Lipopolysaccharide preconditioning protects hepatocytes from ischemia/reperfusion injury (IRI) through inhibiting ATF4-CHOP pathway in mice.
Lipopolysaccharide preconditioning protects hepatocytes from ischemia/reperfusion injury (IRI) through inhibiting ATF4-CHOP pathway in mice.
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脂多糖预处理通过抑制小鼠 ATF4-CHOP 通路来保护肝细胞免受缺血/再灌注损伤 (IRI)。
DOI：
10.1371/journal.pone.0065568
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Rao J;Qin J;Qian X;Lu L;Wang P;Wu Z;Zhai Y;Zhang F;Li G;Wang X
低剂量脂多糖（LPS）预处理诱导的肝脏保护作用已在多个器官的缺血再灌注损伤（IRI）中得到证实，但其潜在的因果机制尚未得到充分阐明。本研究探讨了低剂量LPS预处理对ATF 4-CHOP通路的作用以及该通路对肝脏部分温热IRI小鼠模型组织损伤和炎症的影响。缺血前2天腹腔注射LPS（100 μg/kg/d）。根据血清丙氨酸氨基转移酶水平、组织病理学和半胱天冬酶-3活性评价肝损伤。再灌注后检测ATF 4-CHOP通路及其相关凋亡分子。在体外研究LPS预处理对细胞凋亡和ATF 4-CHOP通路的作用。此外，用ATF 4小干扰RNA（siRNA）测定ATF 4-CHOP通路对细胞凋亡、Caspase-12和Caspase-3的影响。再灌注后还检查了炎性细胞因子的表达。在体外分析LPS预处理或ATF 4 siRNA处理的巨噬细胞中的炎性细胞因子和相关信号通路。LPS预处理可明显减轻IRI后的肝损伤。如体外实验所示，LPS预处理显著降低IRI后ATF 4-CHOP通路的上调，并抑制Caspase-12和Caspase-3的活化。后来的实验表明，ATF 4敲低显著抑制CHOP，切割caspase-12和caspase-3的表达，以及抑制肝细胞凋亡。此外，在LPS预处理的小鼠中，再灌注后TNF-α和IL-6被抑制，而IL-10被上调。低剂量LPS可显著抑制TNF-α、IL-6、ATF 4-CHOP通路、NF-κB通路和ERK 1/2，而诱导IL-10和细胞因子信号转导（SOCS）-3抑制因子的表达。重要的是，ATF 4 siRNA与巨噬细胞中LPS预处理的结果一致。本研究首次证明LPS预处理通过抑制ATF 4-CHOP通路保护肝细胞免受IRI的损伤，这可能是LPS预处理减少相关凋亡分子和调节先天性炎症的关键。
Low-dose lipopolysaccharide (LPS) preconditioning-induced liver protection has been demonstrated during ischemia-reperfusion injury (IRI) in several organs but has not been sufficiently elucidated underlying causal mechanism. This study investigated the role of low-dose LPS preconditioning on ATF4-CHOP pathway as well as the effects of the pathway on tissue injury and inflammation in a mouse model of liver partial-warm IRI. LPS (100 µg/kg/d) was injected intraperitoneally two days before ischemia. Hepatic injury was evaluated based on serum alanine aminotransferase levels, histopathology, and caspase-3 activity. The ATF4-CHOP pathway and its related apoptotic molecules were investigated after reperfusion. The role of LPS preconditioning on apoptosis and ATF4-CHOP pathway was examined in vitro. Moreover, the effects of the ATF4-CHOP pathway on apoptosis, Caspase-12, and Caspase-3 were determined with ATF4 small interfering RNA (siRNA). Inflammatory cytokine expression was also checked after reperfusion. Inflammatory cytokines and related signaling pathways were analyzed in vitro in macrophages treated by LPS preconditioning or ATF4 siRNA. LPS preconditioning significantly attenuated liver injury after IRI. As demonstrated by in vitro experiments, LPS preconditioning significantly reduced the upregulation of the ATF4-CHOP pathway and inhibited Caspase-12 and Caspase-3 activation after IRI. Later experiments showed that ATF4 knockdown significantly suppressed CHOP, cleaved caspase-12 and caspase-3 expression, as well as inhibited hepatocellular apoptosis. In addition, in mice pretreated with LPS, TNF-α and IL-6 were inhibited after reperfusion, whereas IL-10 was upregulated. Similarly, low-dose LPS significantly inhibited TNF-α, IL-6, ATF4-CHOP pathway, NF-κB pathway, and ERK1/2 in high-dose LPS-stimulated macrophages, whereas IL-10 and cytokine signaling (SOCS)-3 suppressor were induced. Importantly, ATF4 siRNA is consistent with results of LPS preconditioning in macrophages. This work is the first time to provide evidence for LPS preconditioning protects hepatocytes from IRI through inhibiting ATF4-CHOP pathway, which may be critical to reducing related apoptosis molecules and modulating innate inflammation.
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DOI：
10.1074/jbc.m109.014092
发表时间：
2010-02-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Armstrong JL;Flockhart R;Veal GJ;Lovat PE;Redfern CP
通讯作者：
Redfern CP
影响因子：
4.2
作者：
Ke, Bibo;Shen, Xiu-Da;Kupiec-Weglinski, Jerzy W.
通讯作者：
Kupiec-Weglinski, Jerzy W.
影响因子：
2.2
作者：
COLLETTI, LM;REMICK, DG;CAMPBELL, DA
通讯作者：
CAMPBELL, DA
影响因子：
5.3
作者：
Galehdar, Zohreh;Swan, Patrick;Cregan, Sean P.
通讯作者：
Cregan, Sean P.
影响因子：
10.8
作者：
Ha, Tuanzhu;Hua, Fang;Li, Chuanfu
通讯作者：
Li, Chuanfu