Chronic obstructive pulmonary disease is a major cause of high morbidity and mortality with a high socioeconomic burden worldwide. The contribution of vascular alterations to the pathogenesis of the disease remains controversial and there is still ongoing debate about the possible development of pulmonary hypertension in COPD. Against this background, the current thesis aimed to decipher the time course for the development of lung emphysema as well asvascular alterations to the pulmonary circulation by use of a mouse model of tobacco smokeinduced COPD. For this purpose, WT mice were exposed for up to eight months to tobacco smoke (6 h/day, 5 days/week). It was demonstrated that both vascular structural and functional alterations occurred, including loss of pulmonary vessels, narrowing of vascular lumen, an increased degree of muscularization, pulmonary hypertension as well as endothelial dysfunction.Against the background, it was hypothesized that oxidative as well nitrosative stress plays a major role to the development of COPD by the regulation of inducible as well as the endothelial NO synthases. An upregulation of the inducible nitric oxide synthase (iNOS) was found in the pulmonary vasculature concomitant with increased nitrotyrosine levels. Comparing the development of vascular alteration and emphysema in WT, iNOS / , and eNOS / mice, this studyfound that iNOS / were completely protected from these structural and functional changes.Moreover, the same effect was observed by the treatment of wild-type mice with the iNOS inhibitor L-NIL. Similar regulatory processes and structural alterations as for tobacco smoke exposed mice were found in GOLD stage IV for explanted COPD patient lungs. Thus, iNOS inhibition may be a strategy for prevention of COPD in the future.
Verknüpfung zu Publikationen oder weiteren Datensätzen
