Preventive effect of irbesartan on bleomycin-induced lung injury in mice.

BACKGROUND Idiopathic pulmonary fibrosis is a specific form of chronic fibrosing interstitial pneumonia that is limited to the lung. Angiotensin receptor blockers (ARBs) and peroxisome proliferator-activated receptor (PPAR) γ ligands have anti-inflammatory and anti-fibrotic effects. We investigated the effects of irbesartan-an ARB with PPAR γ activity-on the development of bleomycin-induced pulmonary fibrosis in mice. METHODS Lung injury was induced in imprinting control region (ICR) mice by intratracheal instillation of 2mg/kg of bleomycin. The treatment group orally received 20mg/kg of irbesartan for 5 consecutive days before instillation. The mice were sacrificed and were evaluated 14 days after bleomycin instillation. RESULTS Irbesartan reduced the fluid content and hydroxyproline level in the lung and improved the pathological findings as indicated by the Ashcroft score. Total cell counts, the numbers of macrophages, neutrophils, and lymphocytes, and the levels of transforming growth factor (TGF) β1 and monocyte chemotactic protein (MCP) 1 in the bronchoalveolar lavage fluid (BALF) were decreased. Treatment with a PPARγ antagonist GW9662 reversed some of the effects of irbesartan. CONCLUSIONS The results of this study indicated that irbesartan attenuated the development of bleomycin-induced pulmonary fibrosis in mice by decreasing TGF-β1 and MCP-1 via blocking of ATI, by binding to CCR2b, and by PPARγ-mediated inhibition of inflammation.

[1]  A. Diehl,et al.  PPARgamma agonists prevent TGFbeta1/Smad3-signaling in human hepatic stellate cells. , 2006, Biochemical and biophysical research communications.

[2]  H. Yang,et al.  Kinetic alterations of angiotensin-II and nitric oxide in radiation pulmonary fibrosis. , 1998, Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer.

[3]  H. Yao,et al.  Losartan Attenuates Bleomycin-Induced Pulmonary Fibrosis in Rats , 2006, Respiration.

[4]  J M Simpson,et al.  Simple method of estimating severity of pulmonary fibrosis on a numerical scale. , 1988, Journal of clinical pathology.

[5]  W. Hsueh,et al.  Osteopontin modulates angiotensin II-induced fibrosis in the intact murine heart. , 2004, Journal of the American College of Cardiology.

[6]  R. Strieter,et al.  Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. , 1996, American journal of respiratory and critical care medicine.

[7]  A. Diehl,et al.  PPARγ Agonists Prevent TGFβ1/Smad3-Signaling in Human Hepatic Stellate Cells , 2006 .

[8]  W. Koenig,et al.  Antidiabetic PPAR&ggr;-Activator Rosiglitazone Reduces MMP-9 Serum Levels in Type 2 Diabetic Patients With Coronary Artery Disease , 2003 .

[9]  R. Phipps,et al.  The peroxisome proliferator-activated receptor gamma (PPARgamma) ligands 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone induce human B lymphocyte and B cell lymphoma apoptosis by PPARgamma-independent mechanisms. , 2006, Journal of immunology.

[10]  B. Uhal,et al.  Regulation of alveolar epithelial cell survival by the ACE-2/angiotensin 1-7/Mas axis. , 2011, American journal of physiology. Lung cellular and molecular physiology.

[11]  M. Fujimura,et al.  Angiotensin II type 2 receptor antagonist reduces bleomycin-induced pulmonary fibrosis in mice , 2008, Respiratory research.

[12]  B. Uhal,et al.  Essential roles for angiotensin receptor AT1a in bleomycin-induced apoptosis and lung fibrosis in mice. , 2003, The American journal of pathology.

[13]  J. Eisenbart,et al.  Proapoptotic Bid is required for pulmonary fibrosis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[14]  U. Kintscher,et al.  PPARgamma-activating angiotensin type-1 receptor blockers induce adiponectin. , 2005, Hypertension.

[15]  S. Abe,et al.  Reduction of bleomycin induced lung fibrosis by candesartan cilexetil, an angiotensin II type 1 receptor antagonist , 2003, Thorax.

[16]  S. Rosselot.  Idiopathic pulmonary fibrosis. , 2014, Nursing standard (Royal College of Nursing (Great Britain) : 1987).

[17]  W. Koenig,et al.  Antidiabetic PPAR gamma-activator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[18]  T. Suga,et al.  Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Ligand, Suppresses Bleomycin-Induced Acute Lung Injury and Fibrosis , 2008, Respiration.

[19]  U. Kintscher,et al.  Angiotensin Type 1 Receptor Blockers Induce Peroxisome Proliferator–Activated Receptor-γ Activity , 2004, Circulation.

[20]  David A. Lynch,et al.  Idiopathic pulmonary fibrosis: Diagnosis and treatment: International Consensus Statement , 2000 .

[21]  I. Puddey,et al.  Angiotensin II Type 1 Receptor Antagonists Inhibit Basal As Well As Low-Density Lipoprotein and Platelet-Activating Factor-Stimulated Human Monocyte Chemoattractant Protein-1 , 2003, Journal of Pharmacology and Experimental Therapeutics.

[22]  H. Bolte,et al.  Standardized quantification of pulmonary fibrosis in histological samples. , 2008, BioTechniques.

[23]  R. Phipps,et al.  The Peroxisome Proliferator-Activated Receptor γ (PPARγ) Ligands 15-Deoxy-Δ12,14-Prostaglandin J2 and Ciglitazone Induce Human B Lymphocyte and B Cell Lymphoma Apoptosis by PPARγ-Independent Mechanisms1 , 2006, The Journal of Immunology.

