Leukotrienes are indicated as mediators of hyperoxia-inhibited alveolarization in newborn rats

We investigated the role of leukotrienes (LT) in hyperoxia-induced changes in lung parenchyma in neonatal rat pups. Rat pups were exposed to 21% O-2 (air) or >95% O-2 from days 4 to 14 after birth and were administered the 5-lipoxygenase (5-LO) inhibitor and LTD(4) receptor antagonist Wy-50295, 5-LO-activating protein inhibitor MK-0591, or vehicle from days 3 to 14. All measurements were done on days 12-14. There was a significant (P < 0.05) increase in peptido-LT output from lung slices of animals exposed to O-2 compared with air-exposed animals. Both Wy-50295 and MK-0591 significantly lowered (P < 0.05) peptido-LT output in O-2-exposed animals. The 6-ketoprostaglandin F-1 alpha output was increased similarly in both vehicle- and drug-treated O-2-exposed animals. O-2 exposure also caused a significant increase in bronchoalveolar lavage fluid protein and extravascular lung water that could not be ameliorated by Wy-50295 or MK-0591. Hyperoxia-induced inhibition of alveolarization, indicated by a significantly (P < 0.05) lower parenchymal tissue density, specific internal surface area, and airspace perimeter-to-area ratio, and a significantly (P < 0.05) higher mean linear intercept and airspace unit volume than air-exposed animals, was prevented by both Wy-50295 and MK-0591. Although hyperoxia had no effect on septal thickness, Wy-50295 caused significant thickening in both air- and O-2-exposed pups. Our studies provide evidence that hyperoxia-induced peptido-LT may mediate O-2-induced inhibition of alveolarization and that this is not caused by an arachidonic acid shunt to cyclooxygenase.