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.

Protective and therapeutic effects of ethanolic extract of Nasturtium officinale (watercress) and vitamin E against bleomycin-induced pulmonary fibrosis in rats

“…NO, an endogenous short-term free radical, is generated by three NO synthase (NOS) isoforms, including neuronal, endothelial, and inducible NOS isoforms ( 31 ). Recent studies have shown that an excessive generation of NO, nitrogen dioxide, and peroxynitrite plays a significant role in the development of pulmonary fibrosis in both human and animal models pulmonary fibrosis ( 32 ). Our results indicated that the serum NO metabolite concentration in the pulmonary fibrosis caused by the BLM was significantly higher than that in the normal group.…”

Early Plasma Matrix Metalloproteinase Profiles. A Novel Pathway in Pediatric Acute Respiratory Distress Syndrome

“…Interestingly, both animals and humans with bleomycininduced pulmonary fibrosis have demonstrated decreased MMP-9/TIMP-1 ratios, and treatment with the antifibrotic drug pirfenidone has been associated with restoration of the MMP-9/TIMP-1 ratio in the lungs, downregulation of the TGF-b pathway, and clinical improvement (18,(58)(59)(60)(61). Other pharmacotherapeutics that have reported efficacy in modulating the MMP-9/TIMP-1 ratio in patients with pulmonary fibrosis include aliskiren, artusenate, bosentan, doxycycline, and induced pluripotent stem cells, although further studies are needed (62)(63)(64)(65)(66).…”

Scutellarin Enhances Antitumor Effects and Attenuates the Toxicity of Bleomycin in H22 Ascites Tumor-Bearing Mice

“…BLM is an efficacious anti-cancer chemotherapeutic agent, but still has side effects that cannot be ignored. BLM induces pulmonary fibrosis, which is a chronic and aggressive lung disorder with only few successful treatments available ( Abuelezz et al, 2016 ). Today, most of the chemotherapeutic drugs have side effects; including bone marrow suppression and immunosuppression.…”