title: Congenital NOS2 deficiency prevents impairment of hypoxic pulmonary vasoconstriction in murine ventilator-induced lung injury.
abstract: Hypoxic pulmonary vasoconstriction (HPV) preserves systemic arterial oxygenation during lung injury by diverting blood flow away from poorly ventilated lung regions. Ventilator-induced lung injury (VILI) is characterized by pulmonary inflammation, lung edema, and impaired HPV leading to systemic hypoxemia. Studying mice congenitally deficient in inducible nitric oxide synthase (NOS2) and wild-type mice treated with a selective NOS2 inhibitor, L-N(6)-(1-iminoethyl)lysine (L-NIL), we investigated the contribution of NOS2 to the impairment of HPV in anesthetized mice subjected to 6 h of either high tidal volume (HV(T)) or low tidal volume (LV(T)) ventilation. HPV was estimated by measuring the changes of left lung pulmonary vascular resistance (LPVR) in response to left mainstem bronchus occlusion (LMBO). LMBO increased the LPVR similarly in wild-type, NOS2(-/-), and wild-type mice treated with L-NIL 30 min before commencing 6 h of LV(T) ventilation (96% +/- 30%, 103% +/- 33%, and 80% +/- 16%, respectively, means +/- SD). HPV was impaired in wild-type mice subjected to 6 h of HV(T) ventilation (23% +/- 16%). In contrast, HPV was preserved after 6 h of HV(T) ventilation in NOS2(-/-) and wild-type mice treated with L-NIL either 30 min before or 6 h after commencing HV(T) ventilation (66% +/- 22%, 82% +/- 29%, and 85% +/- 16%, respectively). After 6 h of HV(T) ventilation and LMBO, systemic arterial oxygen tension was higher in NOS2(-/-) than in wild-type mice (192 +/- 11 vs. 171 +/- 17 mmHg; P < 0.05). We conclude that either congenital NOS2 deficiency or selective inhibition of NOS2 protects mice from the impairment of HPV occurring after 6 h of HV(T) ventilation.
authors.affiliation: Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Yukako
authors.initials: Y
authors.lastname: Hotta
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Graveline
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Evgenov
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Warren M
authors.initials: WM
authors.lastname: Zapol
mesh_terms: D000818:Animals; D016084:Bronchoconstriction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology; D008168:Lung / Q000098:blood supply*; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000235:genetics; D011651:Pulmonary Artery; D012123:Pulmonary Ventilation; D012128:Respiratory Distress Syndrome / Q000209:etiology*; D012131:Respiratory Insufficiency / Q000201:enzymology / Q000517:prevention & control*; D014655:Vascular Resistance; D014661:Vasoconstriction; D012122:Ventilators, Mechanical / Q000009:adverse effects*
chemical_list: D004791:Enzyme Inhibitors; C090663:N(6)-(1-iminoethyl)lysine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine