Autophagy induction by celastrol augments protection against bleomycin-induced experimental pulmonary fibrosis in rats: Role of adaptor protein p62/ SQSTM1

This study is aimed to investigate whether impaired autophagic activity leads to fibrosis and pharmacological induction of autophagy provides protection against bleomycin (BLM)-induced PF. A single dose of BLM (3 U/kg body weight) was administered intratracheally to induce fibrosis in rats. Celastrol, a triterpenoid (5 mg/kg/body weight, intraperitoneally) was given in every 81 h for a period of 28 days. Western blot and Confocal microscopic analysis of rat lung tissue samples revealed that celastrol induces autophagy in BLM-induced rats. Transmission electron microscopic analysis supports the above findings. Celastrol increased the expressions of Beclin 1 and Vps 34, promoted the up-regulation of Atg5-Atg12-16 formation and enhanced the lipidation of LC3-I to LC3-II suggesting induction of autophagy by celastrol provide protection against lung fibrosis. Further, we revealed that celastrol activates autophagy by inhibiting PI3-K/Akt mediated mTOR expression. In addition, we show evidences that lack of autophagy leads to p62, an autophagy adaptor protein accumulation that is degraded by celastrol. This study helps to describe the importance of autophagic cell death as a possible therapeutic target against lung fibrosis, and celastrol as a potential candidate for the treatment options for PF.
Source: Pulmonary Pharmacology and Therapeutics - Category: Respiratory Medicine Source Type: research