[24]  M. Selman,et al.  Idiopathic pulmonary fi brosis , 2011 .

[25]  U. Kintscher,et al.  PPAR&ggr;-Activating Angiotensin Type-1 Receptor Blockers Induce Adiponectin , 2005 .

[26]  B. Uhal,et al.  Angiotensin-TGF-beta 1 crosstalk in human idiopathic pulmonary fibrosis: autocrine mechanisms in myofibroblasts and macrophages. , 2007, Current pharmaceutical design.

[27]  B. H. Shah,et al.  Structural determinants of agonist-induced signaling and regulation of the angiotensin AT1 receptor , 2004, Molecular and Cellular Endocrinology.

[28]  R. Thieringer,et al.  Activation of peroxisome proliferator-activated receptor gamma does not inhibit IL-6 or TNF-alpha responses of macrophages to lipopolysaccharide in vitro or in vivo. , 2000, Journal of immunology.

[29]  S. Reddy,et al.  Nrf2-regulated PPAR{gamma} expression is critical to protection against acute lung injury in mice. , 2010, American journal of respiratory and critical care medicine.

[30]  E. Mazzon,et al.  Effect of rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 on bleomycin-induced lung injury , 2005, European Respiratory Journal.

[31]  R. Thieringer,et al.  Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Inhibit IL-6 or TNF-α Responses of Macrophages to Lipopolysaccharide In Vitro or In Vivo , 2000, The Journal of Immunology.

[32]  S. Kirincich,et al.  Molecular activation of PPARgamma by angiotensin II type 1-receptor antagonists. , 2006, Vascular pharmacology.

[33]  B. Uhal,et al.  JunD and HIF‐1α mediate transcriptional activation of angiotensinogen by TGF‐β1 in human lung fibroblasts , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[34]  S. Kirincich,et al.  Molecular activation of PPARγ by angiotensin II type 1-receptor antagonists , 2006 .

[35]  G. Mancini,et al.  Angiotensin II type 1 receptor blocker inhibits pulmonary injury. , 2005, Clinical and investigative medicine. Medecine clinique et experimentale.

[36]  Irbesartan attenuates Ang II-induced BMP-2 expression in human umbilical vein endothelial cells , 2008, Vascular medicine.

[37]  J. Mullol,et al.  Losartan attenuates bleomycin induced lung fibrosis by increasing prostaglandin E2 synthesis , 2006, Thorax.

[38]  A. Nicholson,et al.  Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features , 2006, European Respiratory Journal.

[39]  J. Abraham,et al.  CTGF expression is induced by TGF- beta in cardiac fibroblasts and cardiac myocytes: a potential role in heart fibrosis. , 2000, Journal of molecular and cellular cardiology.

[40]  G. Filippatos,et al.  Angiotensin II induces apoptosis in human and rat alveolar epithelial cells. , 1999, The American journal of physiology.

[41]  H. Taniguchi,et al.  Gradual Increase of High Mobility Group Protein B1 in the Lungs after the Onset of Acute Exacerbation of Idiopathic Pulmonary Fibrosis , 2011, Pulmonary medicine.

[42]  G. Izbicki,et al.  Time course of bleomycin‐induced lung fibrosis , 2002, International journal of experimental pathology.

[43]  Y. Kiya,et al.  A small difference in the molecular structure of angiotensin II receptor blockers induces AT1 receptor-dependent and -independent beneficial effects , 2010, Hypertension Research.

[44]  M. Ando,et al.  Monocyte chemoattractant protein-1 in idiopathic pulmonary fibrosis and other interstitial lung diseases. , 1994, Human pathology.

[45]  T. Marshall,et al.  Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b , 2006, Theoretical Biology and Medical Modelling.

[46]  H. Collard,et al.  Classification and Natural History of the Idiopathic Interstitial Pneumonias Who Is at Risk of Ipf? What Causes Ipf? , 2022 .

[47]  B. Uhal,et al.  Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor. , 2000, American journal of physiology. Lung cellular and molecular physiology.

[48]  S. Phan,et al.  Costimulation of Fibroblast Collagen and Transforming Growth Factor β1 Gene Expression by Monocyte Chemoattractant Protein-1 via Specific Receptors* , 1996, The Journal of Biological Chemistry.

[49]  T. Naoe,et al.  Mesenchymal stem cells stably transduced with a dominant-negative inhibitor of CCL2 greatly attenuate bleomycin-induced lung damage. , 2011, The American journal of pathology.

[50]  K. Kuwano,et al.  Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of Fas antigen. , 1997, American journal of respiratory cell and molecular biology.

[51]  Hui Wang,et al.  Early lung injury contributes to lung fibrosis via AT1 receptor in rats , 2007, Acta Pharmacologica Sinica.

[52]  M. Suga,et al.  Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases. , 1999, The European respiratory journal.

[53]  T. Ichiki,et al.  ANGIOTENSIN RECEPTORS: MOLECULAR BIOLOGY AND SIGNALLING , 1999, Clinical and experimental pharmacology & physiology.

[54]  A. J. Valente,et al.  Expression of monocyte chemoattractant protein 1 mRNA in human idiopathic pulmonary fibrosis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Jasmine Chen,et al.  Constitutive Activation of Peroxisome Proliferator-activated Receptor-γ Suppresses Pro-inflammatory Adhesion Molecules in Human Vascular Endothelial Cells* , 2002, The Journal of Biological Chemistry.

[56]  A. Takeshita,et al.  Peroxisome proliferator-activated receptor gamma activators downregulate angiotensin II type 1 receptor in vascular smooth muscle cells. , 2000, Circulation.