TY - JOUR T1 - c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis JF - European Respiratory Journal JO - Eur Respir J SP - 187 LP - 195 DO - 10.1183/09031936.00143308 VL - 36 IS - 1 AU - K. Hattar AU - S. Oppermann AU - C. Ankele AU - N. Weissmann AU - R.T. Schermuly AU - R.M. Bohle AU - R. Moritz AU - B. Krögel AU - W. Seeger AU - F. Grimminger AU - U. Sibelius AU - U. Grandel Y1 - 2010/07/01 UR - http://erj.ersjournals.com/content/36/1/187.abstract N2 - 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. ER -