Cysteinyl Leukotrienes Impair Hypoxic Pulmonary Vasoconstriction in Endotoxemic Mice

Abstract

Background Sepsis impairs hypoxic pulmonary vasoconstriction (HPV) in patients and animal models, contributing to systemic hypoxemia. Concentrations of cysteinyl leukotrienes are increased in the bronchoalveolar lavage fluid of patients with sepsis, but the contribution of cysteinyl leukotrienes to the impairment of HPV is unknown. Methods Wild-type mice, mice deficient in leukotriene C(4) synthase, the enzyme responsible for cysteinyl leukotriene synthesis, and mice deficient in cysteinyl leukotriene receptor 1 were studied 18 h after challenge with either saline or endotoxin. HPV was measured by the increase in left pulmonary vascular resistance induced by left mainstem bronchus occlusion. Concentrations of cysteinyl leukotrienes were determined in the bronchoalveolar lavage fluid. Results In the bronchoalveolar lavage fluid of all three strains, cysteinyl leukotrienes were not detectable after saline challenge; whereas endotoxin challenge increased cysteinyl leukotriene concentrations in wild-type mice and mice deficient in cysteinyl leukotriene receptor 1, but not in mice deficient in leukotriene C(4) synthase. HPV did not differ among the three mouse strains after saline challenge (120 ± 26, 114 ± 16, and 115 ± 24%, respectively; mean ± SD). Endotoxin challenge markedly impaired HPV in wild-type mice (41 ± 20%) but only marginally in mice deficient in leukotriene C(4) synthase (96 ± 16%, P < 0.05 vs. wild-type mice), thereby preserving systemic oxygenation. Although endotoxin modestly decreased HPV in mice deficient in cysteinyl leukotriene receptor 1 (80 ± 29%, P < 0.05 vs. saline challenge), the magnitude of impairment was markedly less than in endotoxin-challenged wild-type mice. Conclusion Cysteinyl leukotrienes importantly contribute to endotoxin-induced impairment of HPV in part via a cysteinyl leukotriene receptor 1-dependent mechanism.