesity may not develop even in persons with a genetic predisposition. When there is an abundance of food and a sedentary lifestyle, however, an obesity-prone person will experience greater hunger and reduced satiety, increasing caloric intake and weight gain.

Since the 1980s, there has been a rapid rise in the prevalence of obesity worldwide, a trend that likely results from a variety of complex causes. There is increasing evidence, for example, that the development of obesity on individual or familial levels may be influenced by environmental experiences that occur in early life. For example, if a mother is malnourished during early pregnancy, this results in epigenetic changes to genes involved in the set points for hunger and satiety in the developing child. These changes may then become fixed, resulting in a tendency towards obesity in the offspring.

The biological basis of obesity is further highlighted by the vigorous defense of weight following weight loss. There are at least 10 circulating hormones that modulate hunger. Of these, only one has been confirmed as a hunger-inducing hormone (ghrelin), and it is made and released by the stomach. In contrast, nine hormones suppress hunger, including CCK, PYY, GLP-1, oxyntomodulin, and uroguanylin from the small bowel; leptin from fat cells; and insulin, amylin, and pancreatic polypeptide from the pancreas.

 

After weight loss, regardless of the diet employed, there are changes in circulating hormones involved in the regulation of body weight. Ghrelin levels tend to increase and levels of multiple appetite-suppressing hormones decrease. There is also a subjective increase in appetite. Researchers have shown that even after three years, these hormonal changes persist (NEJM, 365:1597-604, 2011; Lancet Diabetes and Endocrinology, 2:954-62, 2014). This explains why there is a high rate of weight regain after diet-induced weight loss.

Given that the physiological responses to weight loss predispose people to regain that weight, obesity must be considered a chronic disease. Data show that those who successfully maintain their weight after weight loss do so by remaining vigilant and constantly applying techniques to oppose weight regain. These techniques may involve strict diet and exercise practices and/or pharmacotherapy.

It is imperative for society to move away from a view that obesity is simply a lifestyle issue and to accept that it is a chronic disease. Such a change would not only relieve the stigma of obesity but would also empower politicians, scientists and clinicians to tackle the problem more effectively.

Joseph Proietto was the inaugural Sir Edward Dunlop Medical Research Foundation Professor of Medicine in the Department of Medicine, Austin Health at the University of Melbourne in Australia. He is a researcher and clinician investigating and treating obesity and type 2 diabetes.

 

 

A Weighty Anomaly

Why do some obese people actually experience health benefits?

By Jyoti Madhusoodanan | November 1, 2015     http://www.the-scientist.com//?articles.view/articleNo/44304/title/A-Weighty-Anomaly/

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THE ENDOCRINE THEORY: Some researchers have posited that fat cells may secrete molecules that affect glucose homeostasis in muscle or liver tissue.COURTESY OF MITCHELL LAZAR

In the early 19th century, Belgian mathematician Adolphe Quetelet was obsessed with a shape: the bell curve. While helping with a population census, Quetelet proposed that the spread of human traits such as height and weight followed this trend, also known as a Gaussian or normal distribution. On a quest to define a “normal man,” he showed that human height and weight data fell along his beloved bell curves, and in 1823 devised the “Quetelet Index”—more familiar to us today as the BMI, or body mass index, a ratio of weight to height.

Nearly two centuries later, clinicians, researchers, and fitness instructors continue to rely on this metric to pigeonhole people into categories: underweight, healthy, overweight, or obese. But Quetelet never intended the metric to serve as a way to define obesity. And now, a growing body of evidence suggests these categories fail to accurately reflect the health risks—or benefits—of being overweight.

Although there is considerable debate surrounding the prevalence of metabolically healthy obesity, when obesity is defined in terms of BMI (a BMI of 30 or higher), estimates suggest that about 10 percent of adults in the U.S. are obese yet metabolically healthy, while as many as 80 percent of those with a normal BMI may be metabolically unhealthy, with signs of insulin resistance and poor circulating lipid levels, even if they suffer no obvious ill effects. “If all we know about a person is that they have a certain body weight at a certain height, that’s not enough information to know their health risks from obesity,” says health-science researcher Paul McAuley of Winston-Salem State University. “We need better indicators of metabolic health.”

The dangers of being overweight, such as a higher risk of heart disease, type 2 diabetes, and other complications, are well known. But some obese individuals—dubbed the “fat fit”—appear to fare better on many measures of health when they’re heavier. Studies have found lower mortality rates, better response to hemodialysis in chronic kidney disease, and lower incidence of dementia in such people. Mortality, it’s been found, correlates with obesity in a U-shaped curve (J Sports Sci, 29:773-82, 2011). So does extra heft help or hurt?

To answer that question, researchers are trying to elucidate the metabolic reasons for this obesity paradox.

In a recent study, Harvard University epidemiologist Goodarz Danaei and his colleagues analyzed data from nine studies involving a total of more than 58,000 participants to tease apart how obesity and other well-known metabolic risk factors influence the risk of coronary heart disease. Controlling these other risk factors, such as hypertension or high cholesterol, with medication is simpler than curbing obesity itself, Danaei explains. “If you control a person’s obesity you get rid of some health risks, but if you control hypertension or diabetes, that also reduces health risks, and you can do the latter much more easily right now.”

Danaei’s team assessed BMI and metabolic markers such as systolic blood pressure, total serum cholesterol, and fasting blood glucose. The three metabolic markers only explained half of the increased risk of heart disease across all study participants. In obese individuals, the other half appeared to be mediated by fat itself, perhaps via inflammatory markers or other indirect mechanisms (Epidemiology, 26:153-62, 2015). While Danaei’s study was aimed at understanding how obesity hurts health, the results also uncovered unknown mechanisms by which excess adipose tissue might exert its effects. This particular study revealed obesity’s negative effects, but might these unknown mechanisms hold clues that explain the obesity paradox?

Other researchers have suggested additional possibilities—for example, that inflammatory markers such as TNF-α help combat conditions such as chronic kidney disease, or that obesity makes a body more capable of making changes to, and tolerating changes in, blood flow depending on systemic needs (Am J Clin Nutr, 81:543-54, 2005).

According to endocrinologist Mitchell Lazar at the University of Pennsylvania, the key to explaining the obesity paradox may be two nonexclusive ways fat tissue is hypothesized to function. One mechanism, termed the endocrine theory, suggests that fat cells secrete, or don’t secrete enough of, certain molecules that influence glucose homeostasis in other tissues, such as muscle or liver. The first such hormone to be discovered was leptin; later studies reported several other adipocyte-secreted factors, including adiponectin, resistin, and various cytokines.

The other hypothesis, dubbed the spillover theory, suggests that storing lipids in fat cells has some pluses. Adipose tissue might sequester fat-soluble endotoxins, and produce lipoproteins that can bind to and clear harmful lipids from circulation. When fat cells fill up, however, these endotoxins are stashed in the liver, pancreas, or other organs—and that’s when trouble begins. In “fat fit” people, problems typically linked to obesity such as high cholesterol or diabetes may be avoided simply because their adipocytes mop up more endotoxins.

“In this model, one could imagine that if you could store even more fat in fat cells, you could be even more obese, but you might be protected from problems [associated with] obesity because you’re protecting the other tissues from filling up with lipids that cause problems,” says Lazar. “This may be the most popular current model to explain the fat fit.”

Although obesity greatly increases the risk of type 2 diabetes—up to 93-fold in postmenopausal women, for example—not all obese people suffer from the condition. Similarly, a certain subtype of individuals with “normal” BMIs are at greater risk of developing insulin resistance and type 2 diabetes than others with BMIs in the same range. Precisely what distinguishes these two cohorts is still unclear. “Just as important as explaining why some obese people don’t get diabetes is to explain why other subgroups—normal-weight people or those with lipodystrophy—sometimes get it,” Lazar says. “If there are multiple subtypes of obesity and diabetes, can we figure out genetic aspects or biomarkers that cause one of these phenotypes and not the other?”

To Lazar, McAuley, and other researchers, it’s increasingly evident that BMI may not be that metric. Finding better ways to assess a healthy weight, however, has proven challenging. Researchers have tested measures, such as the body shape index (ABSI) or the waist-hip ratio, which attempt to gauge visceral fat—considered to be more metabolically harmful than fat in other body locations. However, these metrics have yet to be implemented widely in clinics, and few are as simple to understand as the BMI (Science, 341:856-58, 2013).

Independent of metrics, however, the health message regarding weight is still unanimous: exercise and healthy dietary choices benefit everyone. “At a certain point, despite all the so-called fit-fat people, the demographics say that there’s a huge risk of diabetes and heart disease at very high BMI,” notes Lazar. “We can’t assume we’ll be one of the lucky ones who will have a BMI in the obese category but will still be protected from heart disease.”

Correction (November 2): The original version of this article misattributed the pull quote above. The attribution for this quote has been corrected, and The Scientist regrets the error.

 

 

THE HEALTH RISK OF OBESITY—BETTER METRICS IMPERATIVE

 Science 23 Aug 2013;  341(6148): 856858     DOI: http://dx.doi.org:/10.1126/science.1241244
Obesity paradoxes.
In this review, we examine the original obesity paradox phenomenon (i.e. in cardiovascular disease populations, obese patients survive better), as well as three other related paradoxes (pre-obesity, “fat but fit” theory, and “healthy” obesity). An obesity paradox has been reported in a range of cardiovascular and non-cardiovascular conditions. Pre-obesity (defined as a body mass index of 25.0-29.9 kg · m⁻²) presents another paradox. Whereas “overweight” implies increased risk, it is in fact associated with decreased mortality risk compared with normal weight. Another paradox concerns the observation than when fitness is taken into account, the mortality risk associated with obesity is offset. The final paradox under consideration is the presence of a sizeable subset of obese individuals who are otherwise healthy. Consequently, a large segment of the overweight and obese population is not at increased risk for premature death. It appears therefore that low cardiorespiratory fitness and inactivity are a greater health threat than obesity, suggesting that more emphasis should be placed on increasing leisure time physical activity and cardiorespiratory fitness as the main strategy for reducing mortality risk in the broad population of overweight and obese adults.
Obesity, insulin resistance, and cardiovascular disease.
Recent Prog Horm Res. 2004;59:207-23.
The ability of insulin to stimulate glucose disposal varies more than six-fold in apparently healthy individuals. The one third of the population that is most insulin resistant is at greatly increased risk to develop cardiovascular disease (CVD), type 2 diabetes, hypertension, stroke, nonalcoholic fatty liver disease, polycystic ovary disease, and certain forms of cancer. Between 25-35% of the variability in insulin action is related to being overweight. The importance of the adverse effects of excess adiposity is apparent in light of the evidence that more than half of the adult population in the United States is classified as being overweight/obese, as defined by a body mass index greater than 25.0 kg/m(2). The current epidemic of overweight/obesity is most-likely related to a combination of increased caloric intake and decreased energy expenditure. In either instance, the fact that CVD risk is increased as individuals gain weight emphasizes the gravity of the health care dilemma posed by the explosive increase in the prevalence of overweight/obesity in the population at large. Given the enormity of the problem, it is necessary to differentiate between the CVD risk related to obesity per se, as distinct from the fact that the prevalence of insulin resistance and compensatory hyperinsulinemia are increased in overweight/obese individuals. Although the majority of individuals in the general population that can be considered insulin resistant are also overweight/obese, not all overweight/obese persons are insulin resistant. Furthermore, the cluster of abnormalities associated with insulin resistance – namely, glucose intolerance, hyperinsulinemia, dyslipidemia, and elevated plasma C-reactive protein concentrations — is limited to the subset of overweight/obese individuals that are also insulin resistant. Of greater clinical relevance is the fact that significant improvement in these metabolic abnormalities following weight loss is seen only in the subset of overweight/obese individuals that are also insulin resistant. In view of the large number of overweight/obese subjects at potential risk to be insulin resistant/hyperinsulinemic (and at increased CVD risk), and the difficulty in achieving weight loss, it seems essential to identify those overweight/obese individuals who are also insulin resistant and will benefit the most from weight loss, then target this population for the most-intensive efforts to bring about weight loss.
Long-Term Persistence of Hormonal Adaptations to Weight Loss

Priya Sumithran, Luke A. Prendergast, Elizabeth Delbridge, Katrina Purcell, Arthur Shulkes, Adamandia Kriketos, and Joseph Proietto

N Engl J Med 2011; 365:1597-1604   October 27, 2011http://dx.doi.org:/10.1056/NEJMoa1105816

After weight loss, changes in the circulating levels of several peripheral hormones involved in the homeostatic regulation of body weight occur. Whether these changes are transient or persist over time may be important for an understanding of the reasons behind the high rate of weight regain after diet-induced weight loss.

