Alleviation of chemotherapy-induced acute lung injury via NLRP3/ ASC/ Caspase-1 signaling pathway

Abstract

Acute lung injury has been reported following various chemotherapeutic agents administration. Several pathways for lung injury have been speculated however, the exact mechanism of the lung injury induced by methotrexate (MTX) is yet to be defined. The potential protective effect of Ginkgo biloba extract (GB), a Chinese herbal medicine, against MTX-induced lung injury is still not reported. Therefore, this study was performed to examine the possible implication of NLRP3 inflammasome and miRNA-21 in the pathogenesis of the MTX-induced lung injury as well as the protective role of GB in ameliorating the induced lung injury. Rats received GB (100 mg/kg/day, orally) for 10 days and MTX (20 mg/kg single dose, intraperitoneally) on the fifth day. MTX-induced lung injury was manifested by lung histopathology. MTX exhibited a marked increase in lung malondialdehyde beside a notable decrease in lung reduced glutathione. Moreover, MTX injection activated the lung NLRP3 inflammasome by significant upregulation of the NLRP3, ASC, caspase-1 lung mRNA expressions and protein levels in addition to lung NF-kBp65 protein expression, and miRNA-21 expression when compared with the normal control group. However, GB administration mitigated lung injury and inhibited the NLRP3 activation. This study is the first report to reveal the involvement of NLRP3 inflammasome in the pathogenesis of MTX-induced lung injury and also to show that the administration of GB alleviates the lung injury induced by MTX via suppressing the oxidative stress, restoring the antioxidant activity, blocking the NLRP3/ASC/Caspase-1 signaling and downregulating the NF-kBp65 protein expression ae well as miRNA-21 expression in lung tissue.

Keywords: ASC; Caspase-1; Ginkgo biloba extract; Lung injury; Methotrexate; NLRP3.