The Fas/FasL pathway impairs the alveolar fluid clearance in mouse lungs

Am J Physiol Lung Cell Mol Physiol. 2013 Sep;305(5):L377-88. doi: 10.1152/ajplung.00271.2012. Epub 2013 Jun 28.


Alveolar epithelial damage is a critical event that leads to protein-rich edema in acute lung injury (ALI), but the mechanisms leading to epithelial damage are not completely understood. Cell death by necrosis and apoptosis occurs in alveolar epithelial cells in the lungs of patients with ALI. Fas activation induces apoptosis of alveolar epithelial cells, but its role in the formation of lung edema is unclear. The main goal of this study was to determine whether activation of the Fas/Fas ligand pathway in the lungs could alter the function of the lung epithelium, and the mechanisms involved. The results show that Fas activation alters the alveolar barrier integrity and impairs the ability of the lung alveolar epithelium to reabsorb fluid from the air spaces. This result was dependent on the presence of a normal Fas receptor and was not affected by inflammation induced by Fas activation. Alteration of the fluid transport properties of the alveolar epithelium was partially restored by β-adrenergic stimulation. Fas activation also caused apoptosis of alveolar endothelial cells, but this effect was less pronounced than the effect on the alveolar epithelium. Thus, activation of the Fas pathway impairs 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.

Keywords: Fas ligand; acute lung injury; alveolar epithelial fluid transport; apoptosis; edema; endothelium; epithelium.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Lung Injury / metabolism
  • Acute Lung Injury / pathology*
  • Adenoma / drug therapy
  • Adenoma / metabolism
  • Adenoma / pathology*
  • Adrenergic beta-Agonists / pharmacology
  • Animals
  • Apoptosis
  • Bronchoalveolar Lavage Fluid
  • Cell Membrane Permeability
  • Cytokines / metabolism
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism*
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Isoproterenol / pharmacology
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / pathology*
  • Pulmonary Edema / drug therapy
  • Pulmonary Edema / metabolism
  • Pulmonary Edema / pathology*
  • Tumor Cells, Cultured
  • fas Receptor / genetics
  • fas Receptor / metabolism*


  • Adrenergic beta-Agonists
  • Cytokines
  • Fas Ligand Protein
  • Fas protein, mouse
  • fas Receptor
  • Isoproterenol