title: Fas-mediated acute lung injury requires fas expression on nonmyeloid cells of the lung.
abstract: Fas (CD95) is a membrane surface receptor, which, in the lungs, is expressed in macrophages, neutrophils, and epithelial cells. In mice, Fas activation leads to a form of lung injury characterized by increased alveolar permeability. We investigated whether Fas-mediated lung injury occurs primarily as a result of Fas activation in myeloid cells (such as macrophages) or in nonmyeloid cells (such as epithelial cells). Chimeric mice lacking Fas in either myeloid or nonmyeloid cells were generated by transplanting marrow cells from lpr mice (which lack Fas) into lethally irradiated C57BL/6 mice (MyFas(-) group) or vice versa (MyFas(+) group). Additional mice transplanted with marrow cells from their same strain served as controls (Fas(+) ctr and Fas(-) ctr groups). Sixty days after transplantation, the mice received intratracheal instillations of the Fas-activating mAb Jo2 (n = 10/group), or an isotype control Ab (n = 10/group), and were euthanized 24-h later. Only animals expressing Fas in nonmyeloid cells (Fas(+) ctr and MyFas(-)) showed significant increases in lung neutrophil content and in alveolar permeability. These same mice showed tissue evidence of lung injury and caspase-3 activation in cells of the alveolar walls. Despite differences in the neutrophilic response and lung injury, there was no statistical difference in the lung cytokine concentrations (KC and MIP-2) among groups. We conclude that Fas-mediated lung injury requires expression of Fas on nonmyeloid cells of the lungs. These findings suggest that the alveolar epithelium is the primary target of Fas-mediated acute lung injury, and demonstrate that apoptotic processes may be associated with neutrophilic inflammation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Matute-Bello
authors.forename: Janet S
authors.initials: JS
authors.lastname: Lee
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Charles W
authors.initials: CW
authors.lastname: Frevert
authors.forename: Steven
authors.initials: S
authors.lastname: Mongovin
authors.forename: Venus
authors.initials: V
authors.lastname: Wong
authors.forename: Kimberly
authors.initials: K
authors.lastname: Ballman
authors.forename: Steven
authors.initials: S
authors.lastname: Sutlief
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
mesh_terms: D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000032:analysis; D004847:Epithelial Cells / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D022423:Myeloid Cells / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000473:pathology; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology*
chemical_list: D016207:Cytokines; D019014:fas Receptor; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases