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Pirfenidone Prevents Heart Fibrosis during Chronic Chagas Disease Cardiomyopathy
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Pirfenidone Prevents Heart Fibrosis during Chronic Chagas Disease Cardiomyopathy
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Journal Article
Pirfenidone Prevents Heart Fibrosis during Chronic Chagas Disease Cardiomyopathy
2024
Overview
Cardiac fibrosis is a severe outcome of Chagas disease (CD), caused by the protozoan Trypanosoma cruzi. Clinical evidence revealed a correlation between fibrosis levels with impaired cardiac performance in CD patients. Therefore, we sought to analyze the effect of inhibitors of TGF-β (pirfenidone), p38-MAPK (losmapimod) and c-Jun (SP600125) on the modulation of collagen deposition in cardiac fibroblasts (CF) and in vivo models of T. cruzi chronic infection. Sirius Red/Fast Green dye was used to quantify both collagen expression and total protein amount, assessing cytotoxicity. The compounds were also used to treat C57/Bl6 mice chronically infected with T. cruzi, Brazil strain. We identified an anti-fibrotic effect in vitro for pirfenidone (TGF-β inhibitor, IC50 114.3 μM), losmapimod (p38 inhibitor, IC50 17.6 μM) and SP600125 (c-Jun inhibitor, IC50 3.9 μM). This effect was independent of CF proliferation since these compounds do not affect T. cruzi-induced host cell multiplication as measured by BrdU incorporation. Assays of chronic infection of mice with T. cruzi have shown a reduction in heart collagen by pirfenidone. These results propose a novel approach to fibrosis therapy in CD, with the prospect of repurposing pirfenidone to prevent the onset of ECM accumulation in the hearts of the patients.
Publisher
MDPI AG
Subject
/ Chagas Cardiomyopathy - drug therapy
/ Chagas Cardiomyopathy - metabolism
/ Chagas Cardiomyopathy - parasitology
/ Chagas Cardiomyopathy - pathology
/ Collagen
/ Fibrosis
/ Humans
/ Kinases
/ Male
/ Mice
/ p38 Mitogen-Activated Protein Kinases - metabolism
/ Protozoa
/ Transforming Growth Factor beta - metabolism
