RT Journal Article
SR Electronic
T1 Fas activation impairs the alveolar epithelial function in mice by mechanisms involving apoptosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP p812
VO 38
IS Suppl 55
A1 Raquel Herrero
A1 Lincoln S. Smith
A1 Osamu Kajikawa
A1 Stephen Mongovin
A1 Venus A. Wong
A1 Gustavo Matute-Bello
A1 Thomas R. Martin
YR 2011
UL http://erj.ersjournals.com/content/38/Suppl_55/p812.abstract
AB Background: Alveolar epithelial damage is a critical event that leads to protein-rich edema in acute lung injury (ALI). Even though Fas activation induces apoptosis of alveolar epithelial cells, its role in the formation of lung edema is unclear.Aim: We investigated whether inhibition of caspase-dependent apoptosis protects against Fas-mediated epithelial injury in mouse lungs.Methods: We administered the pan-caspase inhibitor Z-VAD.fmk (10 mg/kg) or vehicle subcutaneously to mice treated with one intratracheal dose of recombinant human sFasL (rh-sFasL, 25 ng/g) or PBS, then studied the mice 16 h later. We measured alveolar fluid clearance (AFC) by intratracheal instillation of FITC-human albumin, and protein permeability by measuring IgM in bronchoalveolar lavage fluid. Caspase-3 activity and cytokines (IL-1β, IL-6, KC, TNF-α) were measured in lung homogenates.Results: Compared with PBS-treated mice, the intratracheal instillation of rh-sFasL decreased AFC (PBS= 20.0±1.3% vs rh-sFasL= 1.9±2.4%, p<0.05), and increased protein permeability (PBS= 34.7±18.3 vs rh-sFasL= 350±40.4 ng/mL, p<0.05), caspase-3 activity and cytokine production. In contrast, mice treated with rh-sFasL and Z-VAD.fmk had normal AFC (17.0±2.3%, p<0.05) and a smaller increase in protein permeability (152.5±18.4 ng/mL, p<0.05), associated with a reduction of caspase-3 activity and an increase in cytokine production. Z-VAD.fmk was not harmful in PBS-treated mice.Conclusion: Activation of the Fas pathway impairs the alveolar epithelial function in mouse lungs by mechanisms involving caspase-dependent apoptosis, suggesting that targeting apoptotic pathways could reduce the formation of lung edema in ALI.