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Archive for the ‘inflammation independent of lipid levels’ Category


The Promise of Low-Dose Aspirin on Longevity in the Geriatric Population: No Effect on Outcomes in the US and Australia

Reporter: Aviva Lev-Ari, PhD, RN

UPDATED on 10/17/2018

https://www.nejm.org/doi/full/10.1056/NEJMoa1800722

Effect of Aspirin on Disability-free Survival in the Elderly

ORIGINAL ARTICLE

Effect of Aspirin on Disability-free Survival in the Healthy Elderly

J.J. McNeil and Others

    

McNeil et al. conducted the randomized, placebo-controlled Aspirin in Reducing Events in the Elderly (ASPREE) trial to investigate whether the daily use of aspirin, at a dose of 100 mg, in healthy, community-dwelling older adults would prolong a healthy life span, free from dementia and persistent physical disability. Trial participants were community-dwelling men and women from Australia and the United States who were 70 years of age or older (or ≥65 years of age among blacks and Hispanics in the United States).

Clinical Pearls

  Is there any evidence to support the use of aspirin for primary prevention of cardiovascular or other chronic disease in healthy older adults?

Several large, randomized trials have shown the efficacy of aspirin for the secondary prevention of cardiovascular disease among persons with a history of coronary heart disease or stroke. The evidence supporting a benefit of aspirin therapy in the primary prevention of cardiovascular or other chronic disease is less conclusive despite favorable trends suggesting that aspirin use reduces the incidence of cardiovascular events and possibly reduces the incidence of cancer and cancer-related mortality, particularly from colorectal cancer.

  Does the daily use of 100 mg of aspirin prolong a healthy lifespan in older adults without cardiovascular disease, dementia, or physical disability?

In the ASPREE trial, the daily use of 100 mg of enteric-coated aspirin did not differ significantly from placebo in influencing the rates of disability-free survival at a median of 4.7 years. The primary end point of death, dementia, or physical disability occurred in 921 participants in the aspirin group (21.5 events per 1000 person-years) and in 914 in the placebo group (21.2 events per 1000 person-years). The between-group difference was not significant (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11; P=0.79). Among participants who had a primary end-point event, death was the most common first event (in 911 participants [50% of the events] at a mean age of 77.5 years), dementia was the next most common (in 549 participants [30% of the events] at a mean age of 77.7 years), and persistent physical disability was the least common.

Morning Report Questions

Q. How does a daily aspirin dose of 100 mg influence rates of death from any cause and the risk of major hemorrhage in healthy older adults?

A. In the ASPREE trial, the secondary end point of death from any cause, denoting death as the first, second, or third event to occur in the primary end point, occurred in 558 participants in the aspirin group (12.7 events per 1000 person-years) and in 494 participants in the placebo group (11.1 events per 1000 person-years) (hazard ratio, 1.14; unadjusted 95% CI, 1.01 to 1.29). Because there was no adjustment for multiple comparisons of secondary end points, no inferences can be made regarding differences in mortality between the two groups. Major hemorrhage occurred in 3.8% of the participants in the aspirin group, as compared with 2.8% of those in the placebo group (hazard ratio, 1.38; 95% CI, 1.18 to 1.62; P<0.001). Fatal or nonfatal hemorrhagic stroke (including subarachnoid hemorrhage) occurred in 49 participants (0.5%) in the aspirin group and in 40 (0.4%) in the placebo group.

Q. How generalizable are the results of the ASPREE trial?

A. White participants comprised 91% of the overall trial cohort. Owing to the small number of blacks and Hispanics (including participants who were younger than 70 years of age) and other nonwhites, the applicability of the main findings of the ASPREE trial to these subgroups is unclear.

 

Daily Low-Dose Aspirin Found to Have No Effect on Healthy Life Span in Older People?

According to 3 articles published online The New England Journal of Medicine (16 September 2018), daily low-dose aspirin was found to have no effect on healthy life span in older people. This large NIH-funded study examined outcomes in United States and Australia

Results showed that in a large clinical trial to determine the risks and benefits of daily low-dose aspirin in healthy older adults without previous cardiovascular events,

Aspirin did not prolong healthy, independent living (life free of dementia or persistent physical disability).