Weight loss (mean [±SE], 13.5±0.5 kg) led to significant reductions in levels of leptin, peptide YY, cholecystokinin, insulin (P<0.001 for all comparisons), and amylin (P=0.002) and to increases in levels of ghrelin (P<0.001), gastric inhibitory polypeptide (P=0.004), and pancreatic polypeptide (P=0.008). There was also a significant increase in subjective appetite (P<0.001). One year after the initial weight loss, there were still significant differences from baseline in the mean levels of leptin (P<0.001), peptide YY (P<0.001), cholecystokinin (P=0.04), insulin (P=0.01), ghrelin (P<0.001), gastric inhibitory polypeptide (P<0.001), and pancreatic polypeptide (P=0.002), as well as hunger (P<0.001).

What’s new in endocrinology and diabetes mellitus

Large genome wide association studies have demonstrated that variants in the FTO gene have the strongest association with obesity risk in the general population, but the mechanism of the association has been unclear. However, a nonocoding causal variant in FTO has now been identified that changes the function of adipocytes from energy utilization (beige fat) to energy storage (white fat) with a fivefold decrease in mitochondrial thermogenesis [17]. When the effect of the variant was blocked in genetically engineered mice, thermogenesis increased and weight gain did not occur, despite eating a high-fat diet. Blocking the gene’s effect in human adipocytes also increased energy utilization. This observation has important implications for potential new anti-obesity drugs. (See “Pathogenesis of obesity”, section on ‘FTO variants’.)

Liraglutide for the treatment of obesity (July 2015)

Along with diet, exercise, and behavior modification, drug therapy may be a helpful component of treatment for select patients who are overweight or obese. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, used for the treatment of type 2 diabetes, and can promote weight loss in patients with diabetes, as well as those without diabetes.

In a randomized trial in nondiabetic patients who had a body mass index (BMI) of ≥30 kg/m2 or ≥27 kg/m2 with dyslipidemia and/or hypertension, liraglutide 3 mg once daily, compared with placebo, resulted in greater mean weight loss (-8.0 versus -2.6 kg with placebo) [18]. In addition, cardiometabolic risk factors, glycated hemoglobin (A1C), and quality of life improved modestly. Gastrointestinal side effects transiently affected at least 40 percent of the liraglutide group and were the most common reason for withdrawal (6.4 percent). Liraglutide is an option for select overweight or obese patients, although gastrointestinal side effects (nausea, vomiting) and the need for a daily injection may limit the use of this drug. (See “Obesity in adults: Drug therapy”, section on ‘Liraglutide’.)

In a trial designed specifically to evaluate the effect of liraglutide on weight loss in overweight or obese patients with type 2 diabetes (mean weight 106 kg), liraglutide, compared with placebo, resulted in greater mean weight loss (-6.4 kg and -5.0 kg for liraglutide 3 mg and 1.8 mg, respectively, versus -2.2 kg for placebo) [19]. Treatment with liraglutide was associated with better glycemic control, a reduction in the use of oral hypoglycemic agents, and a reduction in systolic blood pressure. Although liraglutide is not considered as initial therapy for the majority of patients with type 2 diabetes, it is an option for select overweight or obese patients with type 2 diabetes who fail initial therapy with lifestyle intervention and metformin.  (See “Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus”, section on ‘Weight loss’.)

The Skinny on Fat Cells

Bruce Spiegelman has spent his career at the forefront of adipocyte differentiation and metabolism.

By Anna Azvolinsky | November 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44312/title/The-Skinny-on-Fat-Cells/

Bruce Spiegelman
Stanley J. Korsmeyer Professor of Cell Biology
and Medicine
Harvard Medical School
Director, Center for Energy Metabolism
and Chronic
Disease, Dana-Farber Cancer Institute, Boston

It’s hard to know whether you have the right stuff to be a scientist, but I had a passion for the research,” says Bruce Spiegelman, professor of cell biology at Harvard Medical School and the Dana-Farber Cancer Institute. After receiving his PhD in biochemistry from Princeton University in 1978, Spiegelman sent an application to do postdoctoral research to just one lab. “I wasn’t thinking I should apply to five different labs. I just marched forward more or less in a straight line,” he says. Spiegelman did know that he had no financial backup and depended on research fellowships throughout the early phase of his science career. “I thought it was fantastic, and still think so, that a PhD in science is supported by the government. I certainly appreciated that, because many of my friends in the humanities had to support themselves by cobbling together fellowships and teaching every semester, whereas we didn’t face similar challenges in the sciences.”

Since his graduate student days, Spiegelman has realized his potential, pioneering the study of adipose tissue biology and metabolism. He was introduced to the field in Howard Green’s laboratory, then at MIT, where Spiegelman began his one and only postdoc in 1978. Green had recently developed a system for culturing adipose cells and asked Spiegelman if he wanted to study fat cell differentiation. “I knew nothing about adipose tissue, but I was really interested in any model of how one cell switches to another. Whether skin or fat didn’t matter too much to me, because I was not coming at this from the perspective of physiology but from the perspective of how do these switches work at a molecular level?”

Spiegelman has stuck with studying the biology and differentiation of fat cells for more than 30 years. While looking for the master transcriptional regulator of fat development—which his laboratory found in 1994—Spiegelman’s group also discovered one of the first examples of a nuclear oncogene that functions as a transcription factor, and, more recently, the team found that brown fat and white fat come from completely different origins and that brown and beige fat are distinct cell types. Spiegelman was also the first to provide evidence for the connection between inflammation, insulin resistance, and fat tissue.

Here, Spiegelman talks about his strong affinity for the East Coast, his laboratory’s search for molecules that can crank up brown fat production and activity, and the culture of his laboratory’s weekly meeting.

Spiegelman Sets Out

First publication. Spiegelman grew up in Massapequa, New York, a town on Long Island. “Birds, insects, fish, and animals were fascinating to me. As a kid, I imagined I would be a wildlife ranger,” he says. Spiegelman and his brother were the first in their family to attend college; Spiegelman entered the College of William and Mary in 1970 thinking he would major in psychology. But before taking his first psychology course, he had to take a biology course, really loved it, and switched his major. For his senior thesis, he chose one of the few labs that did biochemistry-related research. He studied cultures of the filamentous fungus Aspergillus ornatus in which he induced the upregulation of a metabolic enzyme. Spiegelman applied a calculus transformation that related the age of the culture to the age of individual cells, something that had not been previously done. The work earned him his first first-author publication in 1975. “It was not a great breakthrough, but I think it showed that I was maybe applying myself more than the typical undergraduate.”

Full steam ahead. “My interest in laboratory research was intense. Even though it was not particularly inspired work, the first-author publication in a college where not many of the professors published a lot gave me a lot of confidence. It was probably out of proportion to the quality of the actual work.” That confidence and Spiegelman’s interest in the chemistry of living things led him to pursue a PhD in biochemistry at Princeton University. “Very early on, I felt that I couldn’t understand biology if it didn’t go to the molecular level. To me, just describing how an animal lived without understanding how it worked was very unsatisfying. I think it was one of the best decisions that I made in my life, to do a PhD in biochemistry,” he says, “because if you really want to understand living systems, you are very limited in how you can understand them without having a strong background in biochemistry because these are, essentially, chemical systems.”

Embracing molecular biology. Spiegelman initially joined Arthur Pardee’s laboratory, but switched when Pardee left Princeton for Harvard University in 1975. Because he was already collaborating with Marc Kirschner, a cell biologist and biochemist who studies the regulation of the cell cycle and how the cytoskeleton works, it was an easy transition to transfer to the new laboratory. In Kirschner’s group, Spiegelman became the cell biologist among many protein biochemists working on microtubule assembly in vitro. Rather than understanding how the proteins fit together to form the filamentous structures, Spiegelman wanted to understand what controlled their assembly inside cells. Working in mammalian cells, Spiegelman published three consecutive Cell papers on how microtubule assembly occurs in vivo. The firstpaper, from 1977, demonstrated that a nucleotide functions to stabilize the tubulin molecule rather than to regulate tubulin assembly in vivo.

Spiegelman Simmers

A new tool. For his next move, Spiegelman wanted to marry his background in biochemistry and molecular biology with a good cellular model system. He became interested in differentiation at the end of his PhD, while studying how the cytoskeleton is reorganized during neural differentiation, and settled on Green’s MIT laboratory for his postdoc. Green had developed a way to study both skin and fat cell differentiation. Again, Spiegelman was the odd man out, working on the molecular biology of fat cell differentiation while most of the graduate students and postdocs focused on the cellular biology of skin cell differentiation. While there, Spiegelman learned how to clone cDNA—a new method that some researchers thought was just another new fad, he says. “I thought it was pretty obvious that this was a tool that would be a game changer. I could see how I could clone some of the cDNAs and genes that were regulated in the fat cell lineage and then try to understand the regulation of these genes.”

Setting the stage. Spiegelman demonstrated that cAMP regulates the synthesis of certain enzymes in fat cells during differentiation. But while this was the most influential paper from his postdoc, says Spiegelman, it was his demonstration of cloning mRNAs from adipocytes, published in 1983, that set the stage for cloning fat-selective genes. The work, mostly done when Spiegelman was already a new faculty member at the Dana-Farber Cancer Institute, stemmed from his learning molecular cloning in Phillip Sharp’s lab at MIT and Bryan Roberts’s lab at Harvard. “This was the raw material from which we eventually cloned PPARγ and showed it to be the master regulator of fat [cell] development.”

Roots. Spiegelman became an assistant professor at the Harvard Medical School in 1982, when he was not yet 30. Although he had entertained the idea of moving to the West Coast with his wife, whom he had met at Princeton where she obtained a PhD in French literature, Spiegelman says he is really an East Coaster at heart. “My wife and I came to love Boston and were very comfortable there. Our families were both in New York, which was close, but not too close, and we really enjoyed the culture and pace of Boston; it was more ‘us.’ We really liked to visit California but didn’t particularly want to move there. We’re both real Northeastern people.”

Relating to Sisyphus. The transition from doing a postdoc to setting up his own laboratory was “very exciting and terribly stressful,” says Spiegelman. “When I think back, I always tried to be professional with my laboratory, but I was so stressed at suddenly being on my own with no management training.” The people resources he had encountered in his graduate and postdoctoral training labs were also not there yet, and he says his first publication as a principal investigator was like pushing a rock up a hill. But eventually, Spiegelman’s lab built a reputation and reached a critical mass of talented people who advanced the science. Again in 1983, Spiegelman produced a publication showing that morphological manipulation can affect gene expression and adipose differentiation.

End goal. Spiegelman’s goal was to find a master molecule that  orchestrates the conversion of adipocyte precursor cells into bona fide fat cells. Piece by piece, his lab identified the enhancers, promoters, and other regulatory elements involved in adipocyte differentiation. In 1994, graduate student Peter Tontonoz finallyfound that the PPARγ gene, inserted via a retroviral vector into fibroblasts, could induce the cells to become adipose cells. “It took 10 years,” Spiegelman says. Along the way, the laboratory found that c-fos, the product of a famous nuclear oncogene, bound to the promoters of fat-specific genes and worked as a transcription factor. “It was not really known how nuclear oncogenes worked. This was one of the first papers showing that these oncogenes bound to gene promoters and were transcription factors.”

A wider scope. In 1993, graduate student Gökhan Hotamisligil found that tumor necrosis factor-alpha(TNF-α), is induced in the fat tissue of rodent models of obesity and diabetes. The paper sparked the formation of the field of immunometabolism and resulted in the expansion of Spiegelman’s lab into the physiology arena, partly thanks to the guidance of C. Ronald Kahn and Jeff Flier, who both study metabolism and diabetes. But the work initially encountered pushback, says Spiegelman, partly because it was the merging of two fields.

Spiegelman Scales Up

Fat color palette. Brown fat tissue, abundant in infants but scarce in adults, is a metabolically active form of fat that is chock full of mitochondria and is found in pockets in the body distinct from white fat tissue.Pere Puigserver, then a postdoc in Spiegelman’s lab, found that the coactivator PCG-1, binding to PPARγ and other nuclear receptors, could stimulate mitochondrial biogenesis. The PCG-1 gene is turned on by stimuli such as exercise or a cold environment. Later, postdoc Patrick Seale, Spiegelman, and their colleagues showed brown fat cells derive from the same lineage that gives rise to skeletal muscle. “This was a big surprise, maybe the biggest surprise we ever uncovered in the lab,” says Spiegelman.

