Cytokine and adhesion molecule requirements for lung injury induced by anti-glomerular basement membrane antibody.
Acute hemorrhagic lung injury occurs in humans with anti-GBM antibody (Goodpasture's syndrome), however, the mechanism of this injury is still largely unknown. To date, treatment has been confined to steroids and plasmaphoresis. Infusion of anti-GBM antibody into rats caused lung injury with intra-alveolar hemorrhage and intrapulmonary accumulation of neutrophils. Lung injury was dependent on the presence of neutrophils and complement and required both TNF alpha and IL-1. Experiments employing blocking antibodies to adhesion molecules demonstrated requirements for the beta 1 integrin VLA-4, beta 2 integrins LFA-1 and Mac-1, and L-selection. The endothelial cell adhesion molecules, E-selectin and ICAM-1, were also required for the full development of lung injury. Inhibition of TNF alpha or IL-1 or adhesion molecules reduced both lung injury and tissue neutrophil accumulation. Thus, this study underscores cytokine and adhesion molecule requirements for neutrophil mediated injury in lung and kidney caused by anti-GBM, suggesting potential targets for the treatment of Goodpasture's syndrome in humans.
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
M S
MS
Mulligan
A B
AB
Lentsch
T P
TP
Shanley
M
M
Miyasaka
K J
KJ
Johnson
P A
PA
Ward
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D000906:Antibodies / Q000008:administration & dosage*; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001485:Basement Membrane / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003165:Complement System Proteins / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology*; D019041:L-Selectin / Q000378:metabolism; D008168:Lung / Q000276:immunology; D055370:Lung Injury; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000276:immunology; D051381:Rats; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors / Q000378:metabolism; D012756:Sheep; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism
D000906:Antibodies; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D016207:Cytokines; D007074:Immunoglobulin G; D039041:Integrin alpha4beta1; D016023:Integrins; D007375:Interleukin-1; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D016201:Receptors, Lymphocyte Homing; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D003165:Complement System Proteins