title: Celastrol enhances Nrf2 mediated antioxidant enzymes and exhibits anti-fibrotic effect through regulation of collagen production against bleomycin-induced pulmonary fibrosis.
abstract: Pulmonary fibrosis (PF) is characterized by excessive accumulation of extracellular matrix components in the alveolar region which distorts the normal lung architecture and impairs the respiratory function. The aim of this study is to evaluate the anti-fibrotic effect of celastrol, a quinine-methide tri-terpenoid mainly found in Thunder God Vine root extracts against bleomycin (BLM)-induced PF through the enhancement of antioxidant defense system. A single intratracheal instillation of BLM (3 U/kg.bw) was administered in rats to induce PF. Celastrol (5 mg/kg) was given intraperitoneally, twice a week for a period of 28 days. BLM-induced rats exhibits declined activities of enzymatic and non-enzymatic antioxidants which were restored upon treatment with celastrol. BLM-induced rats show increased total and differential cell counts as compared to control and celastrol treated rats. Histopathological analysis shows increased inflammation and alveolar damage; while assay of hydroxyproline and Masson's trichrome staining shows an increased collagen deposition in BLM-challenged rats that were decreased upon celastrol treatment. Celastrol also reduces inflammation in BLM-induced rats as evidenced by decrease in the expressions of mast cells, Tumor necrosis factor-alpha (TNF- α) and matrix metalloproteinases (MMPs) 2 and 9. Further, Western blot analysis shows that celastrol is a potent inducer of NF-E2-related factor 2 (Nrf2) and it restores the activities of Phase II enzymes such as hemoxygenase-1 (HO-1), glutathione-S-transferase (GSTs) and NADP(H): quinine oxidoreductase (NQO1) which were declined upon BLM administration. The results of this study show evidence on the protective effect of celastrol against BLM-induced PF through its antioxidant and anti-fibrotic effects.
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: Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, India.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Dineshbabu
authors.affiliation: Cell Biology Laboratory, Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600 025, India.
authors.forename: Syamala
authors.initials: S
authors.lastname: Soumyakrishnan
authors.affiliation: Department of Biochemistry, 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; D000975:Antioxidants / Q000378:metabolism*; D001761:Bleomycin / Q000494:pharmacology*; D003094:Collagen / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D001761:Bleomycin; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C050414:celastrol
keywords: Bleomycin; Celastrol; Collagen; Nrf2; Phase II enzymes; Pulmonary fibrosis