Warren J S, Barton P A, Mandel D M, Matrosic K
Department of Pathology, University of Michigan Medical School, Ann Arbor.
Lab Invest. 1990 Dec;63(6):746-54.
Recent studies suggest that intrapulmonary tumor necrosis factor (TNF) participates in the pathogenesis of acute IgG immune complex alveolitis through a mechanism involving neutrophil polymorphonuclear leukocyte (PMN) recruitment. There are few in vivo studies that address mechanisms of TNF-dependent PMN recruitment and tissue injury. We have examined the relationship between intrapulmonary TNF and locally generated platelet-activating factor (PAF) in the development of acute alveolitis. Intratracheal instillation of IgG anti-bovine serum albumin followed by intravenous bovine serum albumin results in acute neutrophil-mediated alveolitis. Induction of IgG immune complex lung injury resulted in a marked increase in the whole lung and bronchoalveolar lavage PAF levels. Intratracheal instillation of the PAF antagonists, L-652,731 (Merck, Sharpe, and Dohme, Rahway, New Jersey) or WEB-2086 (Boehringer), attenuated pulmonary vascular leakage and PMN recruitment into the alveolar compartment. Neutralization of intrapulmonary TNF with anti-TNF antibodies reduced pulmonary vascular permeability, PMN recruitment, and whole lung PAF levels. Incubation of isolated mouse alveolar macrophages with recombinant murine TNF resulted in rapid (30 to 60 minutes), cell concentration-dependent PAF release. The presence of high concentrations of PAF in whole lungs obtained from PMN-depleted rats after immune complex deposition suggest that recruited PMN are not the predominant source of intrapulmonary PAF in this model. These data suggest that acute IgG immune complex alveolitis is in part mediated by TNF-triggered PAF production and that locally produced PAF promotes recruitment of PMN into the alveolar compartment.
近期研究表明，肺内肿瘤坏死因子（TNF）通过涉及中性粒细胞多形核白细胞（PMN）募集的机制参与急性IgG免疫复合物肺泡炎的发病过程。关于TNF依赖性PMN募集和组织损伤机制的体内研究较少。我们研究了急性肺泡炎发展过程中肺内TNF与局部产生的血小板活化因子（PAF）之间的关系。气管内注入抗牛血清白蛋白IgG，随后静脉注射牛血清白蛋白，可导致急性中性粒细胞介导的肺泡炎。IgG免疫复合物肺损伤的诱导导致全肺和支气管肺泡灌洗中PAF水平显著升高。气管内注入PAF拮抗剂L-652,731（默克公司，新泽西州拉威市）或WEB-2086（勃林格殷格翰公司）可减轻肺血管渗漏和PMN向肺泡腔的募集。用抗TNF抗体中和肺内TNF可降低肺血管通透性、PMN募集和全肺PAF水平。用重组鼠TNF孵育分离的小鼠肺泡巨噬细胞可导致快速（30至60分钟）、细胞浓度依赖性的PAF释放。免疫复合物沉积后从PMN耗竭的大鼠获得的全肺中存在高浓度的PAF，这表明在该模型中，募集的PMN不是肺内PAF的主要来源。这些数据表明，急性IgG免疫复合物肺泡炎部分由TNF触发的PAF产生介导，并且局部产生的PAF促进PMN向肺泡腔的募集。
