Mechanical ventilation-induced apoptosis in newborn rat lung is mediated via FasL/Fas pathway.
Mechanical ventilation induces pulmonary apoptosis and inhibits alveolar development in preterm infants, but the molecular basis for the apoptotic injury is unknown. The objective was to determine the signaling mechanism(s) of ventilation (stretch)-induced apoptosis in newborn rat lung. Seven-day-old rats were ventilated with room air for 24 h using moderate tidal volumes (8.5 ml/kg). Isolated fetal rat lung epithelial and fibroblast cells were subjected to continuous cyclic stretch (5, 10, or 17% elongation) for up to 12 h. Prolonged ventilation significantly increased the number of apoptotic alveolar type II cells (i.e., terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling and 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 and 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 (JC-1 flow analysis) and no activation of caspase-9]. Universal caspases inhibition and neutralization of FasL abrogated the stretch-induced apoptosis. Prolonged mechanical ventilation induces apoptosis of alveolar type II cells in newborn rats and the mechanism appears to involve activation of the extrinsic death pathway via the FasL/Fas system.
Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute, 555 Univ. Ave., Toronto, Ontario M5G 1X8. martin.post@sickkids.ca.
Andreas A
AA
Kroon
Veronica
V
Delriccio
Irene
I
Tseu
Brian P
BP
Kavanagh
Martin
M
Post
D056809:Alveolar Epithelial Cells / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001696:Biomechanical Phenomena; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000378:metabolism*; D005347:Fibroblasts / Q000502:physiology; D051381:Rats; D012121:Respiration, Artificial / Q000009:adverse effects; D015398:Signal Transduction; D013312:Stress, Physiological; D055397:Ventilator-Induced Lung Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D019014:fas Receptor; D020169:Caspases
Fas ligand; apoptosis; caspases; mechanical ventilation; pneumocytes