Prolonged Mechanical Ventilation Induces Cell Cycle Arrest in Newborn Rat Lung

The molecular mechanism(s) by which mechanical ventilation disrupts alveolar development, a hallmark of bronchopulmonary dysplasia, is unknown.To determine the effect of 24 h of mechanical ventilation on lung cell cycle regulators, cell proliferation and alveolar formation in newborn rats.Seven-day old rats were ventilated with room air for 8, 12 and 24 h using relatively moderate tidal volumes (8.5 mL.kg?).Ventilation for 24 h (h) decreased the number of elastin-positive secondary crests and increased the mean linear intercept, indicating arrest of alveolar development. Proliferation (assessed by BrdU incorporation) was halved after 12 h of ventilation and completely arrested after 24 h. Cyclin D1 and E1 mRNA and protein levels were decreased after 8-24 h of ventilation, while that of p27(Kip1) was significantly increased. Mechanical ventilation for 24 h also increased levels of p57(Kip2), decreased that of p16(INK4a), while the levels of p21(Waf/Cip1) and p15(INK4b) were unchanged. Increased p27(Kip1) expression coincided with reduced phosphorylation of p27(Kip1) at Thr?, Thr? and Thr? (p