Zwacka R M, Zhang Y, Halldorson J, Schlossberg H, Dudus L, Engelhardt J F
Institute for Human Gene Therapy at the University of Pennsylvania Medical Center, Department of Molecular and Cellular Engineering, Philadelphia, Pennsylvania 19104, USA.
J Clin Invest. 1997 Jul 15;100(2):279-89. doi: 10.1172/JCI119533.
The success of orthotopic liver transplantation is dependent on multiple factors including MHC tissue compatibility and ischemic/reperfusion injury. Ischemic/reperfusion (I/R) injury in the liver occurs in a biphasic pattern consisting of both acute phase (oxygen free radical mediated) and subacute phase (neutrophil-mediated) damage. Although numerous studies have given insights into the process of neutrophil recruitment after I/R injury to the liver, the exact mechanism that initiates this subacute response remains undefined. Using a T cell-deficient mouse model, we present data that suggests that T-lymphocytes are key mediators of subacute neutrophil inflammatory responses in the liver after ischemia and reperfusion. To this end, using a partial lobar liver ischemia model, we compared the extent of reperfusion injury between immune competent BALB/c and athymic nu/nu mice. Studies evaluating the extent of liver damage as measured by serum transaminases (GPT) demonstrate similar acute (3-6 h) post-I/R responses in these two mouse models. In contrast, the subacute phase (16-20 h) of liver injury, as measured by both serum GPT levels and percent hepatocellular necrosis, was dramatically reduced in T cell-deficient mice as compared with those with an intact immune system. This reduction in liver injury seen in nu/nu mice was associated with a 10-fold reduction in hepatic neutrophil infiltration. Adoptive transfer of T cell-enriched splenocytes from immune competent mice was capable of reconstituting the neutrophil-mediated subacute inflammatory response within T cell-deficient nu/nu mice. Furthermore, in vivo antibody depletion of CD4(+) T-lymphocytes in immune competent mice resulted in a reduction of subacute phase injury and inflammation as measured by serum GPT levels and neutrophil infiltration. In contrast, depletion of CD8(+) T-lymphocytes had no effect on these indexes of subacute inflammation. Kinetic analysis of T cell infiltration in the livers of BALB/c mice demonstrated a fivefold increase in the number of hepatic CD4(+) T-lymphocytes within the first hour of reperfusion with no significant change in the number of CD8(+) T-lymphocytes. In summary, these results implicate CD4(+) T-lymphocytes as key regulators in initiating I/R-induced inflammatory responses in the liver. Such findings have implications for therapy directed at the early events in this inflammatory cascade that may prove useful in liver transplantation.
原位肝移植的成功取决于多种因素，包括主要组织相容性复合体（MHC）组织相容性和缺血/再灌注损伤。肝脏缺血/再灌注（I/R）损伤呈双相模式，包括急性期（氧自由基介导）和亚急性期（中性粒细胞介导）损伤。尽管众多研究已深入了解肝脏I/R损伤后中性粒细胞募集的过程，但启动这种亚急性反应的确切机制仍不明确。利用T细胞缺陷小鼠模型，我们提供的数据表明，T淋巴细胞是肝脏缺血再灌注后亚急性中性粒细胞炎症反应的关键介质。为此，我们使用部分肝叶缺血模型，比较了免疫健全的BALB/c小鼠和无胸腺裸鼠（nu/nu）的再灌注损伤程度。通过血清转氨酶（GPT）评估肝脏损伤程度的研究表明，这两种小鼠模型在I/R后急性阶段（3 - 6小时）的反应相似。相比之下，与免疫系统完整的小鼠相比，通过血清GPT水平和肝细胞坏死百分比测量，T细胞缺陷小鼠肝脏损伤的亚急性期（16 - 20小时）显著减轻。在裸鼠（nu/nu）中观察到的肝脏损伤减轻与肝脏中性粒细胞浸润减少10倍有关。将免疫健全小鼠富含T细胞的脾细胞进行过继转移，能够在T细胞缺陷的裸鼠（nu/nu）中重建中性粒细胞介导的亚急性炎症反应。此外，对免疫健全小鼠体内的CD4(+) T淋巴细胞进行抗体清除，导致通过血清GPT水平和中性粒细胞浸润测量的亚急性期损伤和炎症减轻。相比之下，清除CD8(+) T淋巴细胞对这些亚急性炎症指标没有影响。对BALB/c小鼠肝脏中T细胞浸润的动力学分析表明，再灌注后第一小时内肝脏CD4(+) T淋巴细胞数量增加了五倍，而CD8(+) T淋巴细胞数量没有显著变化。总之，这些结果表明CD4(+) T淋巴细胞是启动肝脏I/R诱导的炎症反应的关键调节因子。这些发现对于针对这一炎症级联早期事件的治疗具有重要意义，可能对肝移植有用。
