Modulation of bleomycin‐induced oxidative stress and pulmonary fibrosis by N‐acetylcysteine in rats via AMPK/SIRT1/NF‐κβ

• Published in: Clinical and experimental pharmacology & physiology Vol. 47; no. 12; pp. 1943 - 1952
• Main Authors: Mansour, Heba H., Omran, Mervat M., Hasan, Hesham F., El kiki, Shereen M.
• Format: Journal Article
• Language: English
• Published: Australia Wiley Subscription Services, Inc 01.12.2020
• Subjects: Acetylcysteine; Acetylcysteine - pharmacology; AMP; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Antioxidants; Antioxidants - metabolism; Antioxidants - pharmacology; Bleomycin; Bleomycin - toxicity; Collagen; Connective tissue growth factor; Connective tissues; Fibrosis; Growth factors; Inflammation; Interleukins; Kinases; Lipid peroxidation; Lipids; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung diseases; Lungs; Male; NF-kappa B - metabolism; Nitric oxide; N‐acetylcysteine; Oxidative stress; Oxidative Stress - drug effects; PDGF; Peroxidation; Platelet-derived growth factor; Protein kinase; Pulmonary fibrosis; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - drug therapy; Pulmonary Fibrosis - metabolism; Pulmonary Fibrosis - pathology; Rats; Rats, Sprague-Dawley; Rats, Wistar; Signal Transduction - drug effects; SIRT1; SIRT1 protein; Sirtuin 1 - metabolism; TGF‐β1; Tissues; Transforming growth factor-b1; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumors; bleomycin; AMPK; TGF-β1; SIRT1; PDGF; N-acetylcysteine
• ISSN: 0305-1870; 1440-1681; 1440-1681
• DOI: 10.1111/1440-1681.13378

The efficacy of bleomycin (BLM) as an antineoplastic drug is limited to the development of dose and time‐dependent pulmonary fibrosis. This study was intended to investigate the effect of N‐acetylcysteine (NAC) on BLM‐induced pulmonary fibrosis in rats. Twenty rats were randomly divided to the following four groups: Group one served as control; group two received BLM (15 mg/kg, intraperitoneal (ip)) for five consecutive days; group three received NAC (200 mg/kg, ip) for five consecutive days; and group four received NAC 1 hour before BLM for 5 days. The expression of connective tissue growth factor (CTGF), platelet‐derived growth factor (PDGF), silent information regulator l (SIRT1), AMP‐activated protein kinase (AMPK) were determined by qRT‐PCR in lung tissues. The changes in transforming growth factor‐beta1 (TGF‐β1), tumour necrosis factor‐α (TNF‐α), interleukin‐β1 (IL‐β1) and nuclear factor kappa‐β (NF‐κβ) in serum were measured by ELISA. The tissue antioxidant status was determined biochemically. BLM administration caused pulmonary fibrosis as evidenced by increased levels of inflammatory mediators (TGF‐β1, TNF‐α, IL‐β1 and NF‐κβ) in serum (P < .05), elevated lipid peroxidation and nitric oxide and depleted endogenous antioxidants in lung tissue (P < .05). The expression levels of SIRT1 and AMPK were significantly decreased (P < .05), while the expression levels of CTGF and PDGF were increased significantly in the BLM group as compared to the control group (P < .05). These alterations were normalized by NAC intervention. NAC markedly attenuated the lung histopathological changes and reduced collagen deposition. These results suggest that NAC exerted an ameliorative effect against BLM‐induced oxidative damage and pulmonary fibrosis via SIRT1/ AMPK/ NF‐κβ pathways. BLM administration caused pulmonary fibrosis as evidenced by increased levels of serum inflammatory mediators (TGF‐β1, TNF‐α, IL‐β1 and NF‐Kβ), elevated MDA and NO and depleted SOD and GSH in lung tissue. The expression levels of SIRT1 and AMPK were significantly decreased, while the expression levels of CTGF and PDGF were increased significantly in the BLM group. These alterations were normalized by NAC intervention.