Chemokine-endothelin interaction & Chagas' disease

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DESCRIPTION (provided by applicant) Chagas' disease, caused by Trypanosoma cruzi, is an important cause of heart disease in Brazil. The objective of this application is to continue the collaboration between the laboratories Brazil and in the US thereby enhancing the scientific capabilities of the Brazil site. This collaboration will improve our understanding of the events leading to cardiac damage in Chagas' disease. The primary cause of death in individuals with chronic chagasic cardiomyopathy is myocardial dysfunction and dilated cardiomyopathy. We demonstrated that the vasoactive peptide endothelin-1 (ET-1) contributes to the microvascular compromise that occurs early in Chagas' disease. Parasite invasion and the accompanying inflammatory process may result in the release of ET-1 from endothelial cells, cardiac fibroblasts and cardiac myocytes. Several studies have shown the ability of cytokines and chemokines to facilitate the release of ET-1. ET-1 may also activate different cell types to release mediators of the inflammatory process, including cytokines and chemokines. Therefore, not only can ET-1 induce the release of cytokines/chemokines but also these mediators influence its release. We hypothesize that the inflammation elicited in response to T. cruzi infection is characterized by the release of mediators, such as chemokines and ET-1, which in turn can induce and/or facilitate the release of each other. Based on our preliminary observations, we believe that the interaction between ET-1 and chemokines are relevant to control parasite growth, but also underlies the vascular compromise that occurs in the acute phase of the disease. Therefore, we plan to examine in the myocardium of T. cruzi infected rats: (A) the expression of ET-1, endothelin receptors, chemokines and chemokine receptors; (B) the effect of the inhibition of endothelin synthesis and/or endothelin receptor blockade on myocardial inflammation, chemokine expression and function; and (C) the effect of chemokine receptor blockade on tissue inflammation, ET-1, endothelin receptor expression and myocardial function. We hypothesize that markers of myocardial dysfunction accessible by simple blood measurements may be very useful in the diagnosis of the severity of heart dysfunction and follow-up of patients with chronic chagasic cardiomyopathy. We believe that determination of plasma or serum concentration of ET-1, in conjunction with the evaluation of chemokines, TNF-alpha and brain natriuretic factor, may be useful markers of the severity of heart dysfunction in chagasic patients. Therefore, we plan to evaluate the utility of plasma concentrations of ET-1 in predicting the severity of myocardial dysfunction with chronic Chagas' disease. The research will be performed primarily at the Brazil site in collaboration with Herbert Tanowitz at the US site as extension of NIH Grant AI-12770