Fas (CD95) induces alveolar epithelial cell apoptosis in vivo: implications for acute pulmonary inflammation.
Activation of the Fas/FasL system induces apoptosis of susceptible cells, but may also lead to nuclear factor kappaB activation. Our goal was to determine whether local Fas activation produces acute lung injury by inducing alveolar epithelial cell apoptosis and by generating local inflammatory responses. Normal mice (C57BL/6) and mice deficient in Fas (lpr) were treated by intranasal instillation of the Fas-activating monoclonal antibody (mAb) Jo2 or an irrelevant control mAb, and studied 6 or 24 hours later using bronchoalveolar lavage (BAL), histopathology, DNA nick-end-labeling assays, and electron microscopy. Normal mice treated with mAb Jo2 had significant increases in BAL protein at 6 hours, and BAL neutrophils at 24 hours, as compared to lpr mice and to mice treated with the irrelevant mAb. Neutrophil recruitment was preceded by increased mRNA expression for tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-2, macrophage chemotactic protein-1, and interleukin-6, but not interferon-gamma, transforming growth factor-ss, RANTES, eotaxin, or IP-10. Lung sections from Jo2-treated normal mice showed neutrophilic infiltrates, alveolar septal thickening, hemorrhage, and terminal dUTP nick-end-labeling-positive cells in the alveolar septae and airspaces. Type II pneumocyte apoptosis was confirmed by electron microscopy. Fas activation in vivo results in acute alveolar epithelial injury and lung inflammation, and may be important in the pathogenesis of acute lung injury.
Matute-Bello
G
G
Divisions of Pulmonary and Critical Care Medicine, University of Washington, Seattle 98195, USA.
Winn
R K
RK
Jonas
M
M
Chi
E Y
EY
Martin
T R
TR
Liles
W C
WC
D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053222:Fas Ligand Protein; D015870:Gene Expression / Q000187:drug effects; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009504:Neutrophils / Q000166:cytology; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor