Lentsch A B, Edwards M J, Miller F N
Department of Physiology and Biophysics, University of Louisville, KY, USA.
J Lab Clin Med. 1996 Jul;128(1):75-82. doi: 10.1016/s0022-2143(96)90115-8.
Cancer immunotherapy with interleukin-2 (IL-2) is limited by side effects that may cause organ dysfunction. The role of platelets in the generation of IL-2-induced organ dysfunction has not been studied, although various studies have shown that IL-2 therapy activates both platelets and the vascular endothelium. We hypothesized that IL-2 therapy may enhance the thrombogenic response to inflammatory stimuli through increased platelet-endothelial interactions and that these effects could lead to the development of organ dysfunction. C57BI/6 mice were treated with IL-2 intraperitoneally for 2 hours (short term) or 2 to 5 days (long term) and prepared for in vivo microscopy of the ear microcirculation. Mice were injected intra-arterially with fluorescein isothiocyanate conjugated to bovine serum albumin (FITC-BSA). Blue light activation of the FITC-BSA in ear arterioles induced thrombus formation. The time to initial thrombus formation was measured as an index of thrombogenicity. Platelet function was analyzed by aggregometry and platelet expression of IL-2 receptors, and the adhesion molecule lymphocyte function-associated antigen-1 (LFA-1) was analyzed by flow cytometry. Organ dysfunction was evaluated by serum markers. The administration of both short-term and long-term IL-2 reduced the time to initial thrombus formation as compared with controls. In vitro platelet aggregometry revealed no acute alterations in platelet function; however, long-term IL-2 treatment resulted in decreased disaggregation rates. There were no platelet IL-2 receptors present, and the expression of the adhesion molecule LFA-1 was not altered by IL-2. Increased thrombogenicity occurred before the generation of organ dysfunction. These data suggest that increased platelet adherence induced by IL-2 is caused by effects on the endothelium that could result in microvascular thrombus formation and contribute to organ dysfunction.
白细胞介素-2（IL-2）癌症免疫疗法受到可能导致器官功能障碍的副作用的限制。尽管多项研究表明IL-2疗法可激活血小板和血管内皮，但血小板在IL-2诱导的器官功能障碍发生过程中的作用尚未得到研究。我们推测，IL-2疗法可能通过增加血小板与内皮细胞的相互作用来增强对炎症刺激的血栓形成反应，并且这些作用可能导致器官功能障碍的发生。将C57BI/6小鼠腹腔注射IL-2 2小时（短期）或2至5天（长期），并准备用于耳部微循环的体内显微镜检查。通过动脉内注射异硫氰酸荧光素偶联牛血清白蛋白（FITC-BSA）。耳小动脉中FITC-BSA的蓝光激活诱导血栓形成。将初始血栓形成的时间作为血栓形成性的指标进行测量。通过凝集测定法分析血小板功能以及IL-2受体的血小板表达，并通过流式细胞术分析粘附分子淋巴细胞功能相关抗原-1（LFA-1）。通过血清标志物评估器官功能障碍。与对照组相比，短期和长期给予IL-2均缩短了初始血栓形成的时间。体外血小板凝集测定显示血小板功能无急性改变；然而，长期IL-2治疗导致解聚率降低。不存在血小板IL-2受体，并且粘附分子LFA-1的表达未因IL-2而改变。在器官功能障碍发生之前就出现了血栓形成性增加。这些数据表明，IL-2诱导的血小板粘附增加是由对内皮细胞的作用引起的，这可能导致微血管血栓形成并促成器官功能障碍。
