What monocytes may play a role in CHF by secreting inflammatory cytokines? What 3 cytokines may be secreted? What events may lead to the secretion of these cytokines?
Macrophages play a critical role in CHF by secretion of inflammatory cytokines TNFα, IL-1, and IL-6. These three cytokines are induced by “leaky gut syndrome” a condition in which endotoxins from bacteria enter through breaks in the intestinal wall. Also localized damage to myocardial tissue (acute myocardial infarction) or acute myocarditis (caused by viral infection for example) lead to accumulation of “activated” macrophages in cardiac tissue secreting inflammatory cytokines.
Through what receptors and in what tissues does TNFα exert its effects? What processes/diseases have TNFα been associated with?
TNFα exerts its effects via TNFα receptors (TNFR), which are expressed by almost all nucleated cells. TNFα has been implicated in the development of left ventricular dysfunction, increased cardiac myocyte apoptosis, the development of anorexia and cachexia, and reduced cardiac muscle blood flow and endothelial dysfunction.
Through what receptors and in what tissues does IL-6 exert its effects? What processes/diseases have IL-6 been associated with?
Increased concentrations of IL-6 have been shown in the circulation of CHF patients. IL-6 by binding to IL-6 receptor on myocytes produce myocyte hypertrophy, myocardial dysfunction, and muscle wasting.
Through what receptors and in what tissues does IL-1 exert its effects? What processes/diseases have IL-1 been associated with?
IL-1 has been demonstrated in the myocardium of patients with idiopathic dilated cardiomyopathy, and it depresses myocardial contractility in a dose dependent fashion. IL-1 has also been implicated in myocardial apoptosis, hypertrophy, and arrhythmogenesis.
One of the most telling signs of CHF is the increase in adhesion molecules known as? Where are these molecules located? Wht is their ligand? What cytokine increases the production of this molecule? What is the effect of the increased production of this molecule?
One of the most telling signs of CHF is the increase in adhesion molecules know as intercellular adhesion molecules (ICAM) on the endothelial cell wall of blood vessels lining the heart. ICAM is the ligand for LFA-1, which present on monocytes. TNF alpha leads to increased ICAM expression on endothelial cells. Binding of LFA-I on monocytes allows the macrophage precursor to enter between the endothelial cells of the blood vessel in a process know as diapedesis. Once below the endothelial cells, the monocytes and come into contact with connective tissue the monocytes become macrophages. Thus, monocyte infiltration allows for accumulation of activated macrophages within the cardiac tissue
Another consequence of macrophage presence is the production of NO. How is NO produced in macrophages? Why is it produced? What effects does NO have on myocytes?
Another consequence of macrophages presence is the production of nitric oxide. This is a lipophlic small molecular weight molecule, which has a very short half-life once it is produced. NO is produced within macrophages when arginine is catabolized by nitric oxide synthase in the presence of O2 to form citrulline and NO. NO together with reactive oxygen species superoxide anion to form peroxynitrite which is extmely toxic. Both NO and peroxynitrite are made by activated macrophages to deal a lethal blow to intracellular microorganism what inhabit macrophage vesicles. However, overproduction of NO and peroxynitrite presence leads to damaged myocytes and inhibit myocyte contractility.