title: NADPH oxidase inhibition ameliorates Trypanosoma cruzi-induced myocarditis during Chagas disease.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Center for Tropical Diseases, University of Texas Medical Branch, Galveston, TX 77555-1070, USA.
authors.forename: Monisha
authors.initials: M
authors.lastname: Dhiman
authors.forename: Nisha Jain
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D049108:Cell Enlargement; D002598:Chagas Cardiomyopathy / Q000201:enzymology* / Q000469:parasitology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006321:Heart / Q000469:parasitology; D006790:Host-Parasite Interactions; D006984:Hypertrophy; D008297:Male; D051379:Mice; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000469:parasitology / Q000473:pathology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors*; D059208:Parasite Load; D017382:Reactive Oxygen Species / Q000378:metabolism; D020239:Receptor Cross-Talk; D013154:Spleen / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D013601:T-Lymphocytes / Q000469:parasitology / Q000473:pathology; D014349:Trypanosoma cruzi / Q000502:physiology*
chemical_list: D016207:Cytokines; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases