Puglisi R N, Strande L, Santos M, Schulte G, Hewitt C W, Whalen T V
Department of Pediatric Surgery, Children's Regional Medical Center, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden 08103, USA.
J Surg Res. 1996 Oct;65(2):115-8. doi: 10.1006/jsre.1996.0352.
Gut ischemia has been implicated in the pathogenesis of necrotizing enterocolitis. Cyclosporine A and rapamycin, both potent novel immunosuppressants which act on signal transduction pathways in CD4+ T-cells, could potentially modulate immune/inflammatory cellular reactions involved in tissue ischemia/reperfusion injury. We hypothesized that cyclosporine A and rapamycin would preserve mucosal cell function and attenuate inflammatory T-cell-mediated cellular changes associated with small bowel ischemic injury. Forty Sprague-Dawley rats underwent 60 min of gut ischemia by vascular occlusion of the superior mesenteric vessels. Animals were randomized to four groups (n = 10): cyclosporine A (CSA, 5 mg/kg/day SQ), rapamycin (RAP, 2 mg/kg/day SQ), cyclosporine A and rapamycin (C&R), and vehicle given to controls (CON). Following 1 hr of reperfusion, small bowel was harvested for xanthine oxidase (XO, units/mg protein) and maltase (MALT, mM substrate degraded/min/g protein) assays. Blood was obtained from the portal vein for tumor necrosis factor-alpha (TNF-alpha, pg/ml) assay. The results of the study are presented below (mean +/- SEM, *, P < 0.05 versus controls). (Table in text) The results indicate that cyclosporine and rapamycin each play a significant role in attenuating ischemia/reperfusion injury in the gut. These data suggest that there are cytoprotective and anti-inflammatory mechanisms of these drugs independent of T-cell signal transduction that provide some protective effect in small bowel ischemia. Furthermore, T-cell-mediated immune mechanisms may not be associated with the adverse effects of small bowel ischemia/reperfusion injury. Additional investigation will be necessary in order to define the role of T-cell-mediated immune injury in the gut and how this relates to the beneficial effect of immunosuppression in small bowel mucosal ischemic injury.
肠缺血与坏死性小肠结肠炎的发病机制有关。环孢素A和雷帕霉素都是作用于CD4+ T细胞信号转导途径的强效新型免疫抑制剂，它们可能调节与组织缺血/再灌注损伤相关的免疫/炎症细胞反应。我们假设环孢素A和雷帕霉素将保留黏膜细胞功能，并减轻与小肠缺血性损伤相关的炎症性T细胞介导的细胞变化。40只Sprague-Dawley大鼠通过肠系膜上血管闭塞进行60分钟的肠缺血。动物被随机分为四组（n = 10）：环孢素A（CSA，5 mg/kg/天，皮下注射）、雷帕霉素（RAP，2 mg/kg/天，皮下注射）、环孢素A和雷帕霉素（C&R），以及给予对照组（CON）的赋形剂。再灌注1小时后，采集小肠进行黄嘌呤氧化酶（XO，单位/毫克蛋白质）和麦芽糖酶（MALT，毫摩尔底物降解/分钟/克蛋白质）测定。从门静脉取血进行肿瘤坏死因子-α（TNF-α，皮克/毫升）测定。研究结果如下（平均值±标准误，*，与对照组相比P < 0.05）。（文中表格）结果表明，环孢素和雷帕霉素在减轻肠道缺血/再灌注损伤中均发挥重要作用。这些数据表明，这些药物存在独立于T细胞信号转导的细胞保护和抗炎机制，在小肠缺血中提供一定的保护作用。此外，T细胞介导的免疫机制可能与小肠缺血/再灌注损伤的不良反应无关。为了确定T细胞介导的免疫损伤在肠道中的作用以及这与免疫抑制对小肠黏膜缺血性损伤的有益作用之间的关系，还需要进一步研究。