A paler shade of brown. More recently, in 2012, Spiegelman’s laboratory showed that within adult white adipose tissue, there are pockets of a yet another type of fat tissue that he called beige fat. “I think the evidence is very good from rodents that if you activate brown and beige fat, you get metabolic benefit both in obesity and diabetes. So the question now is: Can that be done in humans in a way that’s beneficial and not toxic?”  The lab is now looking to identify molecules that can either ramp up the activity of brown and beige fat or increase the production of both cell types as possible therapeutics for metabolic disorders or even cancer-associated cachexia. “Anyone who says that either approach will work better is being foolish. We just don’t know enough to go after just one or the other.”

On the irisin controversy. After reporting in 2012 that a muscle-related hormone called irisin could switch white fat to metabolically active brown fat, Spiegelman became embroiled in a media-covered debate about whether the molecule really exists; he was also the victim of a potential fraud plot. Most recently, Spiegelman provided thorough evidence that irisin does in fact exist. On the controversy, he says it’s a fine line between defending his scientific integrity and not adding more fuel to the fire or engaging with his harassers. “We have a long track record of doing credible and reproducible science and it was not that complicated to address the paper that claimed irisin was ‘a myth.’ That study used very outmoded scientific approaches.”

Raw talent. Many of Spiegelman’s trainees have gone on to become very successful scientists, including Tontonoz, Hotamisligil, Evan Rosen, and Randy Johnson. “It’s a quantum change in the experience of doing science when you get people who have their own visions. I would have thought that interacting with smart people would mainly help me get my scientific vision accomplished. And that was partly true, but also it changed my vision. When you have people challenging you on a day-to-day basis, you learn from them through the questions they ask and the way they challenge you in a constructive way. They made me a much better scientist.”

Rigorous mentorship.  “I feel very passionately that a major part of my job is to prepare the next generation of scientists. Everyone who comes through my lab will tell you that I take that very seriously. We make sure my students give a lot of talks and get critical assessments of their presentations to our lab group. I am very hands-on both scientifically and in developing the way students project their vision. I had a very good mentor, Marc Kirschner, and I’d like to think that I learned how to be a mentor from him. I want to make sure that when people walk out of my lab they are prepared to run independent research programs.”

Greatest Hits

  • Identified the master regulator of adipogenesis, the nuclear receptor PPARγ
  • Was the first to show that a nuclear oncogene, c-fos, codes for a transcription factor that binds to the promoters of genes
  • Demonstrated that adipose tissue synthesizes tumor necrosis factor-alpha (TNF-α), providing the first direct link between obesity, inflammation, insulin resistance, and fat tissue.
  • Showed that brown fat cells are not developmentally related to white fat
  • Identified beige fat as a distinct cell type, different from either white or brown fat

 

Fanning the Flames

Obesity triggers a fatty acid synthesis pathway, which in turn helps drive T cell differentiation and inflammation.

By Kate Yandell | November 1, 2015

http://www.the-scientist.com//?articles.view/articleNo/44306/title/Fanning-the-Flames/

EDITOR’S CHOICE IN IMMUNOLOGY

The paper
Y. Endo et al., “Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1,” Cell Reports, 12:1042-55, 2015.

Cell Rep. 2015 Aug 11;12(6):1042-55.   http://dx.doi.org:/10.1016/j.celrep.2015.07.014. Epub 2015 Jul 30.
Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1.
  • A high-fat diet augments Th17 cell development and the expression of Acaca
  • ACC1 controls Th17 cell development in vitro and Th17 cell pathogenicity in vivo
  • ACC1 modulates RORγt function in developing Th17 cells
  • Obesity in humans induces ACACA and IL-17A expression in CD4 T cells

Chronic inflammation due to obesity contributes to the development of metabolic diseases, autoimmune diseases, and cancer. Reciprocal interactions between metabolic systems and immune cells have pivotal roles in the pathogenesis of obesity-associated diseases, although the mechanisms regulating obesity-associated inflammatory diseases are still unclear. In the present study, we performed transcriptional profiling of memory phenotype CD4 T cells in high-fat-fed mice and identified acetyl-CoA carboxylase 1 (ACC1, the gene product of Acaca) as an essential regulator of Th17 cell differentiation in vitro and of the pathogenicity of Th17 cells in vivo. ACC1 modulates the DNA binding of RORγt to target genes in differentiating Th17 cells. In addition, we found a strong correlation between IL-17A-producing CD45RO(+)CD4 T cells and the expression of ACACA in obese subjects. Thus, ACC1 confers the appropriate function of RORγt through fatty acid synthesis and regulates the obesity-related pathology of Th17 cells.

Figure thumbnail fx1

http://www.cell.com/cms/attachment/2035221719/2050630604/fx1.jpg

 

 

http://www.the-scientist.com/November2015/NovMediLit_310px.jpg

FEEDING INFLAMMATION: When mice eat a diet high in fat, their CD4 T cells show increased expression of the fatty acid biosynthesis gene Acaca, which encodes the enzyme ACC1 (1). Products of the ACC1 fatty acid synthesis pathway encourage the transcription factor RORγt to bind near the gene encoding the cytokine IL-17A (2). There, RORγt recruits an enzyme called p300 to modify the genome epigenetically and turn on IL-17A. The memory T cells then differentiate into inflammatory T helper 17 cells.
See full infographic: PDF
© STEVE GRAEPEL

Obesity often comes with a side of chronic inflammation, causing inflammatory chemicals and immune cells to flood adipose tissue, the hypothalamus, the liver, and other areas of the body. Inflammation is a big part of what makes obesity such an unhealthy condition, contributing to Type 2 diabetes, heart disease, cancers, autoimmune disorders, and possibly even neurodegenerative diseases.

To better understand the relationship between obesity and inflammation, Toshinori Nakayama, Yusuke Endo, and their colleagues at Chiba University in Japan started with what often leads to obesity: a high-fat diet. They fed mice rich meals for a couple of months and looked at how gene expression in the animals’ T cells compared to gene expression in the T cells of mice fed a normal diet. Most notably, they found increased expression ofAcaca, a gene that codes for a fatty acid synthesis enzyme called acetyl coA carboxylase 1 (ACC1). They went on to show that the resulting increase in fatty acid levels pushed CD4 T cells to differentiate into inflammatory T helper 17 (Th17) cells.

Th17 cells help fight off invading fungi and some bacteria. But these immune cells can also spin out of control in autoimmune diseases such as multiple sclerosis. Nakayama’s team showed that either blocking ACC1 activity with a drug called TOFA or deleting a key portion of Acaca in mouse CD4 T cells reduced the generation of pathologic Th17 cells. Overexpressing Acaca increased Th17-cell generation.

The researchers also demonstrated that mice fed a high-fat diet had elevated susceptibility to a multiple sclerosis–like disease, and that TOFA reduced the symptoms.

“This is a very intriguing finding, suggesting not only that obesity can directly induce Th17 differentiation but also indicating that pharmacologic targeting of fatty acid synthesis may help to interfere with obesity-associated inflammation,” Tim Sparwasser of the Twincore Center for Experimental and Clinical Infection Research in Hannover, Germany, says in an email. Sparwasser and his colleagues had previously shown that ACC1 is required for the differentiation of Th17 cells in mice and humans.

Nakayama explains that CD4 T cells must undergo profound metabolic changes as they mature and differentiate. “The intracellular metabolites, including fatty acids, are essential for cell proliferation and cell growth,” he says in an email. When fatty acid levels in T cells increase, the cells are activated and begin to proliferate.

“It’s a nice illustration of how, really, immune response is so highly connected to the metabolic state of the cell,” says Gökhan S. Hotamisligil of Harvard University’s T.H. Chan School of Public Health who was not involved in the study. “The immune system launches its responses commensurate with the sources of nutrients and energy from the environment,” he adds in an email.

There are still missing pieces in the path from high-fat diet to increased Acaca expression to ACC1’s influence on T-cell differentiation. It also remains to be seen how this plays out in obese humans, although Nakayama and colleagues did show that inhibiting ACC1 reduced pathologic Th17 generation in human immune cell cultures, and that the T cells of obese humans contain elevated levels of ACC1 and show signs of increased differentiation into Th17 cells.

 

The prevalence of obesity has been increasing worldwide, and obesity is now a major public health problem in most developed countries (Gregor and Hotamisligil, 2011, Ng et al., 2014). Obesity-induced inflammation contributes to the development of various chronic diseases, such as autoimmune diseases, metabolic diseases, and cancer (Kanneganti and Dixit, 2012, Kim et al., 2014,Osborn and Olefsky, 2012, Winer et al., 2009a). A number of studies have pointed out the importance of reciprocal interactions between metabolic systems and immune cells in the pathogenesis of obesity-associated diseases (Kaminski and Randall, 2010, Kanneganti and Dixit, 2012, Kim et al., 2014, Mauer et al., 2014, Stienstra et al., 2012, Winer et al., 2011).

Elucidating the molecular mechanisms by which naive CD4 T cells differentiate into effector T cells is crucial for understanding helper T (Th) cell-mediated immune pathogenicity. After antigen stimulation, naive CD4 T cells differentiate into at least four distinct Th cell subsets: Th1, Th2, Th17, and inducible regulatory T (iTreg) cells (O’Shea and Paul, 2010, Reiner, 2007). Several specific master transcription factors that regulate Th1/Th2/Th17/iTreg cell differentiation have been identified, including T-bet for Th1 (Szabo et al., 2000), GATA3 (Yamashita et al., 2004, Zheng and Flavell, 1997) for Th2, retinoic-acid-receptor-related orphan receptor γt (RORγt) for Th17 (Ivanov et al., 2006), and forkhead box protein 3 (Foxp3) for iTreg (Sakaguchi et al., 2008). The appropriate expression and function of these transcription factors is essential for proper immune regulation by each Th cell subset.

Among these Th cell subsets, Th17 cells contribute to the host defense against fungi and extracellular bacteria (Milner et al., 2008). However, the pathogenicity of IL-17-producing T cells has been recognized in various autoimmune diseases, including multiple sclerosis, psoriasis, inflammatory bowel diseases, and steroid-resistant asthma (Bettelli et al., 2006, Coccia et al., 2012, Ivanov et al., 2006,Leonardi et al., 2012, McGeachy and Cua, 2008, Nylander and Hafler, 2012,Stockinger et al., 2007, Sundrud et al., 2009).

An HFD Promotes Th17 Cell Differentiation and Affects the Expression of Fatty Acid Enzymes in Memory CD4 T Cells In Vivo

Inhibition of ACC1 Function Results in Decreased Th17 Cell Differentiation and Ameliorates the Development of Autoimmune Disease

ACC1 Controls the Differentiation of Th17 Cells Both In Vitro and In Vivo

ACC1 Controls the Function, but Not Expression, of RORγt in Differentiating Th17 Cells

Extrinsic Fatty Acid Supplementation Restored Acaca−/− Th17 Cell Differentiation through the Functional Improvement of RORγt

Obese Subjects Show Upregulation of ACACA and Increased Th17 Cells in CD45RO+ Memory CD4 T Cells

We herein identified a critical role that ACC1 plays in Th17 cell differentiation and the pathogenicity of Th17 cells through the control of the RORγt function under obese circumstances. High-fat-induced obesity augments Th17 cell differentiation and the expression of enzymes involved in fatty acid metabolism, including ACC1. Pharmacological inhibition or genetic deletion of ACC1 resulted in impaired Th17 cell differentiation in both mice and humans. In contrast, overexpression of Acaca induced Th17 cells in vivo, leaving the expression ofIfng and Il4 largely unchanged. ACC1 modulated the binding of RORγt to theIl17a gene and the subsequent p300 recruitment in differentiating Th17 cells. Memory CD4 T cells from peripheral blood mononuclear cells (PBMCs) of obese subjects showed increased IL-17A production and ACACA expression. Furthermore, a strong correlation was detected between the proportion of IL-17A-producing cells and the expression level of ACACA in memory CD4 T cells in obese subjects. Thus, our findings provide evidence of a mechanism wherein obesity can exacerbate IL-17-mediated pathology via the induction of ACC1.

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 What is the key method to harness Inflammation to close the doors for many complex diseases?

 

Author and Curator: Larry H Bernstein, MD, FCAP

 

The main goal is to  have a quality of a healthy life.

When we look at the picture 90% of main fluid of life, blood, carried by cardiovascular system with two main pumping mechanisms, lung with gas exchange and systemic with complex scavenger actions, collection of waste, distribution of nutrition and clean gases etc.  Yet without lymphatic system body can’t make up the 100% fluid.  Therefore, 10% balance is completed by lymphatic system as a counter clockwise direction so that not only the fluid balance but also mass balance is  maintained. Finally, the immune system patches the  remaining mechanism by providing cellular support to protect the body because it contains 99% of white cells to fight against any kinds of invasion, attack, trauma.

