Rationale: The molecular mechanism(s) by which mechanical ventilation disrupts alveolar development, a hallmark of bronchopulmonary dysplasia, is unknown. Objective: To determine the effect of 24 h of mechanical ventilation on lung cell cycle regulators, cell proliferation and alveolar formation in newborn rats. Methods: Seven-day old rats were ventilated with room air for 8, 12 and 24 h using relatively moderate tidal volumes (8.5 mL.kg-1). Measurement and Main Results: 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 p27Kip1 was significantly increased. Mechanical ventilation for 24 h also increased levels of p57Kip2, decreased that of p16INK4a, while the levels of p21Waf/Cip1 and p15INK4b were unchanged. Increased p27Kip1 expression coincided with reduced phosphorylation of p27Kip1 at Thr157, Thr187 and Thr198 (p<0.05), thereby promoting its nuclear localization. Similar -but more rapid- changes in cell cycle regulators were noted when 7-day rats were ventilated with high tidal volume (40 mL.kg-1) and when fetal lung epithelial cells were subjected to a continuous (17% elongation) cyclic stretch. Conclusion: This is the first demonstration that prolonged (24 h) of mechanical ventilation causes cell cycle arrest in newborn rat lungs; the arrest occurs in G1 and is caused by increased expression and nuclear localization of Cdk inhibitor proteins (p27Kip1, p57Kip2) from the Kip family.

Additional Metadata
Keywords airway pressure, animal cell, animal experiment, animal tissue, article, artificial ventilation, blood gas analysis, cell cycle G1 phase, cell cycle arrest, cell cycle regulation, cell proliferation, controlled study, cyclin D2, cyclin E, cyclin E1, cyclin dependent kinase inhibitor 1, cyclin dependent kinase inhibitor 1B, cyclin dependent kinase inhibitor 2A, cyclin dependent kinase inhibitor 2B, down regulation, elastin, fetus, growth inhibition, long term care, lung alveolus cell, lung development, newborn, nonhuman, protein dephosphorylation, protein expression, protein localization, rat, therapy effect, tidal volume, transcription regulation, unclassified drug
Persistent URL dx.doi.org/10.1371/journal.pone.0016910, hdl.handle.net/1765/23174
Citation
Kroon, A.A, Wang, J, Kavanagh, B, Huang, Z, Kuliszewski, M, van Goudoever, J.B, & Post, M.R. (2011). Prolonged mechanical ventilation induces cell cycle arrest in newborn rat lung. PLoS ONE, 6(2). doi:10.1371/journal.pone.0016910