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NADPH oxidase inhibition ameliorates Trypanosoma cruzi ‐induced myocarditis during Chagas disease
Author(s) -
Dhiman Monisha,
Garg Nisha Jain
Publication year - 2011
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2975
Subject(s) - apocynin , nadph oxidase , immunology , biology , chemistry , endocrinology , medicine , oxidative stress
Trypanosoma cruzi , the aetiological agent of Chagas disease, invades nucleated mammalian cells including macrophages. In this study, we investigated the crosstalk between T. cruzi ‐induced immune activation of reactive oxygen species (ROS) and pro‐inflammatory responses, and their role in myocardial pathology. Splenocytes of infected mice (C3H/HeN) responded to Tc ‐antigenic stimulus by more than a two‐fold increase in NADPH oxidase (NOX) activity, ROS generation, cytokine production (IFN‐γ > IL‐4 > TNFα > IL1‐β≈ IL6), and predominant expansion of CD4 + and CD8 + T cells. Inhibition of NOX, but not of myeloperoxidase and xanthine oxidase, controlled the ROS (>98%) and cytokine (70–89%) release by Tc ‐stimulated splenocytes of infected mice. Treatment of infected mice with apocynin (NOX inhibitor) in drinking water resulted in a 50–90% decline in endogenous NOX/ROS and cytokine levels, and splenic phagocytes' proliferation. The splenic percentage of T cells was maintained, though more than a 40% decline in splenic index (spleen weight/body weight) indicated decreased T‐cell proliferation in apocynin‐treated/infected mice. The blood and tissue parasite burden were significantly increased in apocynin‐treated/infected mice, yet acute myocarditis, ie inflammatory infiltrate consisting of macrophages, neutrophils, and CD8 + T cells, and tissue oxidative adducts (eg 8‐isoprostanes, 3‐nitrotyrosine, and 4‐hydroxynonenal) were diminished in apocynin‐treated/infected mice. Consequently, hypertrophy (increased cardiomyocytes' size and β‐ MHC, BNP , and ANP mRNA levels) and fibrosis (increased collagen, glycosaminoglycans, and lipid contents) of the heart during the chronic phase were controlled in apocynin‐treated mice. We conclude that NOX/ROS is a critical regulator of the splenic response (phagocytes, T cells, and cytokines) to T. cruzi infection, and bystander effects of heart‐infiltrating phagocytes and CD8 + T cells resulting in cardiac remodelling in chagasic mice. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.