Fas ligand-induced murine pulmonary inflammation is reduced by a stable decoy receptor 3 analogue.
Fas ligand (FasL)-induced lung inflammation has recently been suggested to play an important role in the pathogenesis of acute respiratory disease syndrome (ARDS). In order to further explore this connection, we established a FasL-induced murine model of pulmonary inflammation. Instillation of recombinant FasL (rFasL) into the lung induced neutrophil infiltration and increased pulmonary permeability, as evidenced by increased total protein in the airspace; both occur in patients with ARDS. These effects were accompanied with a rapid induction of proinflammatory mediators: cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) and the chemokines macrophage inflammatory protein-2 (MIP-2) and KC. Pretreatment with a FasL antagonist, a decoy receptor 3 analogue (DcR3 analogue), reduced neutrophil infiltration into the airspace and resulted in a highly significant reduction in the levels of GM-CSF, MIP-2 and KC in bronchoalveolar lavage (BAL) fluid. We postulate that rFasL may be responsible for induction of proinflammatory chemokines and cytokines in the lung, which in turn attract neutrophil infiltration into the airspace. This proinflammatory process and the associated pulmonary permeability may, in part, explain the association of FasL with severe pulmonary inflammation, such as ARDS, and shed new light on FasL and its role in lung injury.
D000818:Animals; D054426:Chemokine CXCL2; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000276:immunology; D010538:Peritonitis / Q000276:immunology; D011956:Receptors, Cell Surface / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D012128:Respiratory Distress Syndrome / Q000276:immunology* / Q000517:prevention & control
D054426:Chemokine CXCL2; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D015846:Monokines; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D016178:Granulocyte-Macrophage Colony-Stimulating Factor