Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice (Cell, 2011, 147:293-305)

報告日期: 2012/06/19
報告時間: 15:10/16:00
報告學生: 許佩玲 (英文報告)
講評老師: 謝奇璋
附件下載: 下載[1204-1334225333-1.pdf] 

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

Seimetz, M., Parajuli, N., Pichl, A., Veit, F., Kwapiszewska, G., Weisel, F.C., Milger, K., Egemnazarov, B., Turowska, A., Fuchs, B., et al. (2011). Cell 147, 293–305.


Speaker: Pei-Ling Hsu (許佩玲)               Date: June/12/2012 16:00-16:50

Commentator: Chi-Chang Shieh, M.D.,Ph.D. (謝奇璋醫師)   Location: Room 602


The World Health Organization warns that chronic obstructive pulmonary disease (COPD) may become the third leading cause of death by 2020. Prominent forms of the disease include chronic bronchitis (i.e., inflammation of the larger airways) and emphysema (i.e., destruction of the alveoli, or air sacs). Some patients also have pulmonary hypertension (PH), which can lead to heart failure. However, to the best of our knowledge, no published study directly compares the course of emphysema development and PH. In this paper, the authors provide evidence for a causative role of inducible nitric oxide synthase (iNOS) and peroxynitrite. When the authors exposed mice to tobacco smoke for up to 8 months, the lungs of the mice resembled those of patients with advanced COPD, including loss of alveoli, elastic fibers, and small blood vessels. The lungs of the mice also displayed thickening of the remaining vessels, increased iNOS in smooth muscle, decreased endothelial nitric oxide synthase (eNOS), and increased protein nitration. Use of a mouse model allowed three major insights into the pathogenesis of COPD. First, smoke exposure caused emphysema and pulmonary hypertension in wild-type mice and in mice lacking eNOS, but not in mice lacking iNOS. Moreover, when the authors administered an iNOS inhibitor after 8 months of smoke exposure, the treatment reversed the lung damage within 3 months. Second, the smoke’s effects on pulmonary vasculature and pulmonary arterial pressure preceded those on airways and were not attributable to hypoxia. Third, bone marrow transplantation experiments demonstrated that emphysema depended on iNOS expression in radiation-resistant, nonhematopoietic cells, but pulmonary hypertension required expression of iNOS in cells derived from the bone marrow. These findings could explain the hitherto controversial discussion about the impact of PH on emphysema development in humans, where PH is not always associated with emphysema. Finally, they suggested that selective iNOS inhibitor, N6-(1-iminoethyl)-L-lysine (L-NIL), offered the potential to improve the functional and structural destruction caused by tobacco smoke.



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