Prolonged Mechanical Ventilation Induces Cell Cycle Arrest in Newborn Rat Lung 英文参考文献.docVIP

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Prolonged Mechanical Ventilation Induces Cell Cycle Arrest in Newborn Rat Lung 英文参考文献.doc

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Prolonged Mechanical Ventilation Induces Cell Cycle Arrest in Newborn Rat Lung 英文参考文献

ProlongedMechanicalVentilationInducesCellCycle ArrestinNewbornRatLung AndreasA.Kroon1,5,JinxiaWang1,BrianKavanagh1,3,4,ZhenHuang1,MaciejKuliszewski1,JohannesB. vanGoudoever5,6,7,MartinPost1,2,3 * 1Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Canada, 2Department of Pediatrics University of Toronto, Toronto,Canada,3DepartmentofPhysiology,UniversityofToronto,Toronto,Canada,4DepartmentsofCriticalCareMedicineandAnesthesia,HospitalforSickChildren, UniversityofToronto,Toronto,Canada,5DepartmentofPediatrics,ErasmusMC-Sophia,Rotterdam,TheNetherlands,6DepartmentofPediatrics,AmsterdamMedical CenterEmma’sChildren’sHospital,Amsterdam,TheNetherlands,7DepartmentofPediatrics,FreeUniversityHospital,Amsterdam,TheNetherlands Abstract Rationale: The molecular mechanism(s) by which mechanical ventilation disrupts alveolar development, a hallmark of bronchopulmonarydysplasia,isunknown. Objective: To determine the effect of 24h of mechanical ventilation on lung cell cycle regulators, cell proliferation and alveolarformationinnewbornrats. Methods: Seven-day old rats were ventilated with room air for 8, 12 and 24h using relatively moderate tidal volumes (8.5mL.kg21 ). Measurement and Main Results: Ventilation for 24h (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 12h of ventilation and completely arrested after 24h. Cyclin D1 and E1 mRNA and protein levels were decreased after 8–24h of ventilation, while that of p27Kip1 was significantly increased. Mechanical ventilationfor24halsoincreasedlevelsofp57Kip2,decreasedthatofp16INK4a,whilethelevelsofp21Waf/Cip1 andp15INK4b were unchanged. Increased p27Kip1 expression coincided with reduced phosphorylation of p27Kip1 at Thr157, Thr187 and Thr198 (p,0.05),therebypromotingitsnuclearlocalization.Similar-butmorerapid-change