title: Inducible NOS inhibition reverses tobacco-smoke-induced emphysema and pulmonary hypertension in mice.
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 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.
authors: University of Giessen Lung Center, Excellence Cluster Cardiopulmonary System, Giessen, Germany.
authors: Michael
authors: M
authors: Seimetz
authors: Nirmal
authors: N
authors: Parajuli
authors: Alexandra
authors: A
authors: Pichl
authors: Florian
authors: F
authors: Veit
authors: Grazyna
authors: G
authors: Kwapiszewska
authors: Friederike C
authors: FC
authors: Weisel
authors: Katrin
authors: K
authors: Milger
authors: Bakytbek
authors: B
authors: Egemnazarov
authors: Agnieszka
authors: A
authors: Turowska
authors: Beate
authors: B
authors: Fuchs
authors: Sandeep
authors: S
authors: Nikam
authors: Markus
authors: M
authors: Roth
authors: Akylbek
authors: A
authors: Sydykov
authors: Thomas
authors: T
authors: Medebach
authors: Walter
authors: W
authors: Klepetko
authors: Peter
authors: P
authors: Jaksch
authors: Rio
authors: R
authors: Dumitrascu
authors: Holger
authors: H
authors: Garn
authors: Robert
authors: R
authors: Voswinckel
authors: Sawa
authors: S
authors: Kostin
authors: Werner
authors: W
authors: Seeger
authors: Ralph T
authors: RT
authors: Schermuly
authors: Friedrich
authors: F
authors: Grimminger
authors: Hossein A
authors: HA
authors: Ghofrani
authors: Norbert
authors: N
authors: Weissmann
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000473:pathology* / Q000503:physiopathology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics; D011650:Pulmonary Alveoli / Q000473:pathology / Q000503:physiopathology; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D012907:Smoking / Q000473:pathology*
chemical_list: C090663:N(6)-(1-iminoethyl)lysine; D052247:Nitric Oxide Synthase Type II; D008239:Lysine