title: c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis.
abstract: Anti-neutrophil cytoplasmic antibodies (c-ANCA) targeting proteinase 3 (PR3) are implicated in the pathogenesis of Wegener's granulomatosis (WG). Fulminant disease can present as acute lung injury (ALI). In this study, a model of ALI in WG was developed using isolated rat lungs. Isolated human polymorphonuclear leukocytes (PMNs) were primed with tumour necrosis factor (TNF) to induce surface expression of PR3. Co-perfusion of TNF-primed neutrophils and monoclonal anti-PR3 antibodies induced a massive weight gain in isolated lungs. This effect was not observed when control immunoglobulin G was co-perfused with TNF-primed PMNs. The c-ANCA-induced oedema formation was paralleled by an increase in the capillary filtration coefficient as a marker of increased pulmonary endothelial permeability. In contrast, pulmonary artery pressure was not affected. In the presence of the oxygen radical scavenger superoxide dismutase and a NADPH oxidase inhibitor, c-ANCA-induced lung oedema could be prevented. Inhibition of neutrophil elastase was equally effective in preventing c-ANCA-induced lung injury. In conclusion, anti-PR3 antibodies induced neutrophil mediated, elastase- and oxygen radical-dependent ALI in the isolated lung. This experimental model supports the hypothesis of a pathogenic role for c-ANCA in WG and offers the possibility of the development of therapeutic strategies for the treatment of lung injury in fulminant WG.
authors.affiliation: University of Giessen Lung Center, (UGLC), Medical Clinic V, Justus-Liebig University Giessen, Klinikstrasse 36, D-35392, Germany. katja.hattar@innere.med.unigiessen.de
authors.forename: K
authors.initials: K
authors.lastname: Hattar
authors.forename: S
authors.initials: S
authors.lastname: Oppermann
authors.forename: C
authors.initials: C
authors.lastname: Ankele
authors.forename: N
authors.initials: N
authors.lastname: Weissmann
authors.forename: R T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: R M
authors.initials: RM
authors.lastname: Bohle
authors.forename: R
authors.initials: R
authors.lastname: Moritz
authors.forename: B
authors.initials: B
authors.lastname: Krögel
authors.forename: W
authors.initials: W
authors.lastname: Seeger
authors.forename: F
authors.initials: F
authors.lastname: Grimminger
authors.forename: U
authors.initials: U
authors.lastname: Sibelius
authors.forename: U
authors.initials: U
authors.lastname: Grandel
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology* / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D014890:Granulomatosis with Polyangiitis / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors; D053146:Myeloblastin / Q000276:immunology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D011654:Pulmonary Edema / Q000276:immunology / Q000517:prevention & control; D051381:Rats; D013482:Superoxide Dismutase / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; D019272:Leukocyte Elastase; D053146:Myeloblastin