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.
In this study, the authors examined in newborn rat lung tissues the release of leukotriene B(4) (LTB(4)) from tissue explants in vitro, the protein expression of the LT-synthesizing enzyme, 5-lipoxygenase (5-LO), and its activating protein (FLAP), and the effects of in vivo hyperoxic exposure (>95% O(2)) on these parameters. Basal LTB(4) output increased from 0.98 ng/mgDNA/30 min at day 1 to 3.3 ng/mgDNA/30 min at day 28 (P <.05). Exposure of rat pups to >95% O(2) from days 1 to 7 and 60% O(2) from days 7 to 28 stimulated a 1.6-fold (P <.05) increase in LTB(4) output, compared to normoxic pups (to 1.6 ng/mgDNA/30 min) by day 1 and on day 7. The calcium ionophore, A23187, caused an increase in LTB(4) output from both exposure groups, but LTB(4) output was consistently greater (P <.05) from hyperoxia-exposed pups. Western immunoblotting of lung tissue showed that 5-LO and FLAP protein mass increased (P <.05) from days 4 to 14. Hyperoxia exposure increased the mass of both proteins (P <.05). Immunohistochemistry localized 5-LO and FLAP mainly to alveolar macrophages on day 14, but some staining was evident in parenchymal tissue. These data show that hyperoxia increases LTB(4) output, as well as protein levels of 5-LO and FLAP, in newborn rat lungs during early postnatal life. Elevated LTB(4) may contribute to the etiology of newborn lung disease.
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