title: Aliskiren attenuates bleomycin-induced pulmonary fibrosis in rats: focus on oxidative stress, advanced glycation end products, and matrix metalloproteinase-9.
abstract: Pulmonary fibrosis is a progressive lung disorder with high mortality rate and limited successful treatment. This study was designed to assess the potential anti-oxidant and anti-fibrotic effects of aliskiren (Alsk) during bleomycin (BLM)-induced pulmonary fibrosis. Male Wistar rats were used as control untreated or treated with the following: a single dose of 2.5 mg/kg of BLM endotracheally and BLM and Alsk (either low dose 30 mg/kg/day or high dose 60 mg/kg/day), and another group was given Alsk 60 mg/kg/day alone. Alsk was given by gavage. Alsk anti-oxidant and anti-fibrotic effects were assessed. BLM significantly increased relative lung weight and the levels of lactate dehydrogenase and total and differential leucocytic count in bronchoalveolar lavage that was significantly ameliorated by high-dose Alsk treatment. As markers of oxidative stress, BLM caused a significant increase in the levels of lipid peroxides and nitric oxide accompanied with a significant decrease of superoxide dismutase and glutathione transferase enzymes. High-dose Alsk treatment restored these markers toward normal values. Alsk counteracted the overexpression of advanced glycation end products, matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinases-1 in lung tissue induced by BLM. Fibrosis assessed by measuring hydroxyproline content, which markedly increased in the BLM group, was also significantly reduced by Alsk. These were confirmed by histopathological and immunohistochemical examination which revealed that Alsk attenuates signs of pulmonary fibrosis and decreased the overexpressed MMP-9 and transforming growth factor β1. Collectively, these findings indicate that Alsk has a potential anti-fibrotic effect beside its anti-oxidant activity.
authors.affiliation: Pharmacology Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt. sallyabuelezz@yahoo.com.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Abuelezz
authors.affiliation: Pharmacology Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
authors.forename: Nevien
authors.initials: N
authors.lastname: Hendawy
authors.affiliation: Pathology Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.
authors.forename: Wesam M
authors.initials: WM
authors.lastname: Osman
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000494:pharmacology*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006909:Hydroxyproline / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000577:Amides; D000975:Antioxidants; D015415:Biomarkers; D005650:Fumarates; D017127:Glycation End Products, Advanced; C576839:TIMP1 protein, rat; C508962:Tgfb1 protein, rat; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; C446481:aliskiren; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; D006909:Hydroxyproline
keywords: Advanced glycation end products; Aliskiren; Bleomycin; Matrix metalloprteinase-9; Oxidative stress; Pulmonary fibrosis