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

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.

  • Seimetz, M.
  • Parajuli, N.
  • Pichl, A.
  • Veit, F.
  • Kwapiszewska, G.
  • Weisel, F. C.
  • Milger, K.
  • Egemnazarov, B.
  • Turowska, A.
  • Fuchs, B.
  • Nikam, S.
  • Roth, M.
  • Sydykov, A.
  • Medebach, T.
  • Klepetko, W.
  • Jaksch, P.
  • Dumitrascu, R.
  • Garn, H.
  • Voswinckel, R.
  • Kostin, S.
  • Seeger, W.
  • Schermuly, R. T.
  • Grimminger, F.
  • Ghofrani, H. A.
  • Weissmann, N.


  • Animals
  • *Disease Models, Animal
  • Humans
  • Hypertension, Pulmonary/chemically induced/drug therapy/pathology/physiopathology
  • Lung/blood supply/*pathology/physiopathology
  • Lysine/analogs & derivatives/pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase Type II/*antagonists & inhibitors/genetics
  • Pulmonary Alveoli/pathology/physiopathology
  • Pulmonary Disease, Chronic Obstructive/chemically induced/*drug
  • therapy/*pathology/physiopathology
  • Pulmonary Emphysema/chemically induced/drug therapy/pathology/physiopathology
  • Smoking/*pathology
Publication details
DOI: 10.1016/j.cell.2011.08.035
Journal: Cell
Pages: 293-305
Number: 2
Work Type: Original
Access number: 22000010
See publication on PubMed