Losartan Attenuates Bleomycin-Induced Pulmonary Fibrosis in Rats

Abstract

Background: In addition to regulating blood pressure and body fluid homeostasis, the renin-angiotensin system is also involved in lung fibrogenesis. Objective: To study the effect of losartan, an angiotensin II antagonist, on bleomycin-induced pulmonary fibrosis in rats and its possible mechanism. Methods: Pulmonary fibrosis was induced in SD rats by intratracheal instillation of bleomycin (5 mg·kg^–1). Subsequently, the rats received daily losartan (3, 9 and 27 mg·kg^–1) or prednisone (20 mg·kg^–1) orally. Six rats in each group were sacrificed 14 and 21 days after intratracheal instillation. Hydroxyproline, superoxide dismutase (SOD), and malondialdehyde (MDA) levels in lung tissues were determined by spectroscopy. The levels of TGF-β1 in serum were measured by ELISA. Histological changes in the lungs were evaluated by hematoxylin-eosin stain, and scored. Results: Rat body weight evidently decreased while the indices of lung and hydroxyproline contents in lung tissue were significantly increased 14 and 21 days after intratracheal bleomycin instillation. Inflammatory cell infiltration and fibrotic scores were more prominent in the model group compared to the sham group. Losartan (3, 9 and 27 mg·kg^–1, i.g.) apparently attenuated the degree of pulmonary fibrosis. Further study showed that losartan significantly increased SOD levels while it decreased MDA contents in lung homogenates. Serum TGF-β1 levels of pulmonary fibrosis rats were also decreased by losartan. Conclusions: Losartan had an inhibitory effect on bleomycin-induced pulmonary fibrosis, and its effect may be associated with its anti-free radicals and the reduction in TGF-β1.

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

“…Several reports have promoted Losartan as inhibitor of fibrotic progression in the bleomycin model (Fang, Zhu, Hu, & Liu, 2002;Marshall et al, 2004;Molina-Molina et al, 2006), and a recent report confirmed these findings (Yao, Zhu, Zhao, & Lu, 2006). Losartan was given by daily gavage from day 0 to day 14 or to day 21.…”

“…), Angiotensin converting enzyme inhibitors (Captopril (R. Wang, Ibarra-Sunga, Verlinski, Pick, & Uhal, 2000), Ramipril (Marshall et al, 2004) etc. ), Angiotensin receptor blockers (Losartan (Fang, Zhu, Hu, & Liu, 2002;Marshall et al, 2004;Yao, Zhu, Zhao, & Lu, 2006), Candesartan (Otsuka, Takahashi, Shiratori, Chiba, & Abe, 2004), Valsartan (F. Liu, Xu, & Ye, 2005;Mancini & Khalil, 2005) etc. ), Anticoagulants (TFPI = tissue factor pathway inhibitor (Kijiyama et al, 2006), Urokinase (Hart, Whidden, Green, Henkin, & Woods, 1994;Hattori et al, 2004;Howell et al, 2001;Howell, Laurent, & Chambers, 2002;Ikeda, Hirose, Koto, Hirano, & Shigematsu, 1989), Heparin (Gunther et al, 2003;Piguet, Van, & Guo, 1996), APC = anticoagulant protein C (S. Shimizu et al, 2003;H.…”

“…The drug treated animals also lost less weight and had lower indices of lung fibrosis. The antifibrotic effect of Losartan in the context of pulmonary fibrosis might be associated with antioxidant activity and reduction in TGF-β1 levels (Yao, Zhu, Zhao, & Lu, 2006).…”

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

“…Although several studies have shown that antagonism of angiotensin II signaling results in decreased TGF-b signaling in a variety of tissues, including kidney, lung, skeletal muscle, heart, and aorta (Shihab et al 1997;Sun et al 1998;Lavoie et al 2005;Habashi et al 2006;Yao et al 2006;Cohn et al 2007;Podowski et al 2012), the exact mechanism by which this occurs is not fully understood (Gibbons et al 1992;Stouffer and Owens 1992;Wolf et al 1993Wolf et al , 1999Kagami et al 1994;Lee et al 1995;Campbell and Katwa 1997;Fukuda et al 2000;Boffa et al 2003;Naito et al 2004;RodriguezVita et al 2005;Zhou et al 2006;Chen et al 2013). Suppression of excessive Erk1 and Erk2 MAPK activation with losartan or an inhibitor of MAPK kinase (MAPKK, also known as MEK) has been shown to normalize aortic architecture and aneurysm pathology in MFS mouse models (Habashi et al 2011), indicating that Erk MAPK activation is critical to aneurysm progression.…”

Protective Effect of Valsartan on Beleomycine-Induced Fibrosis

“…Long et al (22) showed an anti-fibrotic effect of valsartan via increased collagen synthesis through the induction of connective tissue growth factor (CTGF) expression. Yao et al investigated the anti-fibrotic effect of losartan and found that the protective effect of losartan may be associated with its antifree radicals and the reduction in TGF-β1 (23). The results of Ghazi-Khansari et al's work (24) showed that captopril and enalapril improved pulmonary fibrosis in histopathological studies as well as decreasing collagen content in the lung tissue.…”