Feeds:
Posts
Comments

Posts Tagged ‘Plasma’


 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

Read Full Post »