title: Prolonged mechanical ventilation induces cell cycle arrest in newborn rat lung.
abstract: BACKGROUND
  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).
  
  
  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 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 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.
  
  
  CONCLUSIONS
  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 (p27(Kip1), p57(Kip2)) from the Kip family.
authors.affiliation: Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Canada.
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Kroon
authors.forename: Jinxia
authors.initials: J
authors.lastname: Wang
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kavanagh
authors.forename: Brian
authors.initials: B
authors.lastname: Kavanagh
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
authors.forename: Maciej
authors.initials: M
authors.lastname: Kuliszewski
authors.forename: Johannes B
authors.initials: JB
authors.lastname: van Goudoever
authors.forename: Martin
authors.initials: M
authors.lastname: Post
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D002453:Cell Cycle / Q000502:physiology*; D049109:Cell Proliferation; D004622:Embryo, Mammalian; D005260:Female; D005333:Fetus / Q000166:cytology / Q000502:physiology; D008168:Lung / Q000166:cytology / Q000196:embryology / Q000254:growth & development* / Q000502:physiology*; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000166:cytology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial / Q000009:adverse effects*; D013997:Time Factors