title: Autophagy induction by celastrol augments protection against bleomycin-induced experimental pulmonary fibrosis in rats: Role of adaptor protein p62/ SQSTM1.
abstract: Pulmonary fibrosis (PF) is a chronic pulmonary disease of unknown cause with high mortality. Autophagy is an important homeostatic process that decides the fate of cells under stress conditions. 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 LC3I to LC3II suggesting induction of autophagy by celastrol provide protection against lung fibrosis. Further, we revealed that celastrol activates autophagy by inhibiting PI3K/Akt mediated mTOR expression. In addition, we show evidences that lack of autophagy leads to accumulation of p62, an autophagy adaptor protein 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.
authors.affiliation: Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, India.
authors.forename: Thomas
authors.initials: T
authors.lastname: Divya
authors.affiliation: Department of Biochemistry and Biotechnology, Central Leather Research Institute, Chennai, 600 020, India.
authors.forename: Anandasadagopan
authors.initials: A
authors.lastname: Sureshkumar
authors.affiliation: Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600 025, India. Electronic address: sudhandiran@yahoo.com.
authors.forename: Ganapasam
authors.initials: G
authors.lastname: Sudhandiran
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D001761:Bleomycin / Q000633:toxicity; D015153:Blotting, Western; D008297:Male; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D053978:Pentacyclic Triterpenes; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D000071456:Sequestosome-1 Protein / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D001761:Bleomycin; D053978:Pentacyclic Triterpenes; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000071456:Sequestosome-1 Protein; D058570:TOR Serine-Threonine Kinases; D014315:Triterpenes; C099718:SQSTM1 protein, human; C050414:celastrol
keywords: Autophagy; Bleomycin; Celastrol; Pulmonary fibrosis; mTOR; p62