Prolonged Mechanical Ventilation Induces Cell Cycle Arrest in Newborn Rat Lung

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 p27Ki

Effect of high tidal volume ventilation and in vitro stretch.

<p>High V_T ventilation of 7-day old rat lungs (A) and a continuous cyclic 17% stretch of fetal lung epithelial cells (B) rapidly decreased type-D cyclins and p^16INK4a while increasing Kip proteins, in particular p27^Kip1. Blots were reprobed with β-actin for equal loading and transfer. Representative blots of 2 experiments carried out in duplicate (A) or 3 experiments (B).</p

Ventilation inhibits lung cell growth.

<p>Immunohistochemistry ((A1) non-ventilated 7-day old rat, (A2) 7-day old rat ventilated for 12 h, (A3) 7-day old rat ventilated for 24 h, (A4) non-ventilated 8-day old rat) illustrates reduction in BrdU uptake (brown color) with duration of ventilation. (B) BrdU labeling index significantly decreased after 12 and 24 h of mechanical ventilation. Medians with 25^th and 75^th quartiles are shown, bars are 5^th and 95^th percentiles, n = 12 rat pups per time group. MV, mechanical ventilation. * p<0.05.</p