Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 18 October 2011
Vol. 4, Issue 195, p. ec288
[DOI: 10.1126/scisignal.4195ec288]

EDITORS' CHOICE

Nitric Oxide Two Ways to Breathe Easier Without iNOS

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

Chronic obstructive pulmonary disease (COPD), which includes chronic bronchitis and emphysema and results from exposure to smoke or air pollutants, is incurable except by lung transplantation and represents a leading cause of death (see Nathan). Seimetz et al. determined that mice exposed to tobacco smoke developed lung emphysema after 6 months and pulmonary hypertension (PH, which often accompanies COPD) within 3 months. Immunofluorescence revealed an increase in the abundance of inducible nitric oxide synthase (iNOS) in the pulmonary vasculature at 3 and 8 months, an increase confirmed by Western blot analysis of homogenized lung tissue, whereas, at 8 months, the abundance of another NOS isoform [endothelial (e) NOS] had decreased. Mice lacking iNOS (iNOS–/– mice) were resistant to smoke-induced emphysema and PH, whereas mice lacking eNOS were not. When administered in parallel with smoke exposure, the iNOS inhibitor L-NIL [N6-(1-iminoethyl)-L-lysine] protected against emphysema and PH; indeed, 3 months of treatment with L-NIL initiated after 8 months of exposure to smoke reversed emphysema and PH. Analyses of chimeric mice [wild-type mice transplanted with bone marrow (BM) from iNOS–/– mice or iNOS–/– mice transplanted with wild-type BM] indicated that the pathogenesis of emphysema was distinct from that of PH: iNOS–/– mice transplanted with wild-type BM were protected against emphysema, whereas wild-type mice transplanted with iNOS–/– bone marrow were protected against PH. Nitric oxide reacts with superoxide to form peroxynitrite, which can react with tyrosine residues to form nitrotyrosine, and Western blot analysis indicated that smoke exposure increased nitrotyrosine in lung tissue of wild-type and eNOS–/– mice, but not iNOS–/– mice, and that this increase was prevented by L-NIL. Analyses of lung tissue from people with end-stage COPD showed changes in structure, iNOS, eNOS, and nitrotyrosine similar to those in the mouse model. Thus, the authors conclude that iNOS associated with distinct cell types plays a critical role in the pathogenesis of COPD and PH and that its inhibition may be of therapeutic value.

M. Seimetz, N. Parajuli, A. Pichl, F. Veit, G. Kwapiszewska, F. C. Weisel, K. Milger, B. Egemnazarov, A. Turowska, B. Fuchs, S. Nikam, M. Roth, A. Sydykov, T. Medebach, W. Klepetko, P. Jaksch, R. Dumitrascu, H. Garn, R. Voswinckel, S. Kostin, W. Seeger, R. T. Schermuly, F. Grimminger, H. A. Ghofrani, N. Weissmann, Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice. Cell 147, 293–305 (2011). [Online Journal]

C. Nathan, Is iNOS beginning to smoke? Cell 147, 257–258 (2011). [Online Journal]

Citation: E. M. Adler, Two Ways to Breathe Easier Without iNOS. Sci. Signal. 4, ec288 (2011).



To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882