Protective effect of ebselen on bleomycin-induced lung fibrosis: analysis of the molecular mechanism of lung fibrosis mediated by oxidized diacylglycerol

摘要

The molecular mechanisms underlying the development of pulmonary fibrosis remain unknown, and effective treatments have not yet been developed. It has been shown that oxidative stress is involved in lung fibrosis. Oxidized diacylglycerol (DAG) produced by oxidative stress is thought to play an important role in lung fibrosis. This study assessed the effect of oxidized DAG in an animal model of pulmonary fibrosis induced by aspiration of bleomycin (BLM) into the lungs. The inhibitory effect of ebselen on pulmonary fibrosis was also investigated. In lung fibrotic tissue induced by BLM, an increase in lipid peroxides and collagen accumulation was observed. Moreover, the levels of oxidized DAG, which has strong protein kinase C (PKC) activation activity, were significantly increased over time following the administration of BLM. Western blotting showed that phosphorylation of PKC alpha and delta isoforms was increased by BLM. Oral administration of ebselen significantly suppressed the increase in oxidized DAG induced by BLM and improved lung fibrosis. PKC alpha and delta phosphorylation were also significantly inhibited. The mRNA expression of alpha-smooth muscle actin and collagen I (marker molecules for fibrosis), as well as the production of transforming growth factor-beta and tumor necrosis factor-alpha(a potentially important factor in the fibrotic process), were increased by BLM and significantly decreased by ebselen. The administration of BLM may induce lipid peroxidation in lung tissue, while the oxidized DAG produced by BLM may induce overactivation of PKC alpha and delta, resulting in the induction of lung fibrosis.