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Cell. 2011 Oct 14;147(2):293-305. doi: 10.1016/j.cell.2011.08.035.

Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice.

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1
University of Giessen Lung Center, Excellence Cluster Cardiopulmonary System, Giessen, Germany.

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the most common causes of death worldwide. We report in an emphysema model of mice chronically exposed to tobacco smoke that pulmonary vascular dysfunction, vascular remodeling, and pulmonary hypertension (PH) precede development of alveolar destruction. We provide evidence for a causative role of inducible nitric oxide synthase (iNOS) and peroxynitrite in this context. Mice lacking iNOS were protected against emphysema and PH. Treatment of wild-type mice with the iNOS inhibitor N(6)-(1-iminoethyl)-L-lysine (L-NIL) prevented structural and functional alterations of both the lung vasculature and alveoli and also reversed established disease. In chimeric mice lacking iNOS in bone marrow (BM)-derived cells, PH was dependent on iNOS from BM-derived cells, whereas emphysema development was dependent on iNOS from non-BM-derived cells. Similar regulatory and structural alterations as seen in mouse lungs were found in lung tissue from humans with end-stage COPD.

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PMID:
22000010
DOI:
10.1016/j.cell.2011.08.035
[Indexed for MEDLINE]
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