RT Journal Article
SR Electronic
T1 c-ANCA-induced neutrophil-mediated lung injury: a model of acute Wegener's granulomatosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 187
OP 195
DO 10.1183/09031936.00143308
VO 36
IS 1
A1 K. Hattar
A1 S. Oppermann
A1 C. Ankele
A1 N. Weissmann
A1 R.T. Schermuly
A1 R.M. Bohle
A1 R. Moritz
A1 B. Krögel
A1 W. Seeger
A1 F. Grimminger
A1 U. Sibelius
A1 U. Grandel
YR 2010
UL http://erj.ersjournals.com/content/36/1/187.abstract
AB 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.