Risk of dying from a range of causes, including cancer and heart disease, varied and will require further analysis and additional follow-up of study participants. These initial findings from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, partially supported by the National Institutes of Health.

ASPREE is an international, randomized, double-blind, placebo-controlled trial that enrolled 19,114 older people (16,703 in Australia and 2,411 in the United States). The study began in 2010 and enrolled participants aged 70 and older; 65 was the minimum age of entry for African-American and Hispanic individuals in the United States because of their higher risk for dementia and cardiovascular disease. At study enrollment, ASPREE participants could not have dementia or a physical disability and had to be free of medical conditions requiring aspirin use. They were followed for an average of 4.7 years to determine outcomes.

In the total study population, treatment with 100 mg of low-dose aspirin per day did not affect survival free of dementia or disability. Among the people randomly assigned to take aspirin,

  • 90.3% remained alive at the end of the treatment without persistent physical disability or dementia, compared with 90.5% of those taking a placebo.
  • Rates of physical disability were similar, and rates of dementia were almost identical in both groups. However,
  • the group taking aspirin had an increased risk of death compared to the placebo group: 5.9% of participants taking aspirin and 5.2% taking placebo died during the study.

This effect of aspirin has not been noted in previous studies; and caution is needed in interpreting this finding. The higher death rate in the aspirin-treated group was due primarily to a higher rate of cancer deaths. A small increase in new cancer cases was reported in the group taking aspirin but the difference could have been due to chance. The authors also analyzed the ASPREE results to determine whether cardiovascular events took place. They found that

  • the rates for major cardiovascular events — including coronary heart disease, nonfatal heart attacks, and fatal and nonfatal ischemic stroke — were similar in the aspirin and the placebo groups. In the aspirin group, 448 people experienced cardiovascular events, compared with 474 people in the placebo group.

Significant bleeding — a known risk of regular aspirin use — was also measured. The authors noted that

  • aspirin was associated with a significantly increased risk of bleeding, primarily in the gastrointestinal tract and brain. Clinically significant bleeding — hemorrhagic stroke, bleeding in the brain, gastrointestinal hemorrhages or hemorrhages at other sites that required transfusion or hospitalization — occurred in 361 people (3.8%) on aspirin and in 265 (2.7%) taking the placebo.
  • As would be expected in an older adult population, cancer was a common cause of death, and 50% of the people who died in the trial had some type of cancer.
  • Heart disease and stroke accounted for 19% of the deaths and major bleeding for 5%.

The ASPREE team is continuing to analyze the results of this study and has implemented plans for monitoring participants. As these efforts continue, the authors emphasized that older adults should follow the advice from their own physicians about daily aspirin use. It is important to note that the new findings do not apply to people with a proven indication for aspirin such as stroke, heart attack or other cardiovascular disease. In addition, the study did not address aspirin’s effects in people younger than age 65. Also, since only 11% of participants had regularly taken low-dose aspirin prior to entering the study, the implications of ASPREE’s findings need further investigation to determine whether healthy older people who have been regularly using aspirin for disease prevention should continue or discontinue use.

SOURCE

From: OnTarget <ontarget@targethealth.com>

Date: September 23, 2018 at 10:47:06 PM EDT

To: avivalev-ari@alum.berkeley.edu

Subject: OnTarget Newsletter

 

Other 121 articles on ASPIRIN were published in this Open Access Online Scientific Journal, including the following:

https://pharmaceuticalintelligence.com/?s=Aspirin

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A new mechanism of action to attack in the treatment of coronary artery disease (CAD), Novartis developed Ilaris (canakinumab), a human monoclonal antibody targeting the interleukin-1beta innate immunity pathway

Reporter: Aviva Lev-Ari, PhD, RN

 

Speaking at an ESC press briefing, Ridker said, “This is what personalized predictive medicine is all about.” Once a patient has experienced an MI, there is always residual risk of recurrence. Thus, he suggested that residual risk can be divided into

  • residual lipid-driven risk and
  • residual inflammatory-driven risk.

canakinumab might prove to be most useful if it were given to an identified high-responder group. Findings in the hs-CRP responders:

Patients whose hs-CRP declined to 1.8 mg/L or less had a much more robust response. In that subgroup, the number needed to treat to prevent a primary endpoint event was 50 at 2 years and 30 at 3.7 years.

