Mulligan M S, Warren J S, Smith C W, Anderson D C, Yeh C G, Rudolph A R, Ward P A
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109.
J Immunol. 1992 May 15;148(10):3086-92.
Acute lung injury produced by deposition of IgA immune complexes is complement-dependent, neutrophil-independent, oxygen radical-mediated, and may be a result of the formation of the hydroxyl radical (HO) generated directly or indirectly from activated lung macrophages. The current studies were designed to evaluate further the pathophysiologic events that occur after intrapulmonary deposition of IgA immune complexes. Pretreatment of rats with the human recombinant soluble complement receptor-1 resulted in marked attenuation of IgA immune complex-induced lung injury. Intravenous administration of antibody to CD18, but not antibody to CD11b, was highly protective against lung injury. Treatment of animals with either anti-endothelial leukocyte-adhesion molecule-1 or anti-TNF-alpha, both of which were highly protective against IgG immune complex-induced lung injury, had no protective effects in the model of IgA immune complex-induced lung injury. Immunohistochemical analysis revealed up-regulation of the endothelial leukocyte adhesion molecule-1 in the pulmonary vasculature after deposition of IgA immune complexes. This up-regulation was TNF-alpha-dependent. The arginine analog, NG-monomethyl-L-arginine, was highly protective against IgA immune complex-induced lung injury. This protective effect was reversed by the co-presence of L-arginine (but not D-arginine). Protective interventions against IgA immune complex-induced lung injury were inversely correlated with the numbers of macrophages that could be retrieved by lung lavage. These data suggest fundamental differences in the pathogenesis of lung injury after intrapulmonary deposition of IgA immune complexes, as compared with injury caused by deposition of IgG immune complexes. In the latter, neutrophils, intrapulmonary generation of TNF-alpha, and up-regulation of pulmonary vascular endothelial leukocyte-adhesion molecule-1 are required for the full development of lung injury, whereas no such requirements appear in the case of IgA immune complex-induced lung injury. Full expression of IgA immune complex-induced lung injury also appears to require L-arginine, suggesting a possible role for nitric oxide or its derivatives in events ultimately leading to injury.
IgA免疫复合物沉积所致的急性肺损伤是补体依赖性、非中性粒细胞依赖性、氧自由基介导的，可能是活化的肺巨噬细胞直接或间接产生的羟基自由基（HO）形成的结果。当前的研究旨在进一步评估IgA免疫复合物肺内沉积后发生的病理生理事件。用人重组可溶性补体受体-1预处理大鼠可显著减轻IgA免疫复合物诱导的肺损伤。静脉注射抗CD18抗体而非抗CD11b抗体对肺损伤具有高度保护作用。用抗内皮白细胞黏附分子-1或抗TNF-α治疗动物，这两种药物对IgG免疫复合物诱导的肺损伤均有高度保护作用，但在IgA免疫复合物诱导的肺损伤模型中无保护作用。免疫组织化学分析显示，IgA免疫复合物沉积后肺血管内皮白细胞黏附分子-1上调。这种上调是TNF-α依赖性的。精氨酸类似物NG-单甲基-L-精氨酸对IgA免疫复合物诱导的肺损伤具有高度保护作用。L-精氨酸（而非D-精氨酸）的共同存在可逆转这种保护作用。针对IgA免疫复合物诱导的肺损伤的保护性干预措施与通过肺灌洗回收的巨噬细胞数量呈负相关。这些数据表明，与IgG免疫复合物沉积所致的损伤相比，IgA免疫复合物肺内沉积后肺损伤的发病机制存在根本差异。在后者中，中性粒细胞、肺内TNF-α的产生以及肺血管内皮白细胞黏附分子-1的上调是肺损伤充分发展所必需的，而在IgA免疫复合物诱导的肺损伤中似乎没有这些要求。IgA免疫复合物诱导的肺损伤的充分表达似乎也需要L-精氨酸，这表明一氧化氮或其衍生物在最终导致损伤的事件中可能发挥作用。
