Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist

Abstract

Background: Signalling of angiotensin II via angiotensin II type 1 receptor (AT1) promotes cardiac and renal fibrosis, but its role in lung fibrosis is little understood. Using a rat bleomycin (BLM) induced model of pulmonary fibrosis, we examined the expression of AT1 in the lung and the effect of an AT1 antagonist on pulmonary fibrosis. Methods: Adult male Sprague-Dawley rats were given 0.3 mg/kg BLM intratracheally. Two days earlier they had received 10 mg/kg/day of the AT1 antagonist candesartan cilexetil mixed in the drinking water. AT1 expression in the lungs was examined by immunohistochemistry and immunoblot methods. The effect of the AT1 antagonist on pulmonary fibrosis was studied by analysis of bronchoalveolar lavage (BAL) fluid, histopathology, and hydroxyproline assay. Results: Immunohistochemical studies showed overexpression of AT1 in inflammatory immune cells, alveolar type II cells, and fibroblasts. A quantitative assay for AT1 showed that AT1 expression was significantly upregulated in cells from BAL fluid after day 3 and in the lung homogenates after day 21. Candesartan cilexetil significantly inhibited the increase in total protein and albumin, as well as the increase in total cells and neutrophils in BAL fluid. On day 21 candesartan cilexetil also ameliorated morphological changes and an increased amount of hydroxyproline in lung homogenates. In addition, BLM increased the expression of transforming growth factor (TGF)-b 1 in BAL fluid on day 7; this increase was significantly reduced by candesartan cilexetil. Conclusion: AT1 expression is upregulated in fibrotic lungs. Angiotensin II promotes lung fibrosis via AT1 and, presumably, in part via TGF-b 1 .

Protective Effect of Valsartan on Beleomycine-Induced Fibrosis

“…Up-regulation in AT1 receptor expression occurred in lung parenchyma after bleomycin-induced lung injury. These studies' results suggest that angiotensinogen and AT1 receptors are expressed in lung tissue (7,8,17). Previous assessments have also shown that AT1 receptor antagonists decrease lung collagen deposition, which was confirmed in our observations (7,17,20).…”

“…The present study showed that valsartan significantly decreased lung inflammatory infiltration after bleomycin exposure. Several studies have reported an anti-inflammatory effect of AT1 receptor blockade (17)(18)(19). An enhancement in lung hydroxyproline content (as a remarkable indicator of collagen quantity) was observed on the 21st day of treatment after bleomycin exposure in the bleomycin group.…”

“…Ang II as a key mediator in the pathogenesis of lung fibrosis could influence the progression of lung injury via a number of mechanisms (17). Several previous investigations have reported an increase in lung Ang II concentrations and lung collagen content.…”

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

“…), 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.…”

Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome

“…The prototype ACE inhibitors captopril or lisinopril attenuated experimental lung fibrosis induced by monocrotaline, 51 bleomycin 52 or paraquat; 53 the ACE inhibitors also were found to be potent inhibitors of bleomycin-or TNF-a-induced apoptosis of lung epithelial cells. 54,55 The ANG receptor AT1 antagonists losartan or candesartan have been shown to prevent lung fibrosis in response to radiation 56 or bleomycin, 57,58 and also blocked apoptosis of lung alveolar epithelial cells in response to bleomycin 57 or the antiarrhythmic agent amiodarone. 59 Given the central role of epithelial cells death in lung injury in a variety of disease states, attention as been focused on defining the role of ANGII in apoptosis of lung alveolar epithelials (AECs).…”