High-intensity intermittent training ameliorates methotrexate-induced acute lung injury

Abstract

Inflammation and oxidative stress are recognized as two primary causes of lung damage induced by methotrexate, a drug used in the treatment of cancer and immunological diseases. This drug triggers the generation of oxidants, leading to lung injury. Given the antioxidant and anti-inflammatory effects of high-intensity intermittent training (HIIT), our aim was to evaluate the therapeutic potential of HIIT in mitigating methotrexate-induced lung damage in rats. Seventy male Wistar rats were randomly divided into five groups: CTL (Control), HIIT (High-intensity intermittent training), ALI (Acute Lung Injury), HIIT+ALI (pretreated with HIIT), and ALI + HIIT (treated with HIIT).HIIT sessions were conducted for 8 weeks. At the end of the study, assessments were made on malondialdehyde, total antioxidant capacity (TAC), superoxide dismutase (SOD), glutathione peroxidase (Gpx), myeloperoxidase (MPO), interleukin 10 (IL-10), tumor necrosis factor-alpha (TNF-α), gene expression of T-bet, GATA3, FOXP3, lung wet/dry weight ratio, pulmonary capillary permeability, apoptosis (Caspase-3), and histopathological indices.Methotrexate administration resulted in increased levels of TNF-α, MPO, GATA3, caspase-3, and pulmonary edema indices, while reducing the levels of TAC, SOD, Gpx, IL-10, T-bet, and FOXP3. Pretreatment and treatment with HIIT reduced the levels of oxidant and inflammatory factors, pulmonary edema, and other histopathological indicators. Concurrently, HIIT increased the levels of antioxidant and anti-inflammatory factors.

Keywords: Acute lung injury; High-intensity intermittent training; Inflammatory factors; Methotrexate; Mohammad Amin Rajizadeh, Mahdiyeh Haj Hosseini, Mina Bahrami, Faegheh Bahri and Fahimeh Rostamabadi equally contributed as first author.; Oxidative stress; Therapeutic effects.

Fig. 1

Timeline of animal Group and study design

Fig. 2

Effect of HIIT on (a) Wet/Dry lung weight ratio n = 7 in each group, (b); permeability of lung capillaries. Data are presented as mean ± SD for n = 5 in each group. * p < 0.05, * p < 0.01 and *** p < 0.001

Fig. 3

The Effect of HIIT on TNFα and IL-10 levels in lung tissue and BAL fluid. Data are presented as mean ± SD and n = 7 in each group. *P < 0.05 and ***P < 0.001 vs Con. ζζ P < 0.01 and ζζζ P < 0.001 vs ALI. ± P < 0.05 vs Post

Fig. 4

Effect of HIIT on (a), MPO, (b), Tbet mRNA expression, (c), FOXP3 mRNA expression, (d), GATA3 mRNA expression in lung tissue. Data are presented as mean ± SD for n = 7 in each group. * p < 0.05, * p < 0.01 and *** p < 0.001

Fig. 5

Effect of HIIT on (a); MDA, (b); TAC, (c); GPX, (d); SOD in lung tissue. Effect of CT on (e) MDA, (f); TAC, (g); Gpx, (h); SOD in BALF. Data are presented as mean ± SD for n = 7 in each group. * p < 0.05, * p < 0.01 and *** p < 0.001

Fig. 6

Effect of HIIT on microscopic presentation of Methotrexate-induced Acute Lung Injury in rats stained by hematoxylin and eosin (light microscopy, 10 X), a Control group, b High-intensity intermittent training group, c Acute Lung Injury group, d HIIT+ALI group, e ALI + HIIT group, f pathological changes score. Data are presented as mean ± SD for n = 7 in each group. * p < 0.05, * p < 0.01 and *** p < 0.001

Fig. 7

Immunohistochemical evaluation of the effect of HIIT on Caspase-3 expression (A-F) in lung tissue of rats. a Control group, b High-intensity intermittent training group, c Acute Lung Injury group, d HIIT+ALI group, e ALI + HIIT group, f Quantitative chart of expression of Active caspase-3 in lung tissue.* p < 0.05, ** p < 0.01, *** p < 0.001