Kelly K J, Williams W W, Colvin R B, Bonventre J V
Medical Service, Massachusetts General Hospital, Boston.
Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):812-6. doi: 10.1073/pnas.91.2.812.
The pathophysiology of ischemic acute renal failure is complex, and the role of leukocyte adhesion in this process is not well defined. A monoclonal antibody (mAb) against intracellular adhesion molecule 1 (anti-ICAM-1), administered at the time of bilateral renal ischemia in the rat, prevented both functional impairment and histologic changes of acute renal failure. Plasma creatinine measured (mg/dl) 24 hr after 30 min of ischemia was 0.61 +/- 0.05 in the anti-ICAM-1-treated animals compared with 2.4 +/- 0.14 (P < 0.0001) in the vehicle-treated ischemic group. Forty-eight hours after ischemia, creatinine values were 0.46 +/- 0.05 and 2.03 +/- 0.22 (P < 0.0001) in anti-ICAM-1 and vehicle-treated groups, respectively. A low dose of anti-ICAM-1 that was itself nonprotective, when given with partially protective doses of a mAb against lymphocyte function-associated antigen-1 (anti-LFA-1), acted synergistically to prevent renal failure. Anti-ICAM-1 mAb also protected the kidney when administered 0.5 or 2 hr but not 8 hr after restoration of blood flow and when the ischemic period was extended to 40 min. Ischemia-induced increases in tissue myeloperoxidase, a marker of neutrophil infiltration, were mitigated with anti-ICAM-1 treatment. Thus, anti-ICAM-1 mAb protected the kidney against ischemic renal failure, even when the antibody was administered after the ischemic period. These results suggest a critical role for leukocytes and adhesion molecules in the pathophysiology of ischemic injury and may have important therapeutic implications.
缺血性急性肾衰竭的病理生理学很复杂，白细胞黏附在此过程中的作用尚未明确。在大鼠双侧肾脏缺血时给予一种针对细胞间黏附分子1的单克隆抗体（抗ICAM-1），可预防急性肾衰竭的功能损害和组织学变化。缺血30分钟后24小时测定的血浆肌酐（mg/dl），抗ICAM-1治疗组动物为0.61±0.05，而溶媒治疗的缺血组为2.4±0.14（P<0.0001）。缺血48小时后，抗ICAM-1组和溶媒治疗组的肌酐值分别为0.46±0.05和2.03±0.22（P<0.0001）。一种本身无保护作用的低剂量抗ICAM-1，与部分保护剂量的抗淋巴细胞功能相关抗原1单克隆抗体（抗LFA-1）联合使用时，具有协同预防肾衰竭的作用。抗ICAM-1单克隆抗体在恢复血流后0.5小时或2小时而非8小时给药时，以及缺血时间延长至40分钟时，也能保护肾脏。抗ICAM-1治疗可减轻缺血诱导的组织髓过氧化物酶增加，髓过氧化物酶是中性粒细胞浸润的标志物。因此，即使在缺血期后给予抗ICAM-1单克隆抗体，它也能保护肾脏免受缺血性肾衰竭的影响。这些结果表明白细胞和黏附分子在缺血性损伤的病理生理学中起关键作用，可能具有重要的治疗意义。