He noted that after a single injection responders have a significant reduction in highly sensitive-CRP and it is those patients who would benefit from continuing on treatment.

“Maybe that first dose could be free,” Ridker added.

Co-investigator, Peter Libby, MD, of Massachusetts General Hospital, put it this way: 30 days after an MI, when a patient is on statin therapy and stable,

  • physicians could check LDL and then initiate more aggressive statin therapy if it is not well-controlled. Similarly,
  • physicians should check hs-CRP, and if it is elevated — 2.0 mg/L or higher — initiating anti-inflammatory therapy targeting interleukin-1 beta would be an option

Interestingly, the treatment had no effect on lipids, which suggests that the benefit was all attributable to the anti-inflammatory activity. 

In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), 150 mg of canakinumab every 3 months reduced high-sensitivity C-reactive protein (hs-CRP) levels by an average of 37% compared with placebo and achieved a 15% reduction in cardiovascular events — mostly MIs — compared with placebo, Paul Ridker, MD, reported here at the European Society of Cardiology 2017 congress.

The CANTOS findings were simultaneously published online by the New England Journal of Medicine.

After a median follow-up of 3.7 years, the event rate was 4.5 per 100 person-years in the placebo group versus 3.86 events per 100 person-years in the canakinumab 150 mg group. Two other arms — canakinumab 50 mg and 300 mg — also achieved reductions in events (4.11 and 3.90 per 100 person-years, respectively) but only the 150-mg dose achieved a statistically significant reduction.

There was no reduction in mortality. The trial recruited patients who had a history of MI and a hs-CRP level of 2.0 mg/L or higher.

  • There was no significant difference in all-cause mortality (HR for all canakinumab doses versus placebo, 0.94; 95% CI 0.83-1.06; P=0.31).

Benefits of Anti-inflammatory Canakinumab

although there was no cardiovascular mortality benefit, there was 30% reduction in need for bypass surgery, angioplasty, and heart failure — all of which means a significant improvement in quality of life. And treatment was also associated with a reduction in gout, rheumatoid arthritis, and osteoarthritis, he said.

Cancer Benefit

There was an apparent decrease in risk of cancer, a finding that was elucidated in a Lancet paper also published today. In the cancer analysis, also authored by Ridker, total cancer mortality was lower only in the 300-mg group, but “[i]ncident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0.61 [95% CI 0.39–0.97]; P=0.034) and 300 mg groups (HR 0.33 [95% CI 0.18–0.59] P<0.0001.”

Negative findings

  • Canakinumab was associated with a higher incidence of fatal infection than placebo — the rate was 0.18 in the 3,344 patient placebo group versus 0.32 among the 6,717 patients who received any dose of the drug, which worked out to 23 deaths versus 78 deaths (P=0.02).
  • VIEW VIDEO

Study Author Paul M. Ridker. Interviewed by Peggy Peck, Editor-in-Chief of MedPage Today

https://www.medpagetoday.com/meetingcoverage/esc/67529

  • VIEW VIDEO

Clinical Impact or No Clinical Impact

Anthony DeMaria, MD discusses the major trials from ESC and what impact, if any, they will have on clinical practice.
Benefit vs Price
On June 28 heart failure specialist Milton Packer, MD, wrote this in his MedPage Today blog: “My prediction: [canakinumab] may cost $64,000 for a 15-20% reduction in the risk of a major cardiovascular event, without decreasing cardiovascular death by itself.
Amgen’s Repatha (evolocumab) is a PCSK9 inhibitor that aggressively lowers lipids and is approved for patients who fail statin therapy, including patients with heterozygous or homozygous familial hypercholesterolemia. But while the lipid reductions with the PCSK9 therapy are impressive, and the FOURIER trial found a 15% reduction in events with treatment, neither evolocumab nor alirocumab (Praluent), a PCSK9 inhibitor from Sanofi/Regeneron have achieved wide uptake as payers balk at the high price tags for the drugs.
Other anti-inflammatory agents:
Ridker said. For example, “we have a [National Heart, Lung, and Blood Institute] trial of methotrexate (RA agent) that is on-going. If that proves to be effective, it would be only pennies per treatment.” At the press conference, Ridker said the methotrexate trial has “randomized about 4,000 patients, and we will need to get to 7,000 so it will be a few years before we have results.”

