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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents

ID: 559718.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis
Authors:Hattar, K.; Oppermann, S.; Ankele, C.; Weissmann, N.; Schermuly, R. T.; Bohle, R. M.; Moritz, R.; Krogel, B.; Seeger, W.; Grimminger, F.; Sibelius, U.; Grandel, U.
Title of Journal:Eur Respir J
Issue / Number:1
Start Page:187
End Page:95
Audience:Not Specified
Abstract / Description: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.
Free Keywords:Acute Lung Injury/drug therapy/*immunology/pathology/prevention & control; Animals; Antibodies, Antineutrophil Cytoplasmic/*immunology/pharmacology; Antibodies, Monoclonal/pharmacology; Disease Models, Animal; Enzyme Inhibitors/pharmacology; Humans; Immunoglobulin G/immunology/pharmacology; Leukocyte Elastase/antagonists & inhibitors; Myeloblastin/immunology; NADPH Oxidase/antagonists & inhibitors; Neutrophil Activation/immunology; Neutrophils/*immunology; Pulmonary Edema/immunology/prevention & control; Rats; Superoxide Dismutase/analysis; Tumor Necrosis Factor-alpha/immunology/pharmacology; Wegener Granulomatosis/drug therapy/*immunology/prevention & control
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:University of Giessen Lung Center, (UGLC), Medical Clinic V, Justus-Liebig University Giessen, Klinikstrasse 36, D-35392, Germany.
Identifiers:ISSN:1399-3003 (Electronic) 0903-1936 (Linking)
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