5-lipoxygenase deficiency prevents respiratory failure and impairment of hypoxic pulmonary vasoconstriction during ventilator-induced lung injury

Hypoxic pulmonary vasoconstriction (HPV) directs blood flow to well-ventilated lung regions preserving systemic oxygenation in pulmonary injury. Mechanical ventilation with high tidal volumes (HVT) progressively injures the lung and decreases gas exchange efficiency. Recent experimental studies have revealed an important role for leukotriene (LT) biosynthesis by 5-lipoxygenase (5LO) in the impairment of HPV by endotoxin. To investigate whether or not impairment of HPV contributes to the hypoxemia associated with HVT and to evaluate the role of LT biosynthesis in ventilator-induced lung injury (VILI), we studied wild-type (WT) and 5LO-deficient (5LO-/-) mice ventilated for up to 10 hours with low tidal volumes (LVT) or HVT. HPV was assessed by measuring the increase of left lung pulmonary vascular resistance (LPVR) induced by left mainstem bronchus occlusion (LMBO). In WT mice, HVT, but not LVT, increased pulmonary vascular permeability and edema formation and led to deterioration in the mechanics of the respiratory system. Systemic oxygenation (PaO2) was impaired (128±20 vs. 229±10 mmHg after LVT, P<0.01), and survival was reduced (20% animals survived vs. 100% during LVT, P<0.01). After six hours of HVT (before the development of pulmonary edema), the LMBO-induced increase in LPVR was markedly impaired (17±8 vs. 99±10% after LVT, P<0.01). HVT increased bronchoalveolar lavage levels of leukotriene B4 (LTB4), cysteinyl-leukotrienes (cysLTs), and neutrophils. In 5LO-/- mice subjected to HVT, the increase of pulmonary vascular permeability and the worsening of respiratory mechanics were markedly attenuated, PaO2 was preserved (255±9 after HVT, P<0.001 vs. WT mice), and survival was increased (100% animals survived, P<0.01 vs. WT mice during HVT). Moreover, HVT did not impair the ability of LMBO to increase LPVR (94±9% after HVT, P<0.01 vs. WT mice). Administration of MK886, a 5LO-activating protein inhibitor, or MK571, a selective cysLT1 receptor antagonist, largely prevented VILI, reducing pulmonary edema and the increase in microvascular permeability, preserving PaO2, and increasing survival. These results demonstrate that HVT ventilation impairs HPV and that 5-lipoxygenase contributes to ventilatorinduced lung injury.