Chemokine-endothelin interaction & Chagas' disease

描述(由申请人提供) 查加斯病是由克氏锥虫引起的，是巴西心脏病的重要原因。这项申请的目的是继续在巴西和美国的实验室之间开展合作，从而加强巴西站点的科学能力。这项合作将提高我们对导致查加斯病心脏损害的事件的理解。慢性心肌病患者的主要死亡原因是心肌功能障碍和扩张型心肌病。我们证明了血管活性多肽内皮素-1(ET-1)参与了Chagas病早期发生的微血管损害。寄生虫入侵和伴随的炎症过程可能导致内皮细胞、心脏成纤维细胞和心肌细胞释放ET-1。一些研究表明，细胞因子和趋化因子能够促进ET-1的释放。ET-1还可以激活不同类型的细胞来释放炎症过程的介质，包括细胞因子和趋化因子。因此，ET-1不仅可以诱导细胞因子/趋化因子的释放，而且这些介质也会影响其释放。我们推测，克氏毛滴虫感染后引起的炎症反应是以释放趋化因子和ET-1等介质为特征的，这些介质反过来可以诱导和/或促进彼此的释放。根据我们的初步观察，我们认为ET-1和趋化因子之间的相互作用与控制寄生虫的生长有关，但也是疾病急性期发生的血管妥协的基础。因此，我们计划在感染毛滴虫的大鼠心肌中检测：(A)ET-1、内皮素受体、趋化因子和趋化因子受体的表达；(B)抑制内皮素合成和/或阻断内皮素受体对心肌炎症、趋化因子表达和功能的影响；(C)趋化因子受体阻断对组织炎症、ET-1、内皮素受体表达和心肌功能的影响。我们推测，通过简单的血液测量可以获得心肌功能障碍的标志物，这可能对诊断慢性心肌病患者心脏功能障碍的严重程度和随访非常有用。我们认为，血浆或血清ET-1浓度的测定，结合趋化因子、肿瘤坏死因子-α和脑利钠因子的评估，可能是心绞痛患者心功能不全严重程度的有用标志。因此，我们计划评估血浆ET-1浓度在预测慢性Chagas病患者心肌功能障碍严重程度中的作用。这项研究将主要在巴西现场进行，与赫伯特·塔诺维茨在美国现场合作，作为NIH Grant AI-12770的延伸

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