Bronchopulmonary dysplasia (BPD) remains an important result of newborn intensive care. Progress in preventing BPD has been limited by an incomplete understanding of the pathophysiology of BPD. As previously described by Northway (Lab Invest 48(6):735,1983) a hallmark of chronic neonatal hyperoxia is decreased pulmonary alveolarization and fibrosis. We used the murine model of neonatal oxygen injury to investigate the effects of chronic hyperoxia on cell proliferation. After 14 days the lungs of newborn FVB/N mice exposed continuously from birth to 85% oxygen had decreased alveolar septation, increased terminal airspace size (407 vs. 2932 um2), and increased fibrosis. To determine whether decreased alveolar septation was associated with changes in cellular proliferation or with cell death, proliferative indexes and apoptosis were measured. After 3 days of hyperoxia, cellular proliferation, measured by BrdU labeling, was significantly less in oxygen exposed pups compared to room air controls (30 + 10% RA vs. 8 + 4% O2). Decreased proliferation continues through the first week (16 + 5% RA vs. 7 + 3% O2 at day 7), but is not different from room air animals at two weeks. Conversely, chronic hyperoxia did not increase apoptosis. Lung inflammation is presumed to play a role in hyperoxic lung injury. Perivascular and peribronchiolar neutrophil infiltrates are present by 1 week of hyperoxic exposure and peaks after 2 weeks. RT-PCR analysis was used to analyze expression of neutrophil chemotactic factors. In oxygen exposed pups, IL-1 and MIP 1α are increased by 5 days and remain elevated through 14 days. No significant differences were seen in TNFα or MIP-2. We conclude that the decreased alveolarization resulting from chronic neonatal hyperoxia is associated with a decrease in cellular proliferation and no change in apoptosis. It remains to be established whether the increase in inflammatory mediators plays a role in neonatal pulmonary oxygen injury. Funded by NIH KO8 HL03101-01A1
