Timing of hyperoxic exposure during alveolarization influences damage mediated by leukotrienes

Hyperoxic exposure of rat pups during alveolarization (postnatal days 4-14) severely retards alveolar development. Some aspects of this inhibition are mediated by leukotrienes (LTs) and may be time sensitive. We determined 1) the effects of exposure to hyperoxia (O(2)) during discrete periods before and during alveolarization on developing alveoli and 2) whether a relationship exists between O(2) and LTs in these periods. Pups were exposed to >95% O(2) from days 1 to 4, 4 to 9, 9 to 14, or 4 to 14 in the absence and presence of the LT synthesis inhibitor MK-0591. Both the level of in vitro lung tissue LT output on days 4, 9, and 14 and the degree of alveolarization on day 14 were determined. Pups exposed to O(2) from days 4 to 9 had a more profound inhibition of alveolarization on day 14 compared with those exposed to O(2) from days 1 to 4 or 9 to 14. Peptido-LT levels were significantly higher in pups exposed to O(2) on days 9 and 14 compared with pups in air and returned to normal once normoxia was restored. LT inhibition from days 4 to 14, 4 to 9, or 9 to 14 in pups exposed to O(2) from days 4 to 14 prevented the O(2)-induced inhibition of alveolarization. These data suggest that developing alveoli are sensitive to LTs shortly before and after day 9, significantly retarding certain parameters of alveolarization on day 14. We conclude that some of the effects of O(2) are not uniform throughout different stages of alveolarization and that this is likely related to the timing of LT exposure.