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233 Mechanical Ventilation-Induced Apoptosis in Newborn Rat Lung is Mediated Via Fasl/Fas Pathway
  1. A Kroon1,2,
  2. V Del Riccio2,
  3. I Tseu2,
  4. Z Huang2,
  5. J Wang2,
  6. M Post2
  1. 1Erasmus MC - Sophia, Rotterdam, The Netherlands
  2. 2Lung Biology Research, Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, ON, Canada

Abstract

Rationale Mechanical ventilation induces pulmonary apoptosis and inhibits alveolar development in preterm infants, but the molecular basis for this apoptotic injury is unknown.

Objective To determine the signaling mechanism(s) of ventilation(stretch)-induced apoptosis in newborn rat lung.

Methods Seven-day old rats were ventilated with room air for 24 h using moderate tidal volumes (8.5 mL.kg-1). Isolated fetal rat lung epithelial and fibroblast cells were subjected to continuous cyclic stretch (5, 10 or 17% elongation) for up to 12 h.

Measurements and main results Prolonged ventilation increased significantly the number of apoptotic alveolar type II cells (i.e. TUNEL-labelling, anti-cleaved caspase-3 immunochemistry) and was associated with increased expression of the apoptotic mediator Fas Ligand (FasL). Fetal lung epithelial cells, but not fibroblasts, subjected to maximal (i.e. 17%, but not lesser elongation) cyclic stretch exhibited increased apoptosis (i.e. nuclear fragmentation; DNA laddering) which appeared to be mediated via the extrinsic pathway (increased expression of FasL and cleaved caspase-3, -7 and -8). The intrinsic pathway appeared not to be involved (minimal mitochondrial membrane depolarization (i.e. JC-1 flow analysis); no activation of caspase-9). Universal caspases inhibition and neutralization of FasL abrogated the stretch-induced apoptosis.

Conclusion Prolonged mechanical ventilation induces apoptosis of alveolar type II cells in newborn rats and the cellular mechanism involves activation of the extrinsic death pathway via the FasL/Fas system.

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