Treinamento intervalado de alta intensidade atenua a inflamação hepática através da via de sinalização TLR4/NF-kB em ratas com hepatotoxicidade induzida por cisplatina

Abstract

Cisplatin (CP) is a chemotherapy agent widely used to treat various types of solid tumors. However, its lack of selectivity affects healthy cells, causing several cytotoxic effects, including hepatotoxicity. Although the underlying mechanisms of hepatotoxicity are not fully understood, evidence suggests a significant involvement of the inflammatory process in the exacerbation and progression of tissue damage. Recently, some studies have reported the hepatoprotective effects mediated by regular aerobic physical exercise. However, it is still unclear which intensity is most effective in enhancing these protective effects, especially in acute liver injuries. Therefore, this study aims to compare the impacts between preconditioning with high-intensity interval training (HIIT) and traditional continuous training of light (LIT) and moderate (MIT) intensities on inflammatory markers in Wistar rats with CP-induced hepatotoxicity. For this purpose, 35 Wistar female rats were divided into five groups (n=7 in each group): control and sedentary (C+S); treated with CP and sedentary (CP+S); treated with CP and subjected to LIT (CP+LIT); treated with CP and subjected to MIT (CP+MIT); and treated with CP and subjected to HIIT (CP+HIIT). The training protocols consisted of treadmill running, 5 days a week, for 8 weeks before the CP treatment. At the end of the 8-week training period, the rats received a single injection of CP (5 mg/kg i.p) or saline, and 7 days after the injection, they were euthanized. Liver samples were collected to evaluate the expression of nuclear factor kappa B (NF-κB), toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1α, IL-1β, IL-6, IL-8, and IL-10, the number of ED-1 positive cells, and M1 (iNOS) and M2 (arginase 1) macrophages markers in the hepatic tissue. Our results show that CP treatment promoted na increase in all pro-inflammatory markers, including TLR4/ NF-κB, pro-inflammatory cytokines, immunostaining of ED-1 positive cells, and expressions of M1 macrophage marker compared to the control group. However, HIIT was the most effective exercise protocol in reducing the increase in all these markes compared to LIT and MIT protocols. Additionally, preconditioning with HIIT potentiated the anti-inflammatory cytokine IL-10 and the M2 macrophage marker expressions, while reducing the expression of the M1 macrophage marker in liver. Thus, the present study suggests that physical preconditioning with HIIT was more effective in promoting hepatoprotective effects than LIT and MIT preconditioning protocols, regulating important inflammatory markers through modulation of the TLR4/NF-κB signaling pathway.