Fas ligand triggers pulmonary silicosis.
We investigated the role of Fas ligand in murine silicosis. Wild-type mice instilled with silica developed severe pulmonary inflammation, with local production of tumor necrosis factor (TNF)-alpha, and interstitial neutrophil and macrophage infiltration in the lungs. Strikingly, Fas ligand-deficient generalized lymphoproliferative disease mutant (gld) mice did not develop silicosis. The gld mice had markedly reduced neutrophil extravasation into bronchoalveolar space, and did not show increased TNF-alpha production, nor pulmonary inflammation. Bone marrow chimeras and local adoptive transfer demonstrated that wild-type, but not Fas ligand-deficient lung macrophages recruit neutrophils and initiate silicosis. Silica induced Fas ligand expression in lung macrophages in vitro and in vivo, and promoted Fas ligand-dependent macrophage apoptosis. Administration of neutralizing anti-Fas ligand antibody in vivo blocked induction of silicosis. Thus, Fas ligand plays a central role in induction of pulmonary silicosis.
Borges
V M
VM
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 21944-970, Rio de Janeiro, Brazil.
Falcão
H
H
Leite-Júnior
J H
JH
Alvim
L
L
Teixeira
G P
GP
Russo
M
M
Nóbrega
A F
AF
Lopes
M F
MF
Rocco
P M
PM
Davidson
W F
WF
Linden
R
R
Yagita
H
H
Zin
W A
WA
DosReis
G A
GA
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D004195:Disease Models, Animal; D053222:Fas Ligand Protein; D005260:Female; D066298:In Vitro Techniques; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000473:pathology; D011828:Radiation Chimera; D012822:Silicon Dioxide / Q000633:toxicity; D012829:Silicosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D014409:Tumor Necrosis Factor-alpha; D012822:Silicon Dioxide