Sepsis impairs hypoxic pulmonary vasoconstriction (HPV) in patients and animal models contributing to systemic hypoxemia. Levels of cysteinyl leukotrienes are elevated in the bronchoalveolar lavage fluid of patients with sepsis, but the contribution of cysteinyl leukotrienes to the impairment of HPV is uncertain.
Wild-type mice, mice deficient in leukotriene C4 synthase, the enzyme responsible for cysteinyl leukotriene synthesis, and mice deficient in cysteinyl leukotriene receptor 1 were studied at 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. Levels of cysteinyl leukotrienes were determined in the bronchoalveolar lavage fluid.
In the bronchoalveolar lavage fluid of all three strains, cysteinyl leukotrienes were not detectable after saline challenge; whereas endotoxin challenge increased cysteinyl leukotriene levels in wild-type mice and mice deficient of cysteinyl leukotriene receptor 1, but not in mice deficient of leukotriene C4 synthase. HPV did not differ between 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 C4 synthase (96±16%, P<0.05 vs. wild-type mice), thereby preserving systemic oxygenation. While 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.
Cysteinyl leukotrienes importantly contribute to endotoxin-induced impairment of HPV in part via a cysteinyl leukotriene receptor 1-dependent mechanisms.