Lentsch A B, Miller F N, Edwards M J
Center for Applied Microcirculatory Research, Department of Physiology, University of Louisville, Kentucky 40292, USA.
Am J Physiol. 1997 Apr;272(4 Pt 1):G727-31. doi: 10.1152/ajpgi.1997.272.4.G727.
The treatment of metastatic cancer with interleukin-2 (IL-2) is limited by systemic toxicities, including hepatic dysfunction. The objective of this study was to determine the cellular mechanisms of IL-2-induced hepatic injury. Intravital microscopy was used for the direct observation of the murine hepatic microcirculation after 2 h, 2 days, and 4 days of IL-2 treatment. At each interval, leukocyte- and platelet-endothelial adherence were observed and quantitated. Simultaneously, sinusoidal perfusion, serum levels of glutamate pyruvate transaminase, and edema were measured as indexes of hepatic toxicity. IL-2 increased neutrophil adhesion acutely in association with decreased sinusoidal perfusion. Leukocyte adhesion subsided at 2 days, but platelet-endothelial interactions were enhanced and 40% of mice receiving IL-2 had microvascular thrombi. These effects occurred in conjunction with decreased sinusoidal perfusion and the development of hepatic edema. After 4 days of IL-2, maximal hepatic edema, hypoperfusion, and increased serum levels of glutamate pyruvate transaminase were associated with increased lymphocyte adhesion and microvascular thrombosis. These data suggest coordinated, temporal roles of leukocytes and platelets in the generation of IL-2-induced hepatic injury.
用白细胞介素-2（IL-2）治疗转移性癌症受到包括肝功能障碍在内的全身毒性的限制。本研究的目的是确定IL-2诱导肝损伤的细胞机制。在IL-2治疗2小时、2天和4天后，采用活体显微镜直接观察小鼠肝脏微循环。在每个时间间隔，观察并定量白细胞和血小板与内皮细胞的黏附情况。同时，测量肝血窦灌注、血清谷丙转氨酶水平和水肿情况，作为肝毒性指标。IL-2急性增加中性粒细胞黏附，同时肝血窦灌注减少。白细胞黏附在2天时消退，但血小板与内皮细胞的相互作用增强，40%接受IL-2治疗的小鼠出现微血管血栓形成。这些效应与肝血窦灌注减少和肝水肿的发展同时出现。IL-2治疗4天后，最大程度的肝水肿、灌注不足以及血清谷丙转氨酶水平升高与淋巴细胞黏附增加和微血管血栓形成有关。这些数据表明白细胞和血小板在IL-2诱导的肝损伤发生过程中具有协同的、随时间变化的作用。
