title: Intrapulmonary tumor necrosis factor triggers local platelet-activating factor production in rat immune complex alveolitis.
abstract: Recent studies suggest that intrapulmonary tumor necrosis factor (TNF) participates in the pathogenesis of acute IgG immune complex alveolitis through a mechanism involving neutrophil polymorphonuclear leukocyte (PMN) recruitment. There are few in vivo studies that address mechanisms of TNF-dependent PMN recruitment and tissue injury. We have examined the relationship between intrapulmonary TNF and locally generated platelet-activating factor (PAF) in the development of acute alveolitis. Intratracheal instillation of IgG anti-bovine serum albumin followed by intravenous bovine serum albumin results in acute neutrophil-mediated alveolitis. Induction of IgG immune complex lung injury resulted in a marked increase in the whole lung and bronchoalveolar lavage PAF levels. Intratracheal instillation of the PAF antagonists, L-652,731 (Merck, Sharpe, and Dohme, Rahway, New Jersey) or WEB-2086 (Boehringer), attenuated pulmonary vascular leakage and PMN recruitment into the alveolar compartment. Neutralization of intrapulmonary TNF with anti-TNF antibodies reduced pulmonary vascular permeability, PMN recruitment, and whole lung PAF levels. Incubation of isolated mouse alveolar macrophages with recombinant murine TNF resulted in rapid (30 to 60 minutes), cell concentration-dependent PAF release. The presence of high concentrations of PAF in whole lungs obtained from PMN-depleted rats after immune complex deposition suggest that recruited PMN are not the predominant source of intrapulmonary PAF in this model. These data suggest that acute IgG immune complex alveolitis is in part mediated by TNF-triggered PAF production and that locally produced PAF promotes recruitment of PMN into the alveolar compartment.
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors: J S
authors: JS
authors: Warren
authors: P A
authors: PA
authors: Barton
authors: D M
authors: DM
authors: Mandel
authors: K
authors: K
authors: Matrosic
mesh_terms: D000542:Alveolitis, Extrinsic Allergic / Q000503:physiopathology*; D000818:Animals; D000906:Antibodies; D000936:Antigen-Antibody Complex; D001381:Azepines / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D007074:Immunoglobulin G; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D008297:Male; D009504:Neutrophils / Q000502:physiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
chemical_list: D000906:Antibodies; D000936:Antigen-Antibody Complex; D001381:Azepines; D005663:Furans; D007074:Immunoglobulin G; D010972:Platelet Activating Factor; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C052518:WEB 2086; C047504:2,5-bis(3,4,5-trimethoxyphenyl)tetrahydrofuran