University of Giessen Lung Center, (UGLC), Medical Clinic V, Justus-Liebig University Giessen, Klinikstrasse 36, D-35392, Germany.
Eur Respir J. 2010 Jul;36(1):187-95. doi: 10.1183/09031936.00143308. Epub 2009 Dec 23.
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.
抗中性粒细胞胞质抗体（c-ANCA）针对蛋白酶 3（PR3）与 Wegener 肉芽肿（WG）的发病机制有关。暴发性疾病可能表现为急性肺损伤（ALI）。在这项研究中，使用离体大鼠肺建立了 WG 的 ALI 模型。用肿瘤坏死因子（TNF）预刺激分离的人多形核白细胞（PMN）以诱导 PR3 的表面表达。TNF 预刺激的中性粒细胞和单克隆抗 PR3 抗体的共灌注诱导离体肺的重量显著增加。当与 TNF 预刺激的 PMN 共灌注对照免疫球蛋白 G 时，未观察到这种作用。c-ANCA 诱导的水肿形成与作为增加肺内皮通透性的标志物的毛细血管滤过系数增加平行。相比之下，肺动脉压不受影响。在存在氧自由基清除剂超氧化物歧化酶和 NADPH 氧化酶抑制剂的情况下，可以预防 c-ANCA 诱导的肺水肿。中性粒细胞弹性蛋白酶抑制剂同样有效地预防 c-ANCA 诱导的肺损伤。总之，抗 PR3 抗体诱导中性粒细胞介导的、弹性蛋白酶和氧自由基依赖性 ALI 在离体肺中。该实验模型支持 c-ANCA 在 WG 中的致病作用假说，并为治疗暴发性 WG 中的肺损伤的治疗策略的开发提供了可能性。
