Inflammatory cells apoptosis

Inflammatory cytokines have been implicated in the pathophysiology of HF.9 Several proinflammatory (e.g., tumor necrosis factor-a [TNF-a], interleukin-1, interleukin-6, and interferon-y) and anti-inflammatory cytokines (e.g., interleukin-10) are overexpressed in the failing heart. The most is known about TNF-a, a pleiotrophic cytokine that acts as a negative inotrope, stimulates cardiac cell apoptosis, uncouples 3-adrenergic receptors from adenylyl cyclase, and is related to cardiac cachexia. The exact role of cytokines and inflammation in HF pathophysiology continues to be studied. 

The effect of MAPK activation on cellular processes that affect cell function and the resulting pharmacology has been delineated using modem techniques such as knock-out cells and animals [1,3,6]. Activation of MAPK in inflammatory cells such as T-cells, B-cells, macrophages and eosinophils leads to expression and/or activation of pro-inflammatory genes and mediators such as interleukin-1(3 (IL-1(3), TNFa, IL-6, chemokines [e.g., IL-8, macrophage inflammatory factor-1 a, (3 (MIP-la,[3)J, MMPs and toxic molecules such as free radicals and nitric oxide [1,3]. These pro-inflammatory mediators induce cellular proliferation, differentiation, survival, apoptosis and tissue degradation/destruction and help induce chronic inflammation. Inhibition of any one or more of the MAPK family... 

Bjorkemd, S., and Bjorkemd, B., 1996a, Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation ofgmel and plaque instability. Am J Pathol. 149 367-380. 

As mentioned previously, glucocorticoids promote apoptosis and reduce survival, differentiation, and proliferation of a number of inflammatory cells. While there is an increase in the number of polymorphonuclear leukocytes in the circulation, corticosteroids cause the involution and atrophy of all lymphoid tissue and decrease the number of circulating lymphocytes. The striking lymphocytopenia is caused in large part by an inhibition of lymphocyte proliferation, although diminished growth with preferential accumulation of cells in the Gi-phase of the cell cycle is followed by cell death. These effects are mainly mediated by alterations in cytokine production and action. 

Methotrexate s principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase, with secondary effects on polymorphonuclear chemotaxis. There is some effect on dihydrofolate reductase and this affects lymphocyte and macrophage function, but this is not its principal mechanism of action. Methotrexate has direct inhibitory effects on proliferation and stimulates apoptosis in immune-inflammatory cells. Additionally, inhibition of proinflammatory cytokines linked to rheumatoid synovitis has been shown, leading to decreased inflammation seen with rheumatoid arthritis. 

The discovery of apoptosis sheds a new light on the role of cell death in myocardial infarction and other cardiovascular diseases. There is mounting evidence that apoptosis plays an important role at multiple points in the evolution of myocardial infarction, and comprises not only cardiomyocytes but also inflammatory cells, as well as cells of granulation tissue and... 

During chronic inflammatory disease, inflammatory cells (neutrophils, mast cells, macrophages, and lymphocytes) become increasingly more damaging to tissues. Anti-inflammatory action of Bik reduces cell death mediated by immune cell. Proinflammatory cytokine tumor necrosis factor-a (TNF-q) and interleukin-1 (3 (IL-1) cause expression of multiple inflammatory and innate immunity genes for additional cytokines, chemokines, adhesion molecules, and enzymes. Aprotinin has been reported to cause a reduction in apoptosis in vivo by decreasing inflammatory cytokine expression (IL-1, IL-6, and TNF -a) thus preventing caspase-8 activation [81],... 

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