These three musketeers, ccardiovascular, lyphatic and immune systems, create the core mechanism of survival during human life.

However, there is a cellular balance between immune and cardiovascular system since blood that made up off 99% red cells and 1% white blood cells that are used to scavenger hunt circulating foreign materials.   These three systems are acting with a harmony not only defend the body but provide basic needs of life.  Thus, controlling angiogenesis and working mechanisms in blood not only helps to develop new diagnostic tools but more importantly establishes long lasting treatments that can harness Immunomodulation.

The word inflammation comes from the Latin “inflammo”, meaning “I set alight, I ignite”.

Medical Dictionary description is:

“A fundamental pathologic process consisting of a dynamic complex of histologically apparent cytologic changes, cellular infiltration, and mediator release that occurs in the affected blood vessels and adjacent tissues in response to an injury or abnormal stimulation caused by a physical, chemical, or biologic agent, including the local reactions and resulting morphologic changes; the destruction or removal of the injurious material; and the responses that lead to repair and healing.”

The five elements makes up the signature of  inflammation:  rubor, redness; calor, heat (or warmth); tumor swelling; and dolor, pain; a fifth sign, functio laesa, inhibited or lost function.   However, these indications may not be present at once.

Please click on to the following link for genetic association of autoimmune diseases (Cho Et al selected major association signals in autoimmune diseases) from Cho JH, Gregersen PK. N Engl J Med 2011;365:1612-1623.

Inflammatory diseases grouped under two classification: the immune system related due to  inflammatory disorders, such as both allergic reactions  and some myopathies, with many immune system disorders.  The examples of inflammatory disorders  include Acne vulgaris, asthma, autoimmune disorders, celiac disease, chronic prostatitis, glomerulonepritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory diseases, reperfusion diseases, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, interstitial cyctitis, The second kind of inflammation are related to  non-immune diseases such as cancer, atherosclerosis, and ischaemic heart disease.

This seems simple yet at molecular physiology and gene activation levels this is a complex response as an innate immune response from body.  There can be acute lasting few days after exposure to bacterial pathogens, injured tissues or chronic inflammation continuing few months to years after unresolved acute responses such as non-degradable pathogens, viral infection, antigens or any  foreignmaterials, or autoimmune responses.

As the system responses arise from plasma fluid, blood vessels, blood plasma through vasciular changes, differentiation in plasma cascade systems like coagulation system, fibrinolysis, complement system and kinin system.  Some of the various mediators include bradykinin produced by kinin system, C3, C5, membrane attack system (endothelial cell activation or endothelial coagulation activation mechanism) created by the complement system; factor XII that can activate kinin, fibrinolysys and coagulation systems at the same time produced in liver; plasmin from fibrinolysis system to inactivate factor Xii and C3 formation, and thrombin of coagulation system with a reaction through protein activated receptor 1 (PAR1), which is a seven spanning membrane protein-GPCR.   This system is quite fragile and well regulated.  For example activation of inactive Factor XII by collagen, platelets, trauma such as cut, wound, surgery that results in basement membrane changes since it usually circulate in inactive form in plasma automatically initiates and alerts kinin, fibrinolysis and coagulation systems.

Furthermore, the changes reflected through receptors and create gene activation by cellular mediators to establish system wide unified mechanisms. These factors (such as IFN-gamma, IL-1, IL-8, prostaglandins, leukotrene B4,  nitric oxide, histamines,TNFa) target immune cells and redesign their responses, mast cells, macrophages, granulocytes, leukocytes, B cells, T cells) platelets, some neuron cells and endothelial cells.  Therefore, immune system can react with non-specific or specific mechanisms either for a short or a long term.

As a result, controlling of mechanisms in blood and prevention of angiogenesis answer to cure/treat many diseases  Description of angiogenesis is simply formation of new blood vessels without using or changing pre-existing capillaries.  This involves serial numbers of events play a central role during physiologic and pathologic processes such as normal tissue growth, such as in embryonic development, wound healing, and the menstrual cycle.  However this system requires three main elements:  oxygen, nutrients and getting rid of waste or end products.

Genome Wide Gene Association Studies, Genomics and Metabolomics, on the other hand, development of new technologies for diagnostics and non-invasive technologies provided better targeting systems.

In this token recent genomewide association studies showed a clear view on a disease mechanism, or that suggest a new diagnostic or therapeutic approach particularly these disorders are related to  genes within the major histocompatibility complex (MHC) that predisposes the most significant genetic effect.  Presumably, these genes are reflecting the immunoregulatory effects of the HLA molecules themselves. As a result, the working mechanism of pathological conditions are revisited or created new assumptions to develop new targets for diagnosis and treatments.

Even though B and T cells are reactive to initiate responses there are several level of mechanisms control the cell differentiation for designing rules during health or diseases. These regulators are in check for both T and B cells.  For example, during Type 1 diabetes there are presence of more limited defects in selection against reactivity with self-antigens like insulin, thus, T cell differentiation is in jeopardy.  In addition, B cells have many active checkpoints to modulate the immune responses like  pre-B cells in the bone marrow are highly autoreactive yet they prefer to stay  in naïve-B cell forms in the periphery through tyrosine phosphatase nonreceptor type 22 (PTPN22) along with many genes play a role in autoimmunity.  In a nut shell this is just peeling the first layer of the onion at the level of Mendelian Genetics.

There is a great work to be done but if one can harness the blood and immune responses many complex diseases patients may have a big relief and have a quality of life.  When we look at the picture 90% of main fluid of life, blood, carried by cardiovascular system with two main pumping mechanisms, lung with gas exchange and systemic with complex scavenger actions, collection of waste, distribution of nutrition and clean gases.  Yet, without lymphatic system body can’t make up the 100% fluid.  Therefore, 10% balance is completed by lymphatic system as a counter clockwise direction so that not only the fluid balance but also mass balance is  maintained. Finally, the immune system patches the  remaining mechanism by providing cellular support to protect the body because it contains 99% of white cells to fight against any kinds of invasion, attack, trauma.

FURTHER READINGS AND REFERENCES:

Arap W, Pasqualini R, Ruoslahti E (1998) Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science (Wash DC)279:377380.

 Brouty BD, Zetter BR (1980) Inhibition of cell motility by interferon.Science (Wash DC) 208:516518.

Ferrara N, Alitalo K (1999) Clinical Applications of angiogenic growth factors and their inhibitorsNat Med 5:13591364.

 

Ferrara N (1999) Role of vascular endothelial growth factor in the regulation of angiogenesisKidney Int 56:794814.

 

Ferrara N (1995) Leukocyte adhesion: Missing link in angiogenesisNature (Lond) 376:467.

 

Kohn EC, Alessandro R, Spoonster J, Wersto RP, Liotta LA (1995) Angiogenesis: Role of calcium-mediated signal transduction. Proc Natl Acad Sci U S A 92:13071311

Meijer DKF, Molema G (1995) Targeting of drugs to the liverSemin Liver Dis 15:202256.

Sidky YA, Borden EC (1987) Inhibition of angiogenesis by interferons: Effects on tumor- and lymphocyte-induced vascular responsesCancer Res47:51555161.

Anonymous (1999a) Genentech takes VEGF back to lab. SCRIP 2493:24.

Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ,Bicknell R (1997) Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest 99:26252634.

 

Yoshida S, Ono M, Shono T, Izumi H, Ishibashi T, Suzuki H, Kuwano M(1997) Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor α-dependent angiogenesis. Mol Cell Biol 17:40154023.

 

Vittet D, Prandini MH, Berthier R, Schweitzer A, Martin SH, Uzan G,Dejana E (1996) Embryonic stem cells differentiate in vitro to endothelial cells through successive maturation stepsBlood 88:34243431.

 

Ruegg C, Yilmaz A, Bieler G, Bamat J, Chaubert P, Lejeune FJ (1998) Evidence for the involvement of endothelial cell integrin αvβ3 in the disruption of the tumor vasculature induced by TNF and IFNNat Med4:408414

Patey N, Vazeux R, Canioni D, Potter T, Gallatin WM, Brousse N (1996) Intercellular adhesion molecule-3 on endothelial cells. Expression in tumors but not in inflammatory responses. Am J Pathol 148:465472.

Oliver SJ, Banquerigo ML, Brahn E (1994) Supression of collagen-induced arthritis using an angiogenesis inhibitor AGM-1470 and microtubule stabilizer taxol. Cell Immunol 157:291299

Molema G, Griffioen AW (1998) Rocking the foundations of solid tumor growth by attacking the tumor’s blood supplyImmunol Today 19:392394.

 

Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M,Ashare AB, Lathi K, Isner JM (1998) Gene therapy for myocardial angiogenesis: Initial clinical results with direct myocardial injection of PhVEGF165 as sole therapy for myocardial ischemiaCirculation98:28002804.

Jain RK, Schlenger K, Hockel M, Yuan F  (1997) Quantitative angiogenesis assays: Progress and problemsNat Med 3:12031208.

Jain RK (1996) 1995 Whitaker Lecture: Delivery of molecules, particles and cells to solid tumors. Ann Biomed Eng 24:457473.

 

Giraudo E, Primo L, Audero E, Gerber H, Koolwijk P, Soker S,Klagsbrun M, Ferrara N, Bussolino F (1998) Tumor necrosis factor-alpha regulates expression of vascular endothelial growth factor receptor-2 and of its co-receptor neuropilin-1 in human vascular endothelial cells. J Biol Chem273:2212822135.

Inflammation Genomics

Kocarnik JM, Pendergrass SA, Carty CL, Pankow JS, Schumacher FR, Cheng I, Durda P, Ambite JL, Deelman E, Cook NR, Liu S, Wactawski-Wende J, Hutter C, Brown-Gentry K, Wilson S, Best LG, Pankratz N, Hong CP, Cole SA, Voruganti VS, Bůžkova P, Jorgensen NW, Jenny NS, Wilkens LR, Haiman CA, Kolonel LN, Lacroix A, North K, Jackson R, Le Marchand L, Hindorff LA, Crawford DC, Gross M, Peters U. Multi-Ancestral Analysis of Inflammation-Related Genetic Variants and C-Reactive Protein in the Population Architecture using Genomics and Epidemiology (PAGE) Study. Circ Cardiovasc Genet. 2014 Mar 12

Ellis J, Lange EM, Li J, Dupuis J, Baumert J, Walston JD, Keating BJ, Durda P, Fox ER, Palmer CD, Meng YA, Young T, Farlow DN, Schnabel RB, Marzi CS, Larkin E, Martin LW, Bis JC, Auer P, Ramachandran VS, Gabriel SB, Willis MS, Pankow JS, Papanicolaou GJ, Rotter JI, Ballantyne CM, Gross MD, Lettre G, Wilson JG, Peters U, Koenig W, Tracy RP, Redline S, Reiner AP, Benjamin EJ, Lange LA. Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novelassociation at CD36 in African Americans. Hum Genet. 2014 Mar 19.

Ricaño-Ponce I, Wijmenga C. Mapping of immune-mediated disease genes. Annu Rev Genomics Hum Genet. 2013;14:325-53. doi: 10.1146/annurev-genom-091212-153450. Epub 2013 Jul 3. Review.

McKillop AM, Flatt PR. Emerging applications of metabolomic and genomic profiling in diabetic clinical medicine. Diabetes Care. 2011 Dec;34(12):2624-30. doi: 10.2337/dc11-0837. Review.

Ricaño-Ponce I, Wijmenga C. Mapping of immune-mediated disease genes. Annu Rev Genomics Hum Genet. 2013;14:325-53. doi: 10.1146/annurev-genom-091212-153450. Epub 2013 Jul 3.Review.

Chen YB, Cutler CS. Biomarkers for acute GVHD: can we predict the unpredictable? Bone Marrow Transplant. 2013 Jun;48(6):755-60. doi: 10.1038/bmt.2012.143. Epub 2012 Aug 6. Review.

Cho JH, Gregersen PK. Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med. 2011 Oct 27;365(17):1612-23. doi: 10.1056/NEJMra1100030. Review.

Shikama N, Nusspaumer G, Hollander GA. Clearing the AIRE: on the pathophysiological basis of the autoimmune polyendocrinopathy syndrome type-1. Endocrinol Metab Clin North Am2009;38:273-288

Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med 2009;360:1646-1654

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Liver Toxicity halts Clinical Trial of IAP Antagonist for Advanced Solid Tumors

Writer/Curator Stephen J. Williams, Ph.D.

