Timing of hyperoxic exposure during alveolarization influences damage mediated by leukotrienes

Abstract

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.

Combined effects of maternal inflammation and neonatal hyperoxia on lung fibrosis and RAGE expression in newborn rats

“…Prolonged exposure of neonatal rats to hyperoxic conditions has been reported to increase lung fibrosis in a manner similar to that observed for human BPD (3,4). Collagen is the major extracellular matrix component of the lungs and is vital for maintaining the normal lung architecture (28).…”

“…Lung injury resolves with fibrosis that is prominent in larger infants who developed bronchopulmonary dysplasia (BPD) after prolonged exposure to oxygen and mechanical ventilation (1,2). Prolonged exposure of neonatal mice to hyperoxic conditions resulted in decreased alveolar septation, increased terminal air space size, and increased lung fibrosis that is similar to human BPD (3,4).…”

Hyperoxia Decreases Matrix Metalloproteinase-9 and Increases Tissue Inhibitor of Matrix Metalloproteinase-1 Protein in the Newborn Rat Lung: Association with Arrested Alveolarization

“…These parameters persist up to d 40 (6). Hyperoxia during the neonatal period also alters lung connective tissue, alters elastic fiber structure and concentration (7), and causes an inflammatory reaction characterized by interalveolar edema and proteinosis (3,5,8). Chronic inflammation of the neonatal lung leads to fibrosis and thickening of the septa (3, 5).…”

“…The process of septation involves budding from the primary septum (saccular wall), formation of a double-capillary network, elongation of septa, coalescence of vessels to form a single capillary layer, and thinning of the septal walls (1,2). Exposure of neonatal rats to hyperoxia during alveolarization interferes with the process of septation; alveolar number and internal surface area are decreased and the parenchymal airspace is enlarged (3)(4)(5). These parameters persist up to d 40 (6).…”

Hyperoxia Causes Inducible Nitric Oxide Synthase-Mediated Cellular Damage to the Immature Rat Brain

“…Exposure to high oxygen concentrations has long been known to cause pulmonary morbidity (21,27,28). It has been shown that hyperoxia serves as a potent trigger of upregulation of iNOS mRNA expression in pulmonary cells within several hours of oxygen exposure in mice (29) as well as in rats (30).…”