Exploring the protective effects of Chrysin against bleomycin -induced lung injury and fibrosis : The role of autophagy and IL-33/ST2

Bleomycin is an effective antineoplastic agent. However, it induces lung fibrosis. Chrysin, a natural flavone, possesses multiple biological activities, such as antioxidant, anti-inflammatory and anti-cancer. This study investigated whether chrysin could protect against the devastating effect bleomycin on lung tissues and the underlying mechanism of this effect. Rats were treated with either bleomycin (15 mg/kg, i.p., 3 times per week for 4 weeks) and/or chrysin (50 mg/kg daily, starting one week before and until the end of the experiment). Markers of lung injury, oxidative stress, inflammation, autophagy, and the IL33/ST2 signaling pathway were assessed. Bleomycin significantly increased the levels of lactate dehydrogenase (LDH) and lipid peroxidation, and it significantly decreased mucin and glutathione compared to the control group. These effects were ameliorated by chrysin treatment. Histopathological analysis found evidence of severe pulmonary inflammation and increased levels of the inflammatory mediators, tumor necrosis factor-alpha, interleukin-6, and nuclear factor kappa-B (NF-κB) (p65). Fibrosis was evident by the increase in α-smooth muscle actin and transforming growth factor-β1 (TGF- β1). Inflammation and fibrosis were reduced in rats that received the chrysin treatment concurrent with bleomycin. In addition, autophagy was inhibited in the lung tissues of bleomycin-treated rats, as evidenced by the reduced expression of ATG4B and LC33. Furthermore, the IL-33/ST2 signaling pathway was activated by bleomycin and this effect was markedly attenuated by chrysin treatment. In conclusion, chrysin mitigated bleomycin-induced pulmonary fibrosis in rats, through its antioxidant and anti-inflammatory effect, as well as having an effect on autophagy and the IL-33/ST2 signaling pathway.