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/67529

176 articles on monoclonal antibody

https://pharmaceuticalintelligence.com/?s=monoclonal+antibody

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 Cholesterol Lowering Novel PCSK9 drugs: Praluent [Sanofi and Regeneron] vs Repatha [Amgen] – which drug cuts CV risks enough to make it cost-effective?

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 11/13/2018

ODYSSEY OUTCOMES: Alirocumab Cost-effective at $6000 a Year

Marlene Busko

November 11, 2018

CHICAGO — Treatment with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab (Praluent, Sanofi/Regeneron) is cost-effective at $6319 a year when the willingness-to-pay threshold is the generally accepted $100,000 per quality-adjusted life-year (QALY), new research reports.

Deepak L. Bhatt, MD, MPH, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, Boston, Massachusetts, presented these cost-effectiveness findings for alirocumab, based on data from the ODYSSEY OUTCOMES trial, here at the American Heart Association (AHA) 2018 Scientific Sessions

As previously reported, results from ODYSSEY OUTCOMES were presented at American College of Cardiology (ACC) 2018 Annual Scientific Session in March and the study was published November 7 in the New England Journal of Medicine.

Strengths of the current cost analysis include that it used actual trial data as opposed to modeling estimates, Bhatt pointed out to theheart.org | Medscape Cardiology.

SOURCE

https://www.medscape.com/viewarticle/904744?nlid=126063_3866&src=WNL_mdplsfeat_181113_mscpedit_card&uac=93761AJ&spon=2&impID=1799507&faf=1

 

Did Amgen’s Repatha cut CV risks enough to make it cost-effective? Analysts say no

Sanofi, Regeneron’s Praluent pulls off PCSK9 coup with 29% cut to death risks in most vulnerable patients
SEE our curations on PCSK9 drugs:

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ODYSSEY Outcomes trial evaluating the effects of a PCSK9 inhibitor, alirocumab, on major cardiovascular events in patients with an acute coronary syndrome to be presented at the American College of Cardiology meeting on March 10.

Reporter: Aviva Lev-Ari, PhD, RN

 

For PCSK9 inhibitors, the effect on major adverse cardiovascular events has always fallen short of expectations based on cholesterol lowering.

But cardiovascular risk reduction is complicated. There is more to the puzzle than cholesterol. Some drugs lower both cholesterol and prevent cardiovascular events, but some people think that the two effects are actually not that closely related.

Milton Packer MD

https://www.medpagetoday.com/blogs/revolutionandrevelation/71435

In a previous trial (FOURIER), another PCSK9 inhibitor had only a modest benefit on its primary endpoint, and it did not reduce cardiovascular death, although the magnitude of cholesterol lowering was striking.

In another trial (SPIRE), a third PCSK9 inhibitor, the clinical trial was terminated prematurely by Pfizer because of reduction of the effect of the drug (a humanized but not fully humanized antibody) due to development of neutralizing antibodies in some of the patients. Actually, in patients treated for more than a year who did not develop neutralizing antibodies, a beneficial effect was seen.

The ODYSSEY Outcomes trial is evaluating the effects of a PCSK9 inhibitor,alirocumab, on major cardiovascular events in patients with an acute coronary syndrome within the prior year. The drug lowers serum cholesterol dramatically, and some are hopeful that that effect will translate into an important reduction in the risk of major adverse cardiovascular events. If you believe that cholesterol reduction inevitably leads to the prevention of cardiovascular death, myocardial infarction and stroke, then you would have high expectations for the ODYSSEY trial.

