Submitted on October 5, 2006
Accepted on August 23, 2007
Congenital NOS2-deficiency prevents impairment of hypoxic pulmonary vasoconstriction in murine ventilator-induced lung injury
Rong Liu1, Yukako Hotta1, Amanda R Graveline2, Oleg V Evgenov1, Emmanuel S. Buys3, Kenneth D. Bloch4, Fumito Ichinose4, and Warren M Zapol5*
1 Anesthesia and Critical Care, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, United States
2 Cardiovascular Research Center, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, United States
3 Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, United States
4 Anesthesia and Critical Care, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, United States; Cardiovascular Research Center, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, United States
5 Anesthesia & Critical Care, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: wzapol{at}partners.org.
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-N6-(1-Iminoethyl)lysine, L-NIL], we investigated the contribution of NOS2 to the impairment of HPV in anesthetized mice subjected to 6 hours of either high tidal volume (HVT) or low tidal volume (LVT) 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 minutes before commencing 6 hours of LVT ventilation (96±30%, 103±33%, and 80±16%, respectively; mean ± SD). HPV was impaired in wild-type mice subjected to 6 hours of HVT ventilation (23±16%). In contrast, HPV was preserved after 6 hours of HVT ventilation in NOS2-/- and wild-type mice treated with L-NIL either 30 minutes before or 6 hours after commencing HVT ventilation (66±22%, 82±29%, and 85±16%, respectively). After 6 hours of HVT 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 hours of HVT ventilation.
