Angiotensin II and the fibroproliferative response to acute lung injury

Abstract

Angiotensin II (ANG II), generated by activation of local renin-angiotensin systems, is believed to play an important role in tissue repair and remodeling, in part via transforming growth factor-beta (TGF-beta). Angiotensin-converting enzyme (ACE) inhibitors have been shown to abrogate experimental lung injury via a number of potential mechanisms; however, the potentially fibroproliferative role for ANG II in the lung has not been characterized. We hypothesized that, after lung injury, ANG II would stimulate fibroblast procollagen synthesis and promote lung collagen deposition in rats. In vitro, ANG II was a potent inducer of procollagen production in human lung fibroblasts via activation of the type 1 receptor and, at least in part, via the autocrine action of TGF-beta. After bleomycin-induced lung injury, an increase in lung ANG II concentration was observed by day 3 that preceded increases in lung collagen and was maintained until death at day 21. Administration of an ACE inhibitor (ramipril) reduced ACE activity, ANG II concentration, TGF-beta expression, and collagen deposition. Losartan (an ANG II type 1 receptor antagonist) also attenuated the increase in TGF-beta expression and lung collagen deposition. These observations suggest that ANG II, possibly generated locally within the lung, may play an important role in the fibrotic response to acute lung injury, at least in part via the action of TGF-beta. ACE inhibitors and receptor antagonists, already widely used clinically, should be assessed as potential new therapies for fibrotic lung disease.

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.…”

“…J. Wang, Giri, Hyde, & Nakashima, 1989), N-Acetylcysteine (Cortijo et al, 2001;Hagiwara, Ishii, & Kitamura, 2000;Mata et al, 2003;Serrano-Mollar et al, 2003;Shahzeidi, Sarnstrand, Jeffery, McAnulty, & Laurent, 1991;Yildirim et al, 2005), Vitamin E (Kilinc et al, 1993), Curcumin (Punithavathi, Venkatesan, & Babu, 2000), Aminoguanidine (X. L. Chen, Huang, Li, Wang, & Wang, 2001; X. L. Chen, Li, Zhou, Ai, & Huang, 2003;de Rezende, Martinez, Capelozzi, Simoes, & Beppu, 2000;Giri, Biring, Nguyen, Wang, & Hyde, 2002;Hu, Xu, & Li, 1999;Yildirim et al, 2004), Melatonin (Arslan, Zerin, Vural, & Coskun, 2002;Genovese, Di Paola et al, 2005;Yildirim et al, 2006), Bilirubin (H. D. , CAPE = caffeic acid phenethyl ester , Erdosteine (Boyaci et al, 2006;Sogut et al, 2004;Yildirim et al, 2005;Yildirim et al, 2004) etc. ), 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.…”

“…), 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.…”

Transforming Growth Factor β1-mediated Activation of the Smooth Muscle α-Actin Gene in Human Pulmonary Myofibroblasts Is Inhibited by Tumor Necrosis Factor-α via Mitogen-activated Protein Kinase Kinase 1-dependent Induction of the Egr-1 Transcriptional Repressor

“…Poor termination of TGF␤1-mediated myofibroblast differentiation could contribute to chronic fibroproliferative disease and excessive scar formation in the injured lung, heart, liver, kidney, and skin potentially causing pathobiologic phenomena referred to as "endless healing" (Tomasek et al, 2002). In particular, pulmonary fibrosis typically is associated with chronic myofibroblast activation, deposition of interstitial collagen and SM␣A, and dysfunctional parenchymal remodeling with a mortality of 50% at 5 y after diagnosis (Zhang et al, 1996;Kunkel et al, 2003;Noble, 2003;Phan, 2003;Selman and Pardo, 2003;Daniels et al, 2004;Marshall et al, 2004;Willis et al, 2006;Wynn, 2007). Similarly, cardiac transplant chronic rejection is associated with pervasive interstitial myofibroblast accumulation and perivascular fibrosis that ultimately impairs heart graft perfusion, performance, and long-term survival (Weber, 1995; Armstrong et al, 1997a,b,c;Subramanian et al, 1998Subramanian et al, , 2002Rosenkranz, 2004).…”

Novel and Extensive Aspects of Paraquat-Induced Pulmonary Fibrogenesis: Comparative and Time-Course Microarray Analyses in Fibrogenic and Non-Fibrogenic Rats

“…Glutamyl aminopeptidase is an enzyme that converts angiotensin II to angiotensin III. It is known that angiotensin II stimulates lung fibroblast proliferation through the activation of TGF-β (Marshall et al, 2000(Marshall et al, , 2004. The P2X receptor is strongly expressed in the pulmonary epithelium and endothelium.…”