ODYSSEY. The trial uses a somewhat more aggressive treatment strategy and has a longer follow-up period than its predecessors. So maybe the benefit will be large. Maybe the drug will even reduce cardiovascular death or all-cause mortality.

In order to enrich the population for cardiovascular events, the trial enrolled patients with an acute coronary syndrome within the prior year. These patients are at high risk of having a recurrence. The problem is that risk is not necessarily related to changes in cholesterol, especially the events occurring early in the trial. And in this type of trial, the analysis tends to give extra weight to early events.

Trials like ODYSSEY are often designed to stop early if the results are unbelievably impressive. The ODYSSEY trial wasn’t stopped early.

the patients entering the ODYSSEY trial are starting out with a serum LDL <100 mg/dL or even <90 mg/dL. Is cholesterol really playing an important role at that level, especially when compared with noncholesterol factors?

SOURCE

https://www.medpagetoday.com/blogs/revolutionandrevelation/71435

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Long-term Canakinumab Treatment Lowering Inflammation Independent of Lipid Levels for Residual Inflammatory Risk Benefit – Personalized Medicine for Recurrent MI, Strokes and Cardiovascular Death

Reporter: Aviva Lev-Ari, PhD, RN

 

SEE UPDATE 4/6/2018

A new mechanism of action to attack in the treatment of coronary artery disease (CAD), Novartis developed Ilaris (canakinumab), a human monoclonal antibody targeting the interleukin-1beta innate immunity pathway

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/04/06/a-new-mechanism-of-action-to-attack-in-the-treatment-of-coronary-artery-disease-cad-novartis-developed-ilaris-canakinumab-a-human-monoclonal-antibody-targeting-the-interleukin-1beta-innate-i/

Major findings from the trial were presented earlier this year. The trial was designed to test whether canakinumab, which lowers inflammation independent of lipid levels, could reduce risk of a future cardiovascular event by reducing inflammation among people who have had a prior heart attack and who have persistently elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) despite aggressive care.

Overall, the trial found a 15 percent reduction in risk of recurrent heart attacks, strokes and cardiovascular death among participants who received canakinumab at doses of either 150 or 300 milligrams given once every three months.

SOURCE

https://hms.harvard.edu/news/banishing-inflammation?utm_source=linkedin&utm_medium=social&utm_campaign=hms-linkedin-general

 

Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial

Prof Paul M Ridker, MD'Correspondence information about the author Prof Paul M Ridker

,

Jean G MacFadyen, BA

,

Brendan M Everett, MD

,

Prof Peter Libby, MD

,

Tom Thuren, MD

,

Prof Robert J Glynn, PhD

on behalf of the

Findings

Baseline clinical characteristics did not define patient groups with greater or lesser cardiovascular benefits when treated with canakinumab. However, trial participants allocated to canakinumab who achieved hsCRP concentrations less than 2 mg/L had a 25% reduction in major adverse cardiovascular events (multivariable adjusted hazard ratio [HRadj]=0·75, 95% CI 0·66–0·85, p<0·0001), whereas no significant benefit was observed among those with on-treatment hsCRP concentrations of 2 mg/L or above (HRadj=0·90, 0·79–1·02, p=0·11). For those treated with canakinumab who achieved on-treatment hsCRP concentrations less than 2 mg/L, cardiovascular mortality (HRadj=0·69, 95% CI 0·56–0·85, p=0·0004) and all-cause mortality (HRadj=0·69, 0·58–0·81, p<0·0001) were both reduced by 31%, whereas no significant reduction in these endpoints was observed among those treated with canakinumab who achieved hsCRP concentrations of 2 mg/L or above. Similar differential effects were found in analyses of the trial prespecified secondary cardiovascular endpoint (which additionally included hospitalisation for unstable angina requiring unplanned revascularisation) and in sensitivity analyses alternatively based on median reductions in hsCRP, on 50% or greater reductions in hsCRP, on the median percent reduction in hsCRP, in dose-specific analyses, and in analyses using a causal inference approach to estimate the effect of treatment among individuals who would achieve a targeted hsCRP concentration.

Interpretation

The magnitude of hsCRP reduction following a single dose of canakinumab might provide a simple clinical method to identify individuals most likely to accrue the largest benefit from continued treatment. These data further suggest that lower is better for inflammation reduction with canakinumab.

