Dragun D, Hoff U, Park J K, Qun Y, Schneider W, Luft F C, Haller H
Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Berlin, Germany.
Kidney Int. 2000 Nov;58(5):2166-77. doi: 10.1111/j.1523-1755.2000.00390.x.
Adhesion molecule expression is important to early transplant failure. However, whether or not adhesion molecule-facilitated inflammation is antigen-dependent is unknown. We tested this hypothesis.
Rat renal grafts were four-hours cold-preserved in University of Wisconsin (UW) solution, transplanted to syngeneic or allogeneic recipients, and harvested after 2, 6, 12, 24, and 48 hours and after 1 week. The first allogeneic group receive no immunosuppression; two additional groups received either low (1.5 mg/kg) or standard (5 mg/kg) cyclosporine A (CsA). Renal function and morphology were determined; frozen sections were immunostained for P-selectin, L-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), platelet endothelial cell adhesion molecule-1 (PECAM-1), leukocyte function associated molecule-1 (LFA-1), very late antigen-4 (VLA-4), as well as for neutrophils and monocytes.
Selectins increased rapidly at 2 hours and quickly decreased by 12 hours. While P-selectin was expressed on vasculature, L-selectin was found on inflammatory cells. Neutrophil influx and that of LFA-1-positive cells occurred early, peaked between 12 and 24 hours, and paralleled the maximal impairment in renal function. ICAM-1 and PECAM-1 showed similar kinetics and a diffuse distribution. VCAM-1 increased more slowly after 12 hours, peaked at 24 hours, and was localized predominantly on the endothelium of elastic vessels. Between 24 hours and 1 week, all grafts progressively developed dense VLA-4-positive monocytic infiltrates adjacent to vessels expressing VCAM-1. Functional, morphological, and immunohistochemical parameters did not differ between isografts and allografts at one week. However, by day 10, allografts showed severe vascular and cellular rejection, while injury in isografts resolved. Immunosuppression with CsA did not reverse the inflammation induced by ischemia-reperfusion injury.
The early inflammation after ischemia-reperfusion injury is largely independent of the immunologic background. We suggest that initial injury prevention should receive the highest priority.
黏附分子的表达对早期移植失败很重要。然而，黏附分子介导的炎症是否依赖抗原尚不清楚。我们对这一假设进行了验证。
将大鼠肾移植器官在威斯康星大学（UW）溶液中冷藏4小时，移植到同基因或异基因受体体内，并在2、6、12、24和48小时以及1周后进行取材。第一组异基因受体未接受免疫抑制；另外两组分别接受低剂量（1.5mg/kg）或标准剂量（5mg/kg）的环孢素A（CsA）。测定肾功能和形态；对冰冻切片进行免疫染色，检测P-选择素、L-选择素、细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）、血小板内皮细胞黏附分子-1（PECAM-1）、白细胞功能相关分子-1（LFA-1）、极迟抗原-4（VLA-4），以及中性粒细胞和单核细胞。
选择素在2小时迅速增加，12小时迅速下降。P-选择素表达于脉管系统，而L-选择素见于炎症细胞。中性粒细胞及LFA-1阳性细胞的流入出现较早，在12至24小时达到峰值，与肾功能的最大损伤同时出现。ICAM-1和PECAM-1表现出相似的动力学特征和弥漫性分布。VCAM-1在12小时后增加较慢，在24小时达到峰值，主要定位于弹性血管的内皮。在24小时至1周之间，所有移植器官在表达VCAM-1的血管附近逐渐出现密集的VLA-4阳性单核细胞浸润。同基因移植和异基因移植在1周时的功能、形态和免疫组化参数无差异。然而，到第10天，异基因移植出现严重的血管和细胞排斥反应，而同基因移植的损伤则消退。CsA免疫抑制并未逆转缺血-再灌注损伤诱导的炎症反应。
缺血-再灌注损伤后的早期炎症在很大程度上与免疫背景无关。我们建议应将预防初始损伤作为首要任务。