A recent press release on FierceBiotech reported the FDA had put a halt on a phase 1 study for advanced refractory solid tumors and lymphomas of Curis Inc. oral inhibitor of apoptosis (IAP) antagonist CUDC-427.  The FDA placed the trial on partial clinical hold following reports of a death of a patient from severe liver failure.  The single-agent, dose escalation Phase 1 study was designed to determine the maximum tolerated dose and recommended doses for a Phase 2 trial. The press release can be found at:

http://www.fiercebiotech.com/press-releases/curis-reports-third-quarter-2013-financial-results-and-provides-cudc-427-de.

According to the report one patient with breast cancer that had metastasized to liver, lungs, bone, and ovaries developed severe hepatotoxicity as evidenced by elevated serum transaminase activities (AST and ALT) and hyper-billirubinemia.  Serum liver enzyme activities did not attenuate upon discontinuation of CUDC-427.  This was unlike prior experience to the CUDC-427 drug, in which decreased hepatic function was reversed upon drug discontinuation.  The patient died from liver failure one month after discontinuation of CUDC-427.

It was noted that no other patient had experienced such a serious, irreversible liver dysfunction.

Although any incidence of hepatotoxicity can be cause for concern, the incidence of IDIOSYNCRATIC IRREVERSIBLE HEPATOTOXICITY warrants a higher scrutiny.

Four general concepts can explain toxicity profiles and divergences between individuals:

  1. Toxicogenomics: Small differences in the genetic makeup between individuals (such as polymorphisms (SNP) could result in differences in toxicity profile for a drug.  This ais a serious possibility as only one patient presented with such irreversible liver damage
  2. Toxicodynamics:  The toxicologic effect is an extension of the pharmacologic mechanism of action (or  lack thereof: could there have been alternate signaling pathways activated in this patient or noncanonical mechanism)
  3. Toxicokinetic:  The differences in toxicological response due to differences in absorption, distribution, metabolism, excretion etc. (kinetic parameters)
  4. Idiosyncratic: etiology is unknown; usually a minority of adverse effects

 

Since there is not enough information to investigate toxicogenomic or toxicokinetic mechanisms for this compound, the rest of this post will investigate the possible mechanisms of hepatotoxicity due to IAP antagonists and clues from other clinical trials which might shed light on a mechanism of toxicity (toxicodynamic) or idiosyncratic events.

Therefore this post curates the current understanding of drug-induced liver injury (DILI), especially focusing on a type of liver injury referred to as idiosyncratic drug-induced liver injury (IDILI) in the context of:

  1. Targeted and newer chemotherapies such as IAP antagonists
  2. Current concepts of mechanisms of IDILI including:

i)        Inflammatory responses provoked by presence of disease

ii)      Cellular stresses, provoked by disease, uncovering NONCANONICAL toxicity pathways

iii)    Pharmacogenomics risk factors of IDILI

Eventually this post aims to stimulate the discussion: 

  • Given inflammation, genetic risk factors, and cellular stresses (seen in clinical setting) have been implicated in idiosyncratic drug-induced liver injury from targeted therapies, should preclinical hepatotoxicity studies also be conducted in the presence of the metastatic disease?
  • Does inflammation and cellular stress from clinical disease unmask NONCANONICAL pharmacologic and/or toxicological mechanisms of action?

Classification of types of Cellular Liver injury:  A listing of types of cellular injury is given for review

I.     Hepatic damage after Acute Exposure

A. Cytotoxic (Necrotic):  irreversible cell death characterized by loss of cell membrane integrity, intracellular swelling, nuclear shrinkage (pyknosis) and eventual cytoplasmic breakdown of nuclear DNA (either by a process known as karyolysis or karyorhexus) localized inflammation as a result of release of cellular constituents.  Intracellular ATP levels are commonly seen in necrotic death.  Necrosis, unlike apoptosis, does not require a source of ATP.  A nice review by Yoshihide Tsujimoto describing and showing (by microscopy) the  differences between apoptosis and necrosis can be found here.

B. Cholestatic:  hepatobiliary dysfunction with bile stasis and accumulation of bile salts.  Cholestatic injury can result in lipid (particularly cholesterol) accumulation in cannicular membranes resulting in decreased permeability of the membrane, hyperbillirubinemia and is generally thought to result in metabolic defects.

C. Lipid Peroxidation: free radical generation producing peroxide of cellular lipids, generally resulting in a cytotoxic cell death

II.     Hepatic damage after Chronic Exposure

A. Chirrotic: Chronic morphologic alteration of the liver characterized by the presence of septae of collagen distributed throughout the major portion of the liver; Forms fibrous sheaths altering hepatic blood flow, resulting in a necrotic process with scar tissue; Alteration of hepatic metabolic systems.

B. Carcinogenesis

III. Idiosyncratic Drug Induced Liver Injury

The aforementioned mechanisms of hepatotoxicity are commonly referred to as the “intrinsic” (or end target-organ) toxicity mechanisms.  Idiosyncratic drug-induced liver injury (IDILI) is not well understood but can be separated into allergic and nonallergic reactions.  Although the risk of acute liver failure associated with idiosyncratic hepatotoxins is low (about 1 in ten thousand patients) there are more than 1,000 drugs and herbal products associated with this type of toxic reaction. Idiosyncratic drug induced liver failure usually gets a black box warning from the FDA. Idiosyncratic drug-induced liver injury differs from “intrinsic” toxicity in that IDILI:

  • Happens in a minority of patients (susceptible patients)
  • Not reproducible in animal models
  • Not dose-dependent
  • Variable time of onset
  • Variable liver pathology (not distinctive lesions)
  • Not related to drug’s pharmacologic mechanism of action (trovafloxacin IDILI vs. levofloxacin)

A great review in Perspectives in Pharmacology written by Robert Roth and Patricia Ganey at Michigan State University explains these differences between intrinsic and idiosyncratic drug-induced hepatotoxicity[1] (however authors do note that there are many similarities between the two mechanisms).    It is felt that drug sensitivity (allergic) and inflammatory responses (nonallergic) may contribute to the occurrence of IDILI.  For instance lipopolysaccharide (LPS) form bacteria can potentiate acetaminophen toxicity.  In fact animal models of IDILI have been somewhat successful:

  • co-treatment of rats and mice with nontoxic doses of trovafloxacin (casues IDILI in humans) and LPS resulted in marked hepatotoxicity while no hepatotoxicity seen with levofloxacin plus LPS[2]
  • correlates well with incidence of human IDILI (adapted from a review Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models (in Pharmacology Reviews)[3].  Idiosyncratic injury damage has been reported for diclofenac, halothane, and sulinac.  These drugs also show hepatotoxicity in the LPS model for IDILI.
  • Roth and Ganey suggest the reason why idiosyncratic hepatotoxicity is not seen  in most acute animal toxicity studies is that, in absence of stress/inflammation  IDILI occurrence is masked by lethality but stress/inflammation shifts increases sensitivity to liver injury at a point before lethality is seen

IDILdosestressrossmantheory

Figure.  Idiosyncratic toxic responses of the liver.    In the absence of stress and/or genetic factors, drug exposure may result in an idiosyncratic liver injury (IDILI) at a point (or dose) beyond the therapeutic range and lethal exposure for that drug.  Preclinical studies, usually conducted at sublethal doses, would not detect DILI .  Stress and/or genetic factors sensitize the liver to toxic effects of the drug (synergism) and DILI is detected at exposure levels closer to therapeutic range.  Note IDILI is not necessarily dose-dependent but cellular stress (like ROS or inflammation) may expose NONCANONICAL mechanisms of drug action or toxicity which result in IDILI. Model adapted from Roth and Ganey.

What Stress factors contribute to IDILI?

Various stresses including inflammation from bacterial, viral infections ,inflammatory cytokines  and stress from reactive oxygen (ROS) have been suggested as mechanisms for IDILI.

  1. Inflammation/Cytokines (also discussed in other sections of this post):  Inflammation has long been associated with human cases of DILI.    Many cytokines and inflammatory mediators have been implicated including TNFα, IL7, TGFβ, and IFNϒ (viral infection) leading some to conclude that serum measurement of cytokines could be a potential biomarker for DILI[4].  In addition, ROS (see below) is generated from inflammation and also considered a risk factor for DILI[5].
  2. Reactive Oxygen (ROS)/Reactive Metabolites: Oxidative stress, either generated from reactive drug metabolites or from mitochondrial sources, has been shown to be involved in apoptotic and necrotic cell death.  Both alterations in the enzymes involved in the generation of and protection from ROS have been implicated in increased risk to DILI including (as discussed further) alterations in mitochondrial superoxide dismutase 2 (SOD2) and glutathione S-transferases.  Both ROS and inflammatory cytokines can promote JNK signaling, which has been implicated in DILI[6].

Dr. Neil Kaplowitz suggested that we:

“develop a unifying hypothesis that involves underlying genetic or acquired mitochondrial abnormalities as a major determinant of susceptibility for a number of drugs that target mitochondria and cause DILI. The mitochondrial hypothesis, implying gradually accumulating and initially silent mitochondrial injury in heteroplasmic cells which reaches a critical threshold and abruptly triggers liver injury, is consistent with the findings that typically idiosyncratic DILI is delayed (by weeks or months), that increasing age and female gender are risk factors and that these drugs are targeted to the liver and clearly exhibit a mitochondrial hazard in vitro and in vivo. New animal models (e.g., the Sod2(+/-) mouse) provide supporting evidence for this concept. However, genetic analyses of DILI patient samples are needed to ultimately provide the proof-of-concept”[7].

Clin Infect Dis. 2004 Mar 38(Supplement 2) S44-8, Figure 1

Clin Infect Dis. 2004 Mar 38(Supplement 2) S44-8, Figure 3

Figures. Mechanisms of Drug-Induced Liver Injury and Factors related to the occurrence of  DILI (used with permission from Oxford Press; reference [7])

To this end, Dr. Brett Howell and other colleagues at the Hamner-UNC Institute for Drug Safety Sciences (IDSS) developed an in-silico model of DILI ( the DILISym™ model)which is based on  depletion of cellular ATP and reactive metabolite formation as indices of DILI.

Have there been Genetic Risk Factors identified for DILI?

Candidate-gene-associated studies (CGAS) have been able to identify several genetic risk factors for DILI including:

  1. Uridine Diphosphate Glucuronosyltransferase 2B7 (UGT2B7): variant increased susceptibility to diclofenac-induced DILI
  2. Adenosine triphosphate-binding cassette C2 (ABCC2) variant ABCC-24CT increased susceptibility to diclofenac-induced DILI
  3. Glutathione S-transferase (GSTT1): patients with a double GSTT1-GSTM1 null genotype had a significant 2.7 fold increased risk of DILI from nonsteroidal anti-inlammatory agents, troglitazone and tacrine.  GSTs are involved in the detoxification of phase 1 metabolites and also protect against cellular ROS.

Although these CGAS confirmed these genetic risk factors,  Stefan Russman suggests a priori genome-wide association studies (GWAS) might provide a more complete picture of genetic risk factors for DILI as CGAS is limited due to

  1. Candidate genes are selected based on current mechanisms and knowledge of DILI so genetic variants with no known knowledge of or mechanistic information would not be detected
  2. Many CGAS rely on analysis of a limited number of SNP and did not consider intronic regions which may control gene expression

A priori GWAS have the advantage of being hypothesis-free, and although they may produce a high number of false-positives, new studies of genetic risk factors of ximelagatran, flucioxaciliin and diclofenac-induced liver injury are using a hybrid approach which combines the whole genome and unbiased benefits of GWAS with the confirmatory and rational design of CGAS[8-10].

Even though idiosyncratic DILI is rare, the severity, unpredictable onset, and unknown etiology and risk factors have prompted investigators such as Stefan Russmann from University Hospital Zurich and Ignazio Grattagliano from University of Bari to suggest:

Identification of risk factors for rare idiosyncratic hepatotoxicity requires special networks that contribute to data collection and subsequent identification of environmental as well as genetic risk factors for clinical cases of idiosyncratic DILI[11].

Therefore, a DILI network project (DILIN) had been developed to collect samples and detailed genetic and clinical data on IDILI cases from multiple medical centers.  The project aims to identify the upstream and downstream genetic risk factors for IDILI[12].  Please see a SlideShare presentation here of the goals of the DILI network project.

Drs Colin Spraggs and Christine Hunt had reviewed possible genetic risk factors of DILI seen with various tyrosine kinase inhibitors (TKIs) including Lapatinib (Tykerb/Tyverb©, a dual inhibitor of  HER2/EGFR heterodimer) and paopanib (Votrient©; a TKI that targets VEGFR1,2,3 and PDGFRs)[13].

