Tumor necrosis factor participates in the pathogenesis of acute immune complex alveolitis in the rat.
We have examined the role of intrapulmonary TNF in a rat model of acute immune complex-triggered alveolitis. Intratracheal instillation of IgG anti-bovine serum albumin (anti-BSA) followed by intravenous infusion of BSA results in acute alveolitis. Over the 4-h course of evolving lung injury, a 10-fold increase in TNF activity occurred in bronchoalveolar lavage (BAL) fluid. Immunohistochemical analysis of lung sections and BAL cells revealed that alveolar macrophages are the chief source of TNF. Antibodies that specifically neutralize rat TNF activity were raised in rabbits immunized with recombinant mouse TNF alpha. When administered into the lungs with anti-BSA, anti-TNF resulted in a marked reduction (up to 61%) in lung injury. Intratracheal instillation of exogenous TNF alone, or in combination with anti-BSA, resulted in an increase in lung injury compared to controls. Morphometric analysis and measurements of myeloperoxidase activities in whole lung extracts from rats treated with anti-TNF revealed a marked reduction in neutrophils compared to positive controls. The anti-TNF antibody preparation did not inhibit in vitro complement activation or diminish neutrophil chemotactic activity present in activated rat serum. These data indicate that intrapulmonary TNF activity is required for the full development of acute immune complex-triggered alveolitis, that alveolar macrophages are the primary source of this cytokine, and that TNF participates in the pathogenesis of immune complex alveolitis through a mechanism involving neutrophil recruitment.
Warren
J S
JS
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602.
Yabroff
K R
KR
Remick
D G
DG
Kunkel
S L
SL
Chensue
S W
SW
Kunkel
R G
RG
Johnson
K J
KJ
Ward
P A
PA
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism; D002199:Capillary Permeability; D002634:Chemotaxis, Leukocyte; D003167:Complement Activation; D007105:Immune Complex Diseases / Q000276:immunology* / Q000473:pathology; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply; D008171:Lung Diseases / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000473:pathology / Q000502:physiology; D011650:Pulmonary Alveoli / Q000276:immunology* / Q000473:pathology; D051381:Rats; D012710:Serum Albumin, Bovine / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; D012710:Serum Albumin, Bovine