Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China.
Department of Anesthesiology, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321, Zhongshan Road, 210008 Nanjing, Jiangsu Province, China.
Free Radic Biol Med. 2018 Aug 20;124:395-407. doi: 10.1016/j.freeradbiomed.2018.06.043. Epub 2018 Jun 30.
Fatty liver is one of the widely accepted marginal donor for liver transplantation, but is also more sensitive to ischemia and reperfusion injury (IRI) and produces more reactive oxygen species (ROS). Moreover, so far, no effective method has been developed to alleviate it. Endoplasmic reticulum stress (ER-stress) of hepatocyte is associated with the occurrence of fatty liver disease, but ER-stress of kupffer cells (KCs) in fatty liver is not clear at all. This study evaluates whether ER-stress of KCs is activated in fatty liver and accelerate IRI of fatty livers. ER-stress of KCs was activated in fatty liver, especially the IRE1α signal pathway. KCs with activated ER-stress secreted more proinflammatory cytokine to induce its M1-phenotypic shift in fatty liver, resulting in more severe IRI. Also, activated ER-stress of BMDMs in vitro by tunicamycin can induce its pro-inflammatory shift and can be reduced by 4-PBA, an ER-stress inhibitor. Knockdown of IRE1α could regulate the STAT1 and STAT6 pathway of macrophage to inhibit the M1-type polarization and promote M2-phenotypic shift. Furthermore, transfusion of IRE1α-knockdown KCs significantly reduced the liver IRI as well as the ROS of HFD feeding mice. Altogether, these data demonstrated that IRE1α of KCs may be a potential target to reduce the fatty liver associated IRI in liver transplantation.
脂肪肝是肝移植中被广泛认可的边缘供体之一，但它对缺血再灌注损伤（IRI）更为敏感，并且会产生更多的活性氧物质（ROS）。此外，到目前为止，还没有开发出有效的方法来缓解这种情况。肝细胞的内质网应激（ER-stress）与脂肪肝的发生有关，但脂肪肝中库普弗细胞（KCs）的 ER-stress 却完全不清楚。本研究评估了 KCs 的 ER-stress 是否在脂肪肝中被激活，并加速脂肪肝的 IRI。脂肪肝中 KCs 的 ER-stress 被激活，特别是 IRE1α 信号通路。激活 ER-stress 的 KCs 会分泌更多的促炎细胞因子，诱导其在脂肪肝中的 M1 表型转变，从而导致更严重的 IRI。此外，通过衣霉素体外激活 BMDMs 的 ER-stress 可以诱导其促炎转变，并且可以被 ER-stress 抑制剂 4-PBA 降低。IRE1α 的敲低可以调节巨噬细胞的 STAT1 和 STAT6 通路，抑制 M1 型极化，并促进 M2 表型转变。此外，IRE1α 敲低的 KCs 的输注可显著减轻 HFD 喂养小鼠的肝脏 IRI 以及 ROS。总之，这些数据表明 KCs 的 IRE1α 可能是减少肝移植中与脂肪肝相关的 IRI 的潜在靶点。