From a compilation of studies:

  • Elevation in serum bilirubin during treatment with lapatinib and pazopanib are associated with UGT1A1 polymorphism related to Gilbert’s syndrome (a clinically benign syndrome)
  • Anecdotal evidence shows that polymorphisms of lapatinib and pazopanib metabolizing enzymes may contribute to differences seen in onset of DILI
  • Pazopanib-induced elevations of ALT correlate with HFE variants, suggesting alterations in iron transport may predispose to DILI
  • Strong correlations between lapatinib-induced DILI and class II HLA locus suggest inflammatory stress response important in DILI

Note that these clinical findings were not evident from the preclinical tox studies. According to the European Medicines Agency assessment report for Tykerb states: “the major findings in repeat dose toxicity studies were attributed to lapatinib pharmacology (epithelial effect in skin and GI system.  The toxic events occurred at exposures close to the human exposure at the recommended dose.  Repeat-dose toxicity studies did not reveal important safety concerns than what would be expected from the mode of action”.

However, it should be noted that in high dose repeat studies in mice and rats, severe lethality was seen with hematologic, gastrointestinal toxicities in combination with altered blood chemistry parameters and yellowing of internal organs.

IAP Antagonists, Mechanism of Action, and Clinical Trials:

A few IAP antagonists which are in early stage development include:

  • Norvatis IAP Inhibitor LCL161: at 2012 San Antonia Breast Cancer Symposium, a phase 1 trial in triple negative breast cancer showed promising results when given in combination with paclitaxel.
  • Ascenta Therapeutics IAP inhibitor AT-406 in phase 1 in collaboration with Debiopharm S.A. showed antitumor efficacy in xenograft models of breast, pancreatic, prostate and lung cancer. The development of this compound is described in a paper by Cai et. al.

National Cancer Institute sponsored trials using antagonists of IAPs include

  • Phase II Study of Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer (NCI-12-C-0191). Principle Investigator: Dr. Christina Annunziata. See the protocol summary. More open trials for this drug are located here.  Closed trials including safety studies can be found here.
  • A Phase 1 non-randomized dose escalation study to determine maximum tolerated dose (MTD) and characterize the safety for the TetraLogic compound TL32711 had just been completed. Results have not been published yet.
  • Closed Clinical trials with the IAP antagonist HGS1029 in advanced solid tumors determined that weekly i.v. administration of HGS1029 reported a safety issue for primary outcome measures

A great review on IAP proteins and their role as regulators of apoptosis and potential targets for cancer therapy [14] can be found as a part of a Special Issue in Experimental Oncology “Apoptosis: Four Decades Later”.  Human IAPs (inhibitors of apoptosis) consist of eight proteins involved in cell death, immunity, inflammation, cell cycle, and migration including:

In general, IAP proteins are directly involved in inhibiting apoptosis by binding and directly inhibiting the effector cysteine protease caspases (caspase 3/7) ultimately responsible for the apoptotic process [15].  IAPs were actually first identified in baculoviral genomes because of their ability to suppress host-cell death responses during viral infection [16]. IAP proteins are often overexpressed in cancers [17].

Apoptosis is separated into two pathways, defined by the initial stress or death signal and the caspases involved:

  1. Extrinsic pathway: initiated by TNFα and death ligand FasLigand;  involves caspase-8; process inhibited by IAP1/2
  2. Intrinsic pathway: initiated by DNA damage, irradiation, chemotherapeutics; mitochondrial pathway involving caspase 9 and cytochrome c release from mitochondria; mitochondria also releases SMAC/DIABLO, which binds and inhibits XIAP (XIAP inhibits the Intrinsic apoptotic pathway.

 intrinsicextrinsicapoptosiswikidot

 

Intrinsic and Extrinsic pathways of apoptosis. Figure photocredit (wikidot.com)

The Curis IAP antagonist (and others) is a SMAC small molecule mimetic. It is interesting to note [18, 19] that IAP antagonists can result in death by

  • Apoptosis: an IAP antagonist in presence of competent TNFα signaling
  • Necrosis: seen with IAP inhibitors in cells with altered TNFα signaling or with presence of caspase inhibitors

IAPs are also involved in the regulation of signaling pathways such as:

NF-ΚB signaling pathway

NF-ΚB is a “rapid-acting” transcription factor which has been found to be overexpressed in various cancers.  Under most circumstances NF-ΚB translocation to the nucleus results in transcription of genes related to cell proliferation and survival.  NF-ΚB signaling is broken down in two pathways

  1. Canonical:  Canonical pathway can be initiated (for example in inflammation) when TNF-α binds its receptors activating  death domains (TRADD)
  2. Noncanonical: since requires new protein synthesis takes longer than canonical signaling.  Can be initiated by other TNF like ligands like CD40

IAP1/2 is a negative regulator of the noncanonical NF-ΚB signaling pathway by promoting proteosomal degradation of the TRAF signaling complex. A wonderfully annotated list of NF-ΚB target genes can be found on the Thomas Gilmore lab site at Boston University at http://www.bu.edu/nf-kb/gene-resources/target-genes/ .

NF-ΚB has been considered a possible target for chemotherapeutic development however Drs. Veronique Baud and Michael Karin have pondered the utility of IAP antagonists as a good target in their review: Is NF-ΚB a good target for cancer therapy?: Hopes and pitfalls [20].  The authors discuss issues such that IAP antagonism induced both the classical and noncanonical NF-ΚB pathway thru NIK stabilization, resulting in stabilization of NF-ΚB signaling and thereby undoing any chemotherapeutic effect which would be desired.

AKT signaling

IAPs have been shown to interact with other proteins including a report that SIAP regulates AKT activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian cancer cells and could be another mechanism involved in cisplatin resistance[21].   In addition there have been reports that IAPs can regulate JNK and MAPK signaling.

Therefore, IAPs are involved in CANONICAL and NONCANONICAL pathways.

IAPs can Regulate Pro-Inflammatory Cytokines

A recent 2013 JBC paper [22]showed that IAPs and their antagonists can regulate spontaneous and TNF-induced proinflammatory cytokine and chemokine production and release

  • IAP required for production of multiple TNF-induced proinflammatory mediators
  • IAP antagonism decreased TNF-mediated production of chemokines and cytokines
  • But increased spontaneous release of chemokines

In addition Rume Damgaard and Mads Gynd-Hansen have suggested that IAP antagonists may be useful in treating inflammatory diseases like Crohn’s disease as IAPs regulate innate and acquired immune responses[23].

Toxicity profiles of IAP antagonists

NOTE: In a paper in Toxicological Science from 2012[24], Rebecca Ida Erickson form Genentech reported on the toxicity profile of the IAP antagonist GDC-0152 from a study performed in dogs and rats. A dose-dependent toxicity profile from i.v. administration was consistent with TNFα-mediated toxicity with

  • Elevated plasma cytokines and an inflammatory leukogram
  • Increased serum transaminases
  • Inflammatory infiltrate and apoptosis/necrosis in multiple tissues

In a related note, a similar type of fatal idiosyncratic hepatotoxicity was reported in a 62 year-old man treated with the Raf kinase inhibitor sorafenib for renal cell carcinoma[25]: Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma; Case Report  in BMC Cancer.

At week four after initiation of sorafenib treatment, the patient noticed increasing fatigue, malaise, gastrointestinal discomfort and abdominal rash.  Although treatment was discontinued, jaundice developed and blood test revealed an acute hepatitis with

  • Elevated serum ALT
  • Elevated serum alkaline phosphatase
  • Increased prothrombin time
  • Increased LDH

…elevated levels seen in the case with the aforementioned IAP antagonist.  Autopsy revealed

  • Lobular hepatitis
  • Mononuclear cell infiltrate
  • Hepatocyte necrosis

These findings are in line with a drug-induced inflammation and IDILI. In addition to hepatotoxicity, renal insufficiency developed in this patient. The authors had suggested the death was probably due to “an idiosyncratic allergic reaction to sorafenib manifesting as hepatotoxicity with associated renal impairment”.  The authors also noted that genome wide association studies of idiosyncratic drug-induced liver injury support involvement of major histocompatibility complex (MHC) polymorphisms[26].  MHC involvement has also been associated with lapatanib and pazopanib hepatotoxicity [27, 28].

Curis has been involved in another novel oncology therapeutic, a first in class.

Last year Roche and Genentech had won approval for a Hedgehog pathway inhibitor vismodegib for treatment of advanced basal cell carcinoma (reported at FierceBiotech©). Vismodegib was initially developed in collaboration with Curis, Inc.  The hedgehog signaling pathway, which controls the function of Gli factors (involved in stem cell differentiation), is overactive in advanced basal cell carcinoma as well as other cancer types.

As an additional reference, the FDA National Center for Toxicological Research has developed THE LIVER TOXICITY KNOWLEDGE BASE (LTKB).

“The LTKB is a project designed to study drug-induced liver injury (DILI). Liver toxicity is the most common cause for the discontinuation of clinical trials on a drug, as well as the most common reason for an approved drug’s withdrawal from the marketplace. Because of this, DILI has been identified by the FDA’s Critical Path Initiatives as a key area of focus in a concerted effort to broaden the agency’s knowledge for better evaluation tools and safety biomarkers.”

A nice SlideShow of Toxicity of Targeted Therapies can be found here: http://www.slideshare.net/RashaHaggag/toxicities-of-targeted-therapies

Also please note that ALL GENES in this article are linked to their GENECARD 

REFERENCES

1.            Roth RA, Ganey PE: Intrinsic versus idiosyncratic drug-induced hepatotoxicity–two villains or one? The Journal of pharmacology and experimental therapeutics 2010, 332(3):692-697.

2.            Waring JF, Liguori MJ, Luyendyk JP, Maddox JF, Ganey PE, Stachlewitz RF, North C, Blomme EA, Roth RA: Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils. The Journal of pharmacology and experimental therapeutics 2006, 316(3):1080-1087.

3.            Deng X, Luyendyk JP, Ganey PE, Roth RA: Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models. Pharmacological reviews 2009, 61(3):262-282.

4.            Laverty HG, Antoine DJ, Benson C, Chaponda M, Williams D, Kevin Park B: The potential of cytokines as safety biomarkers for drug-induced liver injury. European journal of clinical pharmacology 2010, 66(10):961-976.

5.            Schwabe RF, Brenner DA: Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury: role of IKK, JNK, and ROS pathways. American journal of physiology Gastrointestinal and liver physiology 2006, 290(4):G583-589.

6.            Seki E, Brenner DA, Karin M: A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology 2012, 143(2):307-320.

7.            Kaplowitz N: Drug-induced liver injury. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2004, 38 Suppl 2:S44-48.

8.            Kindmark A, Jawaid A, Harbron CG, Barratt BJ, Bengtsson OF, Andersson TB, Carlsson S, Cederbrant KE, Gibson NJ, Armstrong M et al: Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. The pharmacogenomics journal 2008, 8(3):186-195.

9.            Aithal GP, Ramsay L, Daly AK, Sonchit N, Leathart JB, Alexander G, Kenna JG, Caldwell J, Day CP: Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 2004, 39(5):1430-1440.

10.          Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP: Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007, 132(1):272-281.

11.          Russmann S, Kullak-Ublick GA, Grattagliano I: Current concepts of mechanisms in drug-induced hepatotoxicity. Current medicinal chemistry 2009, 16(23):3041-3053.

12.          Fontana RJ, Watkins PB, Bonkovsky HL, Chalasani N, Davern T, Serrano J, Rochon J: Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct. Drug safety : an international journal of medical toxicology and drug experience 2009, 32(1):55-68.

13.          Spraggs CF, Xu CF, Hunt CM: Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics 2013, 14(5):541-554.

14.          de Almagro MC, Vucic D: The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Experimental oncology 2012, 34(3):200-211.

15.          Deveraux QL, Takahashi R, Salvesen GS, Reed JC: X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997, 388(6639):300-304.

16.          Crook NE, Clem RJ, Miller LK: An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. Journal of virology 1993, 67(4):2168-2174.

17.          Tamm I, Kornblau SM, Segall H, Krajewski S, Welsh K, Kitada S, Scudiero DA, Tudor G, Qui YH, Monks A et al: Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clinical cancer research : an official journal of the American Association for Cancer Research 2000, 6(5):1796-1803.

18.          Laukens B, Jennewein C, Schenk B, Vanlangenakker N, Schier A, Cristofanon S, Zobel K, Deshayes K, Vucic D, Jeremias I et al: Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor alpha-induced necroptosis. Neoplasia 2011, 13(10):971-979.

