HMGB1-associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats
HMGB1-associated necroptosis and Kupffer cells M1 polarization underlies remote liver injury induced by intestinal ischemia/reperfusion in rats
复制标题
HMGB1相关的坏死性凋亡和库普弗细胞M1极化是大鼠肠道缺血/再灌注引起的远程肝损伤的基础
DOI：
10.1096/fj.201900817r
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发表时间：
2020-01-21
期刊：
影响因子：
4.8
通讯作者：
Huang, Wenqi
中科院分区：
文献类型：
--
作者：
Wen, Shihong;Li, Xiang;Huang, Wenqi
缺血肠的再灌注常常导致驱动远端器官损伤，特别是与肝细胞功能障碍相关的损伤。确切的分子机制和有效的多器官保护策略仍有待开发。在目前的研究中，根据组织病理学评分增加，血清乳酸脱氢酶（LDH），丙氨酸氨基转移酶（ALT）/天冬氨酸氨基转移酶（AST）水平，以及在大鼠肠缺血/再灌注（I/R）损伤模型中细菌移位增强，在再灌注6小时后发现显著的远端肝功能障碍。此外，组织中受体相互作用蛋白激酶1/3（RIP 1/3）和磷酸化MLKL的表达显著升高，表明发生坏死性凋亡并导致急性远端肝功能损害。抑制坏死性凋亡途径可减弱HMGB 1细胞质易位和组织损伤。同时，巨噬细胞耗竭研究表明，枯否细胞（KCs）是导致肝损伤的主要原因。阻断HMGB 1通过抑制肝细胞坏死性凋亡、组织炎症、肝KCs和循环巨噬细胞M1极化部分恢复了肝功能。更重要的是，HMGB 1中和进一步保护肠道I/R相关的肝损伤在微生物耗尽的大鼠。因此，肠I/R可能与肝细胞坏死性凋亡引起的急性肝损伤相关，并且可以通过给予Nec-1和使用中和抗体和抑制剂抑制HMGB 1来改善。坏死性凋亡抑制和HMGB 1中和/抑制可能成为有效的药理学疗法，以最大限度地减少肠I/R诱导的急性远端器官功能障碍。
Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor-interacting protein kinase 1/3 (RIP1/3) and phosphorylated-MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage-depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What's more, HMGB1 neutralization further protects against intestinal I/R-associated liver damage in microbiota-depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec-1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R-induced acute remote organ dysfunction.