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Cigarette smoke induces pro-inflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase as seen in macrophages

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Abbreviations:

Chronic obstructive pulmonary disease (COPD)

Reactive oxygen species (ROS)

Hydroxyl radicals (·OH)

Glutathione (GSH)

Histone deacetylase (HDAC)

TNF (Tumour necrosis factor)

IκB kinase complex (IKK)

Interleukin (IL)

Cigarette smoking is the major etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), which is characterized by an abnormal inflammatory response in the lungs to cigarette smoke with a progressive and irreversible airflow limitation. Chronic airway inflammation is an archetypal feature of COPD, and increased oxidative stress has been suggested to be responsible for triggering inflammatory events observed within the lungs of smokers and COPD patients. Although the precise mechanisms behind the pathogenesis of COPD are yet to be fully dissected, the current hypothesis suggests that cigarette smoke causes airway inflammation by activating macrophages, neutrophils, and T lymphocytes, which release proteases and reactive oxygen species (ROS) leading to cellular injury. As a consequence, chronic inflammatory processes are triggered that lead to small airway obstruction. An increased oxidant burden in smokers may be derived from the fact that cigarette smoke contains an estimated 1017 oxidants/free radicals and 4,700 chemical compounds, including reactive aldehydes (carbonyls) and quinones, per puff. Many of these are relatively long-lived, such as tar-semiquinone, which can generate hydroxyl radicals (·OH) and H2O2 by the Fenton reaction. One consequence of this increased oxidative stress is activation of redox-sensitive transcription factors, such as NF-κB and activator protein-1 (AP-1), which are critical to transcription of proinflammatory genes (IL-8, IL-6, and TNF-α). However, the precise transcriptional mechanisms leading to enhanced gene expression in response to cigarette smoke are still not clearly understood.

Cigarette smoke-mediated oxidative stress induces an inflammatory response in the lungs by stimulating the release of proinflammatory cytokines. Chromatin remodeling due to histone acetylation and deacetylation is known to play an important role in transcriptional regulation of proinflammatory genes. The aim of this study was to investigate the molecular mechanism(s) of inflammatory responses caused by cigarette smoke extract (CSE) in the human macrophage-like cell line MonoMac6 and whether the treatment of these cells with the antioxidant glutathione (GSH) monoethyl ester, or modulation of the thioredoxin redox system, can attenuate cigarette smoke-mediated IL-8 release. Exposure of MonoMac6 cells to CSE (1% and 2.5%) increased IL-8 and TNF-alpha production vs. control at 24 h and was associated with significant depletion of GSH levels associated with increased reactive oxygen species release in addition to activation of NF-kappaB. Inhibition of IKK ablated the CSE-mediated IL-8 release, suggesting that this process is dependent on theNF-kappaB pathway. CSE also reduced histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein levels. This was associated with posttranslational modification of HDAC1, HDAC2, and HDAC3 protein by nitrotyrosine and aldehyde-adduct formation. Pretreatment of cells with GSH monoethyl ester, but not thioredoxin/thioredoxin reductase, reversed cigarette smoke-induced reduction in HDAC levels and significantly inhibited IL-8 release. Thus cigarette smoke-induced release of IL-8 is associated with activation of NF-kappaB via IKK and reduction in HDAC levels/activity in macrophages. Moreover, cigarette smoke-mediated proinflammatory events are regulated by the redox status of the cells.

Source References:

http://ajplung.physiology.org/content/291/1/L46.long

http://carcin.oxfordjournals.org/content/23/9/1511.abstract?ijkey=3ea9eff65782ab8153fac166b1d85336efb795b8&keytype2=tf_ipsecsha

http://www.ncbi.nlm.nih.gov/pubmed/101105?dopt=Abstract

http://www.sciencemag.org/content/293/5535/1653.abstract?ijkey=cde39cb6af6142beff66405c8aed965e998d48c1&keytype2=tf_ipsecsha

http://www.ncbi.nlm.nih.gov/pubmed/8319604?dopt=Abstract

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