Abstract
RationaleThe molecular mechanism(s) by which mechanical ventilation disrupts alveolar development, a hallmark of bronchopulmonary dysplasia, is unknown.ObjectiveTo determine the effect of 24 h of mechanical ventilation on lung cell cycle regulators, cell proliferation and alveolar formation in newborn rats.MethodsSeven-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 ResultsVentilation 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.ConclusionThis 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.
Highlights
Introduction of more gentle ventilation strategies -together with surfactant replacement and antenatal corticosteroids- has improved the survival rate of very premature infants
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 cyclindependent kinases (Cdk) inhibitor proteins (p27Kip1, p57Kip2) from the Kip family
There are two distinct Cdk inhibitors (CKI) families in mammalian cells: INK4 proteins, which block the progression of the cell cycle by binding to either Cdk4 or Cdk6 and inhibiting the action of cyclin D; and, Cip/Kip proteins that inhibit a broader spectrum of cyclin-Cdk complexes [14,15,16]
Summary
Introduction of more gentle ventilation strategies -together with surfactant replacement and antenatal corticosteroids- has improved the survival rate of very premature infants. Infants born at #26 weeks of gestation are at the greatest risk of developing such ‘new’ BPD [2], a syndrome of arrested lung development with fewer and larger alveoli and dysmorphic vasculature [3]. Lung development between 24–32 weeks of gestation is characterized by extensive vasculogenesis within the developing terminal saccules, followed by secondary crest formation as well as interstitial extracellular matrix loss and remodeling [7]. This tissue remodeling requires well-coordinated regulation of cell proliferation and apoptosis. There are two distinct CKI families in mammalian cells: INK4 proteins, which block the progression of the cell cycle by binding to either Cdk or Cdk and inhibiting the action of cyclin D; and, Cip/Kip proteins that inhibit a broader spectrum of cyclin-Cdk complexes [14,15,16]
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