Congenital NOS2 deficiency prevents impairment of hypoxic pulmonary vasoconstriction in murine ventilator-induced lung injury

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.sup.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.sub.T]) or low tidal volume ([LV.sub.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.sup.-/-], and wild-type mice treated with L-NIL 30 min before commencing 6 h of [LV.sub.T] ventilation (96% [+ or -] 30%, 103% [+ or -] 33%, and 80% [+ or -] 16%, respectively, means[+ or -] SD). HPV was impaired in wild-type mice subjected to 6 h of [HV.sub.T] ventilation (23% [+ or -] 16%). In contrast, HPV was preserved after 6 h of [HV.sub.T] ventilation in NOS[2.sup.-/-] and wild-type mice treated with L-NIL either 30 min before or 6 h after commencing [HV.sub.T] ventilation (66% [+ or -] 22%, 82% [+ or -] 29%, and 85% [+ or -] 16%, respectively). After 6 h of [HV.sub.T] ventilation and LMBO, systemic arterial oxygen tension was higher in [NOS2.supb.-/-] than in wild-type mice (192 [+ or -] 11 vs. 171 [+ or -] 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.sub.T] ventilation. mechanical ventilation; nitric oxide synthase; hypoxia