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Angiotensin II antagonism fails to ameliorate bleomycin-induced pulmonary fibrosis in mice

¹ Thoracic Diseases Research Unit, Division of Pulmonary and Critical Care Medicine, and ² Division of Cardiovascular Diseases, Dept of Medicine, ³ Dept of Molecular Pharmacology and Experimental Therapeutics, and ⁴ Dept of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, USA

CORRESPONDENCE: A. H. Limper, 8–24 Stabile Building, Mayo Clinic, Rochester, MN 55905, USA. Fax: 1 5072844521. E-mail: limper.andrew@mayo.edu

Keywords: Basic mechanisms, bleomycin, interstitial lung disease, losartan, lung fibrosis, mice

Received: July 30, 2004
Accepted December 14, 2004

Based on current evidence, transforming growth factor (TGF)-ß plays a central pathogenic role in the development of pulmonary fibrosis. There is growing evidence that angiotensin II can serve as a stimulus for TGF-ß-mediated lung fibrosis. However, the role of angiotensin II in the pathobiology of pulmonary fibrosis in vivo remains unclear and the therapeutic potential for targeting angiotensin II in a bleomycin-induced pulmonary fibrosis model is not well known.

Therefore, the aim of this study was to test whether the angiotensin II antagonist, losartan, attenuated the development of bleomycin-induced pulmonary fibrosis in two distinct murine strains, C57/BL6 and Sv129. This was determined by histopathology and quantification of collagen content by hydroxyproline assay.

Despite demonstrable angiotensin II antagonism in vivo and a reduction in measures of acute lung injury, losartan therapy, at a dose shown to reduce renal and cardiac fibrosis in mice, failed to significantly ameliorate bleomycin-induced pulmonary fibrosis.

In conclusion, these data suggest that the pulmonary fibrotic disease process in vivo is not solely dependent on angiotensin II activity and the potential for angiotensin II receptor blockers as a therapeutic strategy in patients with pulmonary fibrosis may be limited.

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