ROLE OF ENDOTHELIAL-LEUKOCYTE ADHESION MOLECULE-1 (ELAM-1) IN NEUTROPHIL-MEDIATED LUNG INJURY IN RATS
ROLE OF ENDOTHELIAL-LEUKOCYTE ADHESION MOLECULE-1 (ELAM-1) IN NEUTROPHIL-MEDIATED LUNG INJURY IN RATS
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DOI：
10.1172/jci115446
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发表时间：
1991-10-01
影响因子：
15.9
通讯作者：
WARD, PA
中科院分区：
文献类型：
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作者：
MULLIGAN, MS;VARANI, J;WARD, PA
两种抗人内皮细胞-白细胞粘附分子-1（ELAM-1）的鼠单克隆抗体（CL-3和CL-37，均为F（ab '）2）与经肿瘤坏死因子（TNF-α）预处理的大鼠肺动脉内皮细胞发生化学反应。 CL-3，而不是CL-37，在体外阻断中性粒细胞对TNF-α处理的内皮细胞的粘附和佛波酯激活的中性粒细胞对TNF-α处理的大鼠内皮细胞的杀伤。 在用CL-3全身治疗的大鼠中，糖原诱导的腹膜渗出物中的中性粒细胞蓄积减少了70%。 在相同条件下，用CL-37抗ELAM-1治疗动物不会减少中性粒细胞蓄积。 当在大鼠的真皮和肺中诱导IgG免疫复合物沉积时，用CL-3抗ELAM-1治疗显著减少血管损伤，如通过血管渗透性（I-125-白蛋白渗漏）和出血（Cr-51-红细胞外渗）的变化所测量的。 CL-3抗ELAM-1的保护作用与中性粒细胞的募集大大减少有关（如通过髓过氧化物酶的组织提取和通过经由支气管肺泡灌洗从肺中回收中性粒细胞在形态学上评估的）。 CL-37在肺部沉积免疫复合物后在体内没有保护作用。 使用CL-3或CL-37抗ELAM-1，对经历IgG免疫复合物诱导的损伤的肺的免疫组织化学分析揭示了肺脉管系统（小静脉和间质毛细血管）中ELAM-1的显著上调，在肺中免疫复合物沉积后3和4小时之间出现峰值强度。 在这些相同的条件下，脾脏、肝脏和肾脏的血管床未能显示ELAM-1的上调。 如果抗ELAM-1制剂首先被已用TNF-α预处理的人脐静脉内皮细胞单层吸收，则大鼠肺的免疫组织化学反应性被消除。 未处理的人内皮细胞不能引起抗ELAM-1制剂的肺反应性的丧失。 这些数据表明，在免疫复合物沉积期间，ELAM-1在大鼠的肺血管系统中上调，并且ELAM-1似乎在中性粒细胞的募集中起专性作用。
Two murine monoclonal antibodies (CL-3 and CL-37, both F(ab')2) to human endothelial-leukocyte adhesion molecule-1 (ELAM-1) were found to react immunohistochemically with rat pulmonary artery endothelial cells that had been pretreated with tumor necrosis factor (TNF-alpha). CL-3, but not CL-37, blocked in vitro adherence of neutrophils to TNF-alpha-treated endothelial cells and the killing of TNF-alpha-treated rat endothelial cells by phorbol ester activated neutrophils. In rats treated systemically with CL-3, there was a 70% reduction in accumulation of neutrophils in glycogen-induced peritoneal exudates. Treatment of animals with CL-37 anti-ELAM-1 did not reduce neutrophil accumulation under the same conditions. When IgG immune complex deposition was induced in dermis and in lungs of rats, treatment with CL-3 anti-ELAM-1 markedly reduced vascular injury as measured by changes in vascular permeability (leakage of I-125-albumin) and hemorrhage (extravasation of Cr-51-red blood cells). The protective effects of CL-3 anti-ELAM-1 were related to greatly diminished recruitment of neutrophils (as assessed morphologically, by tissue extraction of myeloperoxidase, and by retrieval, via bronchoalveolar lavage, of neutrophils from lung). CL-37 had no protective effects in vivo after deposition of immune complexes in lung. Using either CL-3 or CL-37 anti-ELAM-1, immunohistochemical analysis of lungs undergoing IgG immune complex-induced injury revealed a striking upregulation of ELAM-1 in the lung vasculature (venules and interstitial capillaries), with a peak intensity developing between 3 and 4 h after deposition of immune complexes in lung. Vascular beds of spleen, liver, and kidney failed to show upregulation of ELAM-1 under these same conditions. The immunohistochemical reactivity of rat lung was abolished if the anti-ELAM-1 preparation was first absorbed with monolayers of human umbilical vein endothelial cells that had been pretreated with TNF-alpha. Untreated human endothelial cells failed to cause loss of lung reactivity of the anti-ELAM-1 preparation. These data indicate that ELAM-1 is upregulated in the pulmonary vasculature of rats during deposition of immune complexes and that ELAM-1 appears to play an obligate role in the recruitment of neutrophils.