Author/Authors :
Michael Seimetz، نويسنده , , Nirmal Parajuli، نويسنده , , Alexandra Pichl، نويسنده , , Florian Veit، نويسنده , , Grazyna Kwapiszewska، نويسنده , , Friederike C. Weisel، نويسنده , , Katrin Milger، نويسنده , , Bakytbek Egemnazarov، نويسنده , , Agnieszka Turowska، نويسنده , , Beate Fuchs، نويسنده , , Sandeep Nikam، نويسنده , , Markus Roth، نويسنده , , Akylbek Sydykov، نويسنده , , Thomas Medebach، نويسنده , , Walter Klepetko، نويسنده , , Peter Jaksch، نويسنده , , Rio Dumitrascu، نويسنده , , Holger Garn، نويسنده , , Robert Voswinckel، نويسنده , , Sawa Kostin، نويسنده , , et al.، نويسنده ,
Abstract :
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 N6-(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.