19.          He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X: Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009, 137(6):1100-1111.

20.          Baud V, Karin M: Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nature reviews Drug discovery 2009, 8(1):33-40.

21.          Asselin E, Mills GB, Tsang BK: XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer research 2001, 61(5):1862-1868.

22.          Kearney CJ, Sheridan C, Cullen SP, Tynan GA, Logue SE, Afonina IS, Vucic D, Lavelle EC, Martin SJ: Inhibitor of apoptosis proteins (IAPs) and their antagonists regulate spontaneous and tumor necrosis factor (TNF)-induced proinflammatory cytokine and chemokine production. The Journal of biological chemistry 2013, 288(7):4878-4890.

23.          Damgaard RB, Gyrd-Hansen M: Inhibitor of apoptosis (IAP) proteins in regulation of inflammation and innate immunity. Discovery medicine 2011, 11(58):221-231.

24.          Erickson RI, Tarrant J, Cain G, Lewin-Koh SC, Dybdal N, Wong H, Blackwood E, West K, Steigerwalt R, Mamounas M et al: Toxicity profile of small-molecule IAP antagonist GDC-0152 is linked to TNF-alpha pharmacology. Toxicological sciences : an official journal of the Society of Toxicology 2013, 131(1):247-258.

25.          Fairfax BP, Pratap S, Roberts IS, Collier J, Kaplan R, Meade AM, Ritchie AW, Eisen T, Macaulay VM, Protheroe A: Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma. BMC cancer 2012, 12:590.

26.          Daly AK: Drug-induced liver injury: past, present and future. Pharmacogenomics 2010, 11(5):607-611.

27.          Spraggs CF, Budde LR, Briley LP, Bing N, Cox CJ, King KS, Whittaker JC, Mooser VE, Preston AJ, Stein SH et al: HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011, 29(6):667-673.

28.          Xu CF, Reck BH, Goodman VL, Xue Z, Huang L, Barnes MR, Koshy B, Spraggs CF, Mooser VE, Cardon LR et al: Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma. Journal of hepatology 2011, 54(6):1237-1243.

Other articles on the site about Toxicology and Pharmacology of New Classes of Cancer Chemotherapy include:

FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules

Gamma Linolenic Acid (GLA) as a Therapeutic tool in the Management of Glioblastoma

DNA Methultransferases – Implications to Epigenetic Regulation and Cancer Therapy Targeting: James Shen, PhD

Molecular Profiling in Cancer Immunotherapy: Debraj GuhaThakurta, PhD

AT13148 – A Novel Oral Multi-AGC Kinase Inhibitor Has Potent Antitumor Activity

Targeting Mitochondrial-bound Hexokinase for Cancer Therapy

Breast Cancer, drug resistance, and biopharmaceutical targets

Ubiquitin-Proteosome pathway, Autophagy, the Mitochondrion, Proteolysis and Cell Apoptosis: Part III

Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis

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Reporter: Aviva Lev-Ari, PhD, RN

 

The healing element is also the enemy – an enigma probed by Hebrew University Lautenberg Center researchers

April 3, 2013

Jerusalem – The same factor in our immune system that is instrumental in enabling us to fight off severe and dangerous inflammatory ailments is also a player in doing the opposite at a later stage, causing the suppression of our immune response.

Why and how this happens and what can be done to mediate this process for the benefit of mankind is the subject of an article published online in the journal Immunity by Ph.D. student Moshe Sade-Feldman and Professor Michal Baniyash of the Lautenberg Center for General and Tumor Immunology at The Hebrew University Faculty of Medicine.
Chronic inflammation poses a major global health problem and is common to different pathologies — such as autoimmune diseases (diabetes, rheumatoid arthritis, lupus and Crohn’s), chronic inflammatory disorders, chronic infections (HIV, leprosy, leishmaniasis) and cancer. Cumulative data indicate that at a certain stage of each of these diseases, the immune system becomes suppressed and results in disease progression.
In their previous work, The Hebrew University researchers had shown that in the course of chronic inflammation, unique immune system cells with suppressive features termed myeloid derived suppressor cells (MDSCs) are generated in the bone marrow and migrate into the body’s organs and blood, imposing a general immune suppression.
A complex network of inflammatory compounds persistently secreted by the body’s normal or cancerous cells support MDSC accumulation, activation and suppressive functions. One of these compounds is tumor necrosis factor-a (TNF-a), which under acute immune responses (short episodes), displays beneficial effects in the initiation of immune responses directed against invading pathogens and tumor cells.
However, TNF-a also displays harmful features under chronic responses, as described in pathologies such as rheumatoid arthritis, psoriasis, type II diabetes, Crohn’s disease and cancer, leading to complications and disease progression. Therefore, today several FDA- approved TNF-a blocking reagents are used in the clinic for the treatment of such pathologies.
What has remained unclear until now, however, is just how TNF-a plays its deleterious role in manipulating the host’s immune system towards the generation of a suppressive environment.
In their work, The Hebrew University researchers discovered the mechanisms underlying the TNF-a  function, a key to controlling this factor and manipulating it, perhaps, for the benefit of humans.  Using experimental mouse models, they showed unequivocally how TNF-a is critical in the induction of immune suppression generated during chronic inflammation. The TNF-a was seen to directly affect the accumulation and suppressive function of MDSCs, leading to an impaired host’s immune responses as reflected by the inability to respond against invading pathogens or against developing tumors.
Further, the direct role of how TNF-a works in humans was mimicked by injecting the FDA-approved anti-TNF-a drug, etanercept, into mice at the exacerbated stage of an inflammatory response, when MDSC accumulation was observed in the blood. The etanercept treatment changed the features of MDSCs and abolished their suppressive activity, leading to the restoration of the host’s immune function.
Taken together, the results show clearly how the TNF-a-mediated inflammatory response, whether acute or chronic, will dictate its beneficial or harmful consequence on the immune system. While during acute inflammation TNF-a is vital for immediate immune defense against pathogens and clearance of tumor cells, during chronic inflammation — under conditions where the host is unable to clear the pathogen or the tumor cells — TNF-a is harmful due to the induction of immune suppression.
These results, providing new insight into the relationship between TNF-a and the development of an immune suppression during chronic inflammation, may aid in the generation of better therapeutic strategies against various pathologies when elevated TNF-a and MDSC levels are detected, as seen, for example, in tumor growths.

 

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Can Resolvins Suppress Acute Lung Injury?

Reporter: Larry H Bernstein, MD, FCAP

Putting the brakes on acute lung injury: can resolvins suppress acute lung injury?

Cox RR Jr., Phillips O,and Kolliputi N

http://www.frontiersin.org Front.Physio. 2012;3:445.        http://dx.doi.org/10.3389/fphys.2012.00445
http://www.FrontPhysiol.com/putting_the_brakes_on_acute_lung_injury_can_resolvins_suppress_acute_lung_injury?/

The presence of resolvins, proresolving lipid mediators: their role in the resolution of ALI
Eickmeier et al.,
Mucosal Immunity 2012

conversion of DHA to RvD1 by

  • activation of RvD1 Receptor (ALX/FPR2) in pulmonary mucosa alleviates effects of inflammation in APALI

endogenous attenuation of inflammation in APALI
http://www.MucosalImmunity.com/Eikmeier/The_presence_of_resolvins:_their_role_in_the_resolution_of_ALI

 Putting the brakes on acute lung injury: can resolvins suppress acute lung injury?
Ruan R. Cox Jr., Oluwakemi Phillips and Narasaiah Kolliputi*
Front Physiol. 2012;3:445.   doi: 10.3389/fphys.2012.00445. Epub 2012 Nov 29.       http://dx.doi.org/10.3389/fphys.2012.00445
http://fphys.com/Putting the brakes on acute lung injury: can resolvins suppress acute lung injury?

A commentary on

Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury

by Eickmeier, O., Seki, H., Haworth, O., Hilberath, J. N., Gao, F., Uddin, M., et al. (2012). Mucosal Immunol. doi: 10.1038/mi.2012.66

Acute lung injury (ALI), a syndrome of respiratory failure, is a major clinical problem in the United States. With a high incidence rate, affecting nearly 200,000 annually and a significant morbidity and mortality rate, ALI represents a significant source of health care expenditure with a cost of 3.5–6 billion dollars annually (Treggiari et al., 2004; Rubenfeld et al., 2005; Raghavendran et al., 2011). Pneumocytes, unique cells in the alveolar epithelium, are responsible for

  • facilitating gas exchange,
  • regulating fluid transport, and
  • secreting surfactant to reduce alveolar surface tension.

When the alveolar barrier is disrupted, proteinaceous exudates and extracellular components of necrotic pneumocytes activate resident alveolar macrophages causing massive cytokine release (Ware and Matthay, 2000).  The inflammatory response, if left uncontrolled, can lead to further deterioration of the lung epithelium and the development of a fibroproliferative environment (Raghavendran et al., 2011).

In the July 2012 issue of Mucosal Immunity, Eickmeier et al., discuss the presence of

  1. resolvins,
  2. proresolving lipid mediators, and
  3. present exciting findings on their role in the natural resolution of ALI (Eickmeier et al., 2012).

Resolution phase interaction products (resolvins) are omega-3 polyunsaturated fatty acid derivatives of potent anti-inflammatory precursors, eicosapentaenoic acid (EPA), and docasahexaenoic acid (DHA) (Serhan et al., 2002). “E-series” and “D-series” resolvins are derived from EPA and DHA, respectively. The airway mucosa has been shown to be rich in DHA (Freedman et al., 2004), however, the conversion of DHA to D-series resolvins has not been shown. Resolvin D1 (RvD1), a derivative of DHA, has been found in murine resolving inflammatory peritoneal exudates (Serhan et al., 2002). To investigate the potential role that RvD1 may play in the resolution of ALI, Eickmeier et al. used a murine aspiration pneumonitis acute lung injury (APALI) model induced by hydrochloric acid (HCl) administration into the left lung. Picogram quantities of RvD1 were found using metabolipidomics analysis following HCl instillation. Immunohistochemical analysis showed enhanced expression of RvD1 receptor (ALX/FPR2) as early as 2 h post-APALI. This suggested that there was a conversion of DHA to RvD1 following lung injury. Activation of ALX/FPR2 dampens the inflammatory responses through blockage of proinflammatory MAP kinase and NF-κB signaling (Chiang et al., 2006).  Eickmeier et al. demonstrated that the conversion of DHA in pulmonary mucosa alleviates the effects of inflammation in APALI. AT-RvD1 showed therapeutic effects, and bronchio-alveolar lavage fluid (BALF) collected from AT-RvD1 treated mice contained decreased leukocytes and proinflammatory cytokines in comparison to control. AT-RvD1 treated mice demonstrated decreased lung resistance and improved lung mechanics in comparison to controls. The authors showed that AT-RvD1 restored barrier integrity in APALI mice in comparison to control. The anti-inflammatory effects of ALX/FPR2 activation were shown to be a result of

  • reduced activation and nuclear translocation of the transcription factor NF-κB.

Eickmeier et al., demonstrated that mice treated with AT-RvD1 demonstrated reduced

  • NF-κB phosphorylation, which is necessary for the activation,
  • translocation and DNA binding functions of this proinflammatory molecule.

The work of Eickmeier et al. revealed that RvD1 is a central mediator in the endogenous attenuation of inflammation seen in APALI. In most cases of ALI, the injury is indeed self-limiting and resolves on its own (Dos Santos and Slutsky, 2006). This work gives insight to the mechanism involved in the lung injury resolution process. A recent clinical study demonstrates that,
ALI progression is associated with

  • increased ventilator time and
  • longer intensive care unit (ICU) stays.

These patients show an enhanced proinflammatory cytokine profile which was also correlated with increased morbidity (Dolinay et al., 2012). Previous reports have also demonstrated that ALI/ARDS patients represent 34% of yearly costs for all ICU trauma patients (Treggiari et al., 2004). In the case that the ALI does not resolve, the patient is at risk for developing acute respiratory distress syndrome in as little as 3 days (Marshall et al., 1998). Finding endogenous mediators that may control the ungoverned inflammation seen in ALI is a pivotal step to finding a treatment for this disease that entails more than just supportive care (Marshall et al., 1998). The work of Eickmeier et al. has paved the way for the exploration of the beneficial effects of resolvins in the incidences of other sterile injuries, such as atherosclerosis, gout, Alzheimer’s disease, and diabetes.

