Ischemia and reperfusion injury is an early inflammatory process during liver transplantation that impacts on graft function and clinical outcomes. Interleukin (IL)-33 is a danger-associated molecular pattern involved in kidney ischemia/reperfusion injury and several liver diseases. The aims were to assess whether IL-33 was released as an alarmin responsible for ischemia/reperfusion injury in a mouse model of warm hepatic ischemia, and whether this hypothesis could also apply in the setting of human liver transplantation. First, a model of warm hepatic ischemia/reperfusion was used in wild-type and IL-33–deficient mice. Severity of ischemia/reperfusion injury was assessed with ALT and histological analysis. Then, serum IL-33 was measured in a pilot cohort of 40 liver transplant patients. Hemodynamic postreperfusion syndrome, graft dysfunction (assessed by model for early allograft scoring >6), renal failure, and tissue lesions on time-zero biopsies were assessed. In the mouse model, IL-33 was constitutively expressed in the nucleus of endothelial cells, immediately released in response to hepatic pedicle clamping without neosynthesis, and participated in the recruitment of neutrophils and tissue injury on site. The kinetics of IL-33 in liver transplant patients strikingly matched the ones in the animal model, as attested by serum levels reaching a peak immediately after reperfusion, which correlated to clinical outcomes including postreperfusion syndrome, posttransplant renal failure, graft dysfunction, and histological lesions of ischemia/reperfusion injury. IL-33 was an independent factor of graft dysfunction with a cutoff of IL-33 at 73 pg/ml after reperfusion (73% sensitivity, area under the curve of 0.76). Taken together, these findings establish the immediate implication of IL-33 acting as an alarmin in liver I/R injury and provide evidence of its close association with cardinal features of early liver injury-associated disorders in LT patients.

缺血和再灌注损伤是肝移植过程中的早期炎症过程，会影响移植物功能和临床结果。白细胞介素 (IL)-33 是一种危险相关分子模式，与肾脏缺血/再灌注损伤和多种肝脏疾病有关。目的是评估 IL-33 是否作为引起热肝缺血小鼠模型缺血/再灌注损伤的警报释放，以及该假设是否也适用于人肝移植。首先，在野生型和 IL-33 缺陷型小鼠中使用了热肝缺血/再灌注模型。用 ALT 和组织学分析评估缺血/再灌注损伤的严重程度。然后，在 40 名肝移植患者的试点队列中测量了血清 IL-33。血流动力学再灌注后综合征，评估了移植物功能障碍（由早期同种异体移植物评分 >6 的模型评估）、肾功能衰竭和零时间活检组织损伤。在小鼠模型中，IL-33在内皮细胞核中组成型表达，在没有新合成的情况下响应肝蒂钳立即释放，并参与中性粒细胞的募集和现场组织损伤。肝移植患者中 IL-33 的动力学与动物模型中的动力学惊人地匹配，如血清水平在再灌注后立即达到峰值所证明的，这与包括再灌注后综合征、移植后肾功能衰竭、移植物功能障碍和组织学病变在内的临床结果相关缺血/再灌注损伤。IL-33 是移植物功能障碍的独立因素，再灌注后 IL-33 的临界值为 73 pg/ml（敏感性为 73%，曲线下面积为 0.76）。总之，这些发现确立了 IL-33 在肝 I/R 损伤中作为警报的直接意义，并提供了其与 LT 患者早期肝损伤相关疾病的主要特征密切相关的证据。