Relationship of acute lung inflammatory injury to Fas/FasL system.
There is mounting evidence that apoptosis plays a significant role in tissue damage during acute lung injury. To evaluate the role of the apoptosis mediators Fas and FasL in acute lung injury, Fas (lpr)- or FasL (gld)-deficient and wild-type mice were challenged with intrapulmonary deposition of IgG immune complexes. Lung injury parameters ((125)I-albumin leak, accumulation of myeloperoxidase, and wet lung weights) were measured and found to be consistently reduced in both lpr and gld mice. In wild-type mice, lung injury was associated with a marked increase in Fas protein in lung. Inflamed lungs of wild-type mice showed striking evidence of activated caspase-3, which was much diminished in inflamed lungs from lpr mice. Intratracheal administration of a monoclonal Fas-activating antibody (Jo2) in wild-type mice induced MIP-2 and KC production in bronchoalveolar lavage fluids, and a murine alveolar macrophage cell line (MH-S) showed significantly increased MIP-2 production after incubation with this antibody. Bronchoalveolar lavage fluid content of MIP-2 and KC was substantially reduced in lpr mice after lung injury when compared to levels in wild-type mice. These data suggest that the Fas/FasL system regulates the acute lung inflammatory response by positively affecting CXC-chemokine production, ultimately leading to enhanced neutrophil influx and tissue damage.
Neff
Thomas A
TA
Department of Pathology, The University of Michigan Medical School, 1301 Catherine Rd., Ann Arbor, MI 48109-0602, USA.
Guo
Ren-Feng
RF
Neff
Simona B
SB
Sarma
J Vidya
JV
Speyer
Cecilia L
CL
Gao
Hongwei
H
Bernacki
Kurt D
KD
Huber-Lang
Markus
M
McGuire
Stephanie
S
Hoesel
L Marco
LM
Riedemann
Niels C
NC
Beck-Schimmer
Beatrice
B
Zetoune
Firas S
FS
Ward
Peter A
PA
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D007074:Immunoglobulin G / Q000737:chemistry; D007249:Inflammation / Q000473:pathology*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D055370:Lung Injury; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D009929:Organ Size; D010539:Permeability; D009195:Peroxidase / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D061945:Caspase Inhibitors; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C404915:Cxcl2 protein, mouse; D004791:Enzyme Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D019014:fas Receptor; D009195:Peroxidase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases
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