Br J Pharmacol. 2008 March; 153(S1): S200–S215.
Published online 2007 October 29. doi:  10.1038/sj.bjp.0707489
PMCID: PMC2268040

Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus

C N Serhan1,2,* and N Chiang1
This article has been cited by other articles in PMC.

Abstract

Complete resolution of an acute inflammatory response and its return to homeostasis are essential for healthy tissues. We here consider work to characterize cellular and molecular mechanisms that govern the resolution of self-limited inflammation. Systematic temporal analyses of evolving inflammatory exudates using

  1. mediator lipidomics-informatics,
  2. proteomics, and
  3. cellular trafficking with murine resolving exudates demonstrate
    • novel endogenous pathways of local-acting mediators that share both anti-inflammatory and pro-resolving properties.

In murine systems, resolving-exudate leukocytes switch their phenotype to actively generate new families of mediators from major omega-3 fatty acids EPA and DHA termed resolvins and protectins. Recent advances on their biosynthesis and actions are reviewed with a focus on the E-series resolvins (RvE1, RvE2), D series resolvins (RvD1, RvD2) and the protectins including neuroprotectin D1/protectin D1 (NPD1/PD1) as well as their aspirin-triggered epimeric forms.  These endogenous agonists of resolution pathways constitute a novel genus of chemical mediators that possess

  • pro-resolving,
  • anti-inflammatory, and
  • antifibrotic as well as
  • host-directed antimicrobial actions.
    These may be useful in the design of new therapeutics and treatments for diseases with the underlying trait of uncontrolled inflammation and redox organ stress.
Keywords: leukocytes, eicosanoids, resolvins, acute inflammation, ω-3 fatty acids, protectins

Introduction

Acute inflammation has several outcomes that include

  • progression to chronic inflammation,
  • scarring and fibrosis or
  • complete resolution (Cotran et al., 1999).

With the isolation of endogenous anti-inflammatory and pro-resolving mediators and their characterization, it became clear that resolution is an active process involving biochemical circuits that

The resolution phase has emerged as a new terrain for drug design and resolution-directed therapeutics (Gilroy et al., 2004Lawrence et al., 2005). A pro-resolving small molecule can, in addition to serving as

  • an agonist of anti-inflammation, also
  • promote the uptake and clearance of apoptotic neutrophils (polymorphonuclear leukocyte, PMN)

A recent consensus report from investigators at the forefront of this emerging area has addressed these definitions to help delineate this new terrain (Serhan et al., 2007). Some agents such as the widely used COX-2 inhibitors proved to be resolution toxic (Gilroy et al., 1999Bannenberg et al., 2005Serhan et al., 2007), whereas others can possess pro-resolving actions, such as

Interest in natural resolving mechanisms has been heightened in recent years (Henson, 2005Luster et al., 2005Serhan and Savill, 2005) because inflammation (characterized by the cardinal symptoms dolor, calor, rubor and loss of function) is now recognized as a central feature in the pathogenesis of many prevalent diseases in modern Western civilization, such as

  1. stroke,
  2. Alzheimer’s and
  3. Parkinson’s diseases (Majno and Joris, 1996;Nathan, 2002Erlinger et al., 2004Hansson et al., 2006).

Resolution of inflammation is required for the return from inflammatory disease to health, that is, catabasis (Bannenberg et al., 2005). New evidence from this laboratory and others indicates that the catabasis from inflammation to the ‘normal’ noninflamed state is not merely passive termination of inflammation but rather an actively regulated program of resolution (Serhan et al., 2007). This event is accompanied by lipid mediator class switching from pro-inflammatory prostaglandins (PGs) and leukotrienes (LT) to the biosynthesis of anti-inflammatory mediators, such as lipoxins (LXs) (Levy et al., 2001), as well as the appearance of new families of pro-resolving mediators biosynthesized in exudates from ω-3 polyunsaturated fatty acid (PUFA) precursors (Serhan et al., 20002002Hong et al., 2003) (Figure 1a).   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268040/bin/0707489f1.gif

The essential roles of omega-3 PUFAs in preventing disease in rodents were established in 1929 (Burr and Burr, 1929). In humans, the beneficial actions of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major omega-3 PUFA, remains a topic of interest because structure–activity relationships remained to be established.  One theory suggests that the omega-3 PUFA compete with the storage of arachidonic acid (AA),

  • replacing it and blocking the production of pro-inflammatory eicosanoids (Lands, 1987).

Along with the pro-inflammatory PGs and LT, the n−6 essential fatty acid AA is precursor to LX and aspirin-triggered LX, which possess potent anti-inflammatory and pro-resolving actions. Therefore, the popular view of essential n−6 and n−3 PUFA actions in inflammation and homeostasis was incomplete.   http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268040/table/tbl1/?report=thumb

The evidence available to date  indicates that

The term resolvins (resolution-phase interaction products) was first introduced to signify that the new structures were endogenous mediators possessing potent anti-inflammatory and immunomodulatory actions demonstrated in the nanogram dose range in vivo(Serhan et al., 2002). These include

  • reducing neutrophil traffic and pro-inflammatory cytokines, as well as
  • lowering the magnitude of the inflammatory response in vivo (Serhan et al., 20002002).

The terms protectin and neuroprotectin (when generated in neural tissues) (Serhan et al., 2006a) were introduced given the anti-inflammatory (Hong et al., 2003) as well as the protective actions of the
DHA-derived mediator NPD1/PD1 in neural systems (Mukherjee et al., 2004),

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268040/bin/0707489f2.gif

RvE1 possesses an interesting and novel distinct structure consisting of

  • a conjugated diene plus
  • conjugated diene chromophore present within the same molecule.

Both biogenic (Serhan et al., 2000) and total organic syntheses were achieved and its complete stereochemical assignment was established along with that of several related natural isomers (Arita et al., 2005a). RvE1 proved to be 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoicacid.

Human recombinant 5-LOX generates resolvin E2 (RvE2) from a common precursor of E-series resolvins, namely 18-HEPE. RvE2, which is 5S,18-dihydroxyeicosapentaenoic acid, stopped zymosan-induced PMN infiltration, displaying potent anti-inflammatory properties in murine peritonitis (Tjonahen et al., 2006). In addition, RvE1 and RvE2, when given together, displayed additive action in controlling PMN infiltration. These results demonstrate that RvE2, together with RvE1, may contribute to the beneficial actions of ω-3 fatty acids in human diseases. Moreover, they indicate that the 5-LOX, in human leukocytes, is a pivotal enzyme that is temporally and spatially regulated in vivo to produce either pro- or anti-inflammatory local chemical mediators.

Resolvins of the E-series comprise several molecules. Among them, RvE1 was the first isolated and studied in depth. RvE1 displayed potent stereoselective actions in vivo and with isolated cells.
At nanomolar levels in vitro, RvE1 dramatically reduced

  1. human PMN transendothelial migration,
  2. dendritic cell (DC) migration and
  3. interleukin (IL)-12 production
    (Serhan et al., 2002Arita et al., 2005a).

These new findings provide evidence for

  • endogenous mechanism(s) that may account for some of the widely touted beneficial actions noted with dietary supplementation with ω-3 PUFA (EPA and DHA),
  • thereby providing new approaches for the treatment of gastrointestinal mucosal and oral inflammation.

The new families of EPA- and DHA-derived chemical mediators, namely the resolvins and protectins, qualify as ‘resolution agonists’ along with the n−6 derived agonists of resolution, the LX, in this new arena of immunomodulation and tissue protection. These are conserved structures in evolution, because rainbow trout biosynthesize resolvins and protectins, which are present in their neural and hematopoietic tissues (Hong et al., 2005). Their functional roles in fish and lower phyla remain to be established, but are likely to involve

  1. cell trafficking,
  2. motility and
  3. protection.

Additionally, they now open new avenues to design ‘resolution-targeted’-based therapies where aberrant uncontrolled inflammation and/or impaired resolution are components of the disease pathophysiology.

Lipoxin A4 Regulates Natural Killer Cell and Type 2 Innate Lymphoid Cell Activation in Asthma
C Barnig, M Cernadas, S Dutile,…BR Levy.
Sci Transl Med 27 Feb 2013: 5(174) 174ra26   http://dx.doi.org/10.1126/scitranslmed.3004812   http://www.scitranslmed.com//LipoxinA4_Regulates_Natural_Killer_Cell_and_Type2_Innate_Lymphoid_Cell_Activation_in_Asthma/


Asthma is a prevalent disease of chronic inflammation in which endogenous counterregulatory signaling pathways are dysregulated. Recent evidence suggests that innate lymphoid cells (ILCs), including natural killer (NK) cells and type 2 ILCs (ILC2s), can participate in the regulation of allergic airway responses, in particular airway mucosal inflammation.
Both NK cells and ILC2s expressed

Lipoxin A4, a natural pro-resolving ligand for ALX/FPR2 receptors, significantly

Together, these findings indicate that ILCs are targets for lipoxin A4 to decrease airway inflammation and mediate the catabasis of eosinophilic inflammation

Neutrophil granulocyte migrates from the blood...

Neutrophil granulocyte migrates from the blood vessel to the matrix, sensing proteolytic enzymes, in order to determine intercellular connections (to the improvement of its mobility) and envelop bacteria through Phagocytosis. (Photo credit: Wikipedia)

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Approach to Controlling Pathogenic Inflammation in Arthritis

Curator: Larry H Bernstein, MD, FCAP

A network approach to controlling pathogenic inflammation: Sequence sharing pattern peptides downregulate experimental arthritis

a new approach to network regulation of inflammation based on

Chai Ezerzer, Raanan Margalit and Irun R. Cohen

Aberrant inflammation probably results from aberrant regulation of the molecules that mediate inflammation; the actual molecules mediating inflammation –

  • chemokines,
  • cytokines, and
  • growth factors and their receptors –
    • would appear to be normal in their chemical structure.

If faulty regulation is indeed the problem,

  • a reasonable approach to alleviating inflammatory diseases might be to influence the interactions
  • within the network of connectivity of the disease-associated proteins (DAPs).
Aberrant inflammation appears to be a pathogenic factor in autoimmune diseases and other noxious inflammatory
conditions in which the inflammatory process
  1. is misapplied,
  2. exaggerated,
  3. recurrent or chronic.
The protein molecules involved in pathogenic inflammation—
disease-associated proteins (DAP )
  1. chemokines,
  2. cytokines, and
  3. growth factors and their receptors,
  • appear normal; their networks of interaction are at fault.

These researchers asked the question – 

  • whether shared amino acid sequence motifs among DAPs
  • might identify novel peptide treatments for regulating inflammation.

We aligned the sequences of 37 DAPs previously discovered to be associated with arthritis

  • to uncover shared sequence motifs.

We focused on chemokine receptor molecules because

  • chemokines and chemokine receptors play important roles in directing the migration of inflammatory cells into sites of tissue inflammation.
  •  different chemokine receptors shared amino acid sequence motifs in their extra-cellular loop domains (ECL2);
  • the ECL2 loop is outside of the known ligand binding site.

These shared sequence motifs established what we term a sequence-sharing network (SSN). SSN motifs exhibited very low E-values,

  • indicating their preservation during evolution.
This study demonstrates a new
  • approach to network regulation of inflammation based on peptide sequence motifs
  • shared by the second extra-cellular loop (EC L2) of different chemokine receptors;
  • previously known chemokine receptor binding sites have not involved the EC L2 loop.
These motifs of 9 amino acids, which were detected by sequence alignment, manifest very low E-values
  • compared with slightly modified sequence variations,
  • indicating that they were not likely to have evolved by chance.
To test whether this shared sequence network (SSN) might serve a regulatory function,
  • theysynthesized 9-amino acid SSN peptides from the EC L2 loops of three different chemokine receptors.
Theye administered these peptides to rats during the
Two of the peptides significantly downregulated the arthritis; one of the peptides
  • synergized with non-specific anti-inflammatory treatment with dexamethasone.
These findings suggest that
  • the SSN peptide motif reported here is likely to have adaptive value in controlling inflammation.
  • detection of SSN motif peptides could provide a network-based approach to immune modulation.
administering a highly connected chemokine receptor peptide motif , as done here, induced
  • the downregulation of inflammation in a rat model of arthritis.
Thus, study of the SSN provides a new network approach toward modulating inflammation
English: Typical chemokine receptor structure ...

English: Typical chemokine receptor structure showing seven transmembrane domains and a chanracteristic “DRY” motif in the second intracelluar domain. (Photo credit: Wikipedia)

Structure of Chemokines

Structure of Chemokines (Photo credit: Wikipedia)

Chemokine receptor

Chemokine receptor (Photo credit: Wikipedia)

 

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