Inducible NOS Inhibition Reverses Tobacco-Smoke-Induced Emphysema and Pulmonary Hypertension in Mice

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• 作者：Michael Seimetz¹ ;   ; ⁵ ; Nirmal Parajuli¹ ;   ; ⁵ ; Alexandra Pichl¹ ; Florian Veit¹ ; Grazyna Kwapiszewska¹ ; Friederike  ; C. Weisel¹ ; Katrin Milger¹ ; Bakytbek Egemnazarov¹ ; Agnieszka Turowska⁴ ; Beate Fuchs¹ ; Sandeep Nikam² ; Markus Roth¹ ; Akylbek Sydykov¹ ; Thomas Medebach¹ ; Walter Klepetko³ ; Peter Jaksch³ ; Rio Dumitrascu¹ ; Holger Garn⁴ ; Robert Voswinckel² ; Sawa Kostin² ; Werner Seeger¹ ; Ralph  ; T. Schermuly² ; Friedrich Grimminger¹ ; Hossein  ; A. Ghofrani¹ ; Norbert Weissmann¹ ;   ; ^{norbert.weissmann@innere.med.uni-giessen.de}
• 刊名：Cell
• 出版年：2011
• 出版时间：14 October 2011
• 年：2011
• 卷：147
• 期：2
• 页码：293-305
• 全文大小：2070 K

文摘

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Summary

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 mlns="""">iNOS were protected against emphysema and PH. Treatment of wild-type mice with the iNOS inhibitor N^mlns="""">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 mlns="""">iNOS in bone marrow (BM)-derived cells, PH was dependent on mlns="""">iNOS from BM-derived cells, whereas emphysema development was dependent on mlns="""">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.