Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats.
Farnesoid X Receptor Activation Attenuates Intestinal Ischemia Reperfusion Injury in Rats.
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DOI：
10.1371/journal.pone.0169331
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Pirenne J
中科院分区：
文献类型：
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作者：
Ceulemans LJ;Verbeke L;Decuypere JP;Farré R;De Hertogh G;Lenaerts K;Jochmans I;Monbaliu D;Nevens F;Tack J;Laleman W;Pirenne J
法尼醇 X 受体 (FXR) 在回肠中大量表达，如炎症性肠病的临床前模型所示，它作为肠道先天免疫和稳态的关键调节剂发挥着肠道保护作用。由于肠道缺血再灌注损伤（IRI）的特点是通透性过高、细菌移位和炎症，我们的目的是首次研究FXR激动剂奥贝胆酸（OCA）是否可以减轻肠道缺血再灌注损伤。在经过验证的肠道 IRI 大鼠模型（剖腹手术 + 临时肠系膜动脉夹闭）中，测试了 3 种条件（n = 16/组）：仅剖腹手术（假手术组）；缺血60min+再灌注60min+赋形剂预处理（IR组）；缺血60min+再灌注60min+OCA预处理（IR+OCA组）。在IRI之前24小时和4小时通过强饲法施用载体或OCA（INT-747，2*30mg/kg）。分析了以下终点：7 天生存率；肠细胞活力的生物标志物（L-乳酸、I-FABP）；组织学（绒毛/隐窝的形态损伤和绒毛长度）；肠道通透性（使用室）；内毒素易位（脂多糖测定）；细胞因子（IL-6、IL-1-β、TNFα、IFN-γ、IL-10、IL-13）；细胞凋亡（裂解的 caspase-3）；和自噬（LC3，p62）。研究发现肠道 IRI 与高死亡率相关（90%）；肠道完整性丧失（结构和功能）；增加内毒素易位和促炎细胞因子的产生；和自噬的抑制。相反，OCA 预处理将 7 天生存率提高了 50%，这与预防上皮损伤、保留肠道结构和通透性有关。此外，FXR 激动导致促炎细胞因子释放减少并减轻自噬抑制。使用 FXR 激动剂 OCA 进行预处理可提高肠道 IRI 啮齿动物模型的存活率，保留肠道屏障功能并抑制炎症。这些结果使 FXR 成为治疗与肠道缺血相关的各种疾病的有希望的靶点。
The farnesoid X receptor (FXR) is abundantly expressed in the ileum, where it exerts an enteroprotective role as a key regulator of intestinal innate immunity and homeostasis, as shown in pre-clinical models of inflammatory bowel disease. Since intestinal ischemia reperfusion injury (IRI) is characterized by hyperpermeability, bacterial translocation and inflammation, we aimed to investigate, for the first time, if the FXR-agonist obeticholic acid (OCA) could attenuate intestinal ischemia reperfusion injury. In a validated rat model of intestinal IRI (laparotomy + temporary mesenteric artery clamping), 3 conditions were tested (n = 16/group): laparotomy only (sham group); ischemia 60min+ reperfusion 60min + vehicle pretreatment (IR group); ischemia 60min + reperfusion 60min + OCA pretreatment (IR+OCA group). Vehicle or OCA (INT-747, 2*30mg/kg) was administered by gavage 24h and 4h prior to IRI. The following end-points were analyzed: 7-day survival; biomarkers of enterocyte viability (L-lactate, I-FABP); histology (morphologic injury to villi/crypts and villus length); intestinal permeability (Ussing chamber); endotoxin translocation (Lipopolysaccharide assay); cytokines (IL-6, IL-1-β, TNFα, IFN-γ IL-10, IL-13); apoptosis (cleaved caspase-3); and autophagy (LC3, p62). It was found that intestinal IRI was associated with high mortality (90%); loss of intestinal integrity (structurally and functionally); increased endotoxin translocation and pro-inflammatory cytokine production; and inhibition of autophagy. Conversely, OCA-pretreatment improved 7-day survival up to 50% which was associated with prevention of epithelial injury, preserved intestinal architecture and permeability. Additionally, FXR-agonism led to decreased pro-inflammatory cytokine release and alleviated autophagy inhibition. Pretreatment with OCA, an FXR-agonist, improves survival in a rodent model of intestinal IRI, preserves the gut barrier function and suppresses inflammation. These results turn FXR into a promising target for various conditions associated with intestinal ischemia.
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影响因子：
14.2
作者：
Groschwitz, Katherine R.;Hogan, Simon P.
通讯作者：
Hogan, Simon P.
DOI：
10.1124/jpet.108.144600
发表时间：
2009-01-01
影响因子：
3.5
作者：
Kong, Bo;Luyendyk, James P.;Guo, Grace L.
通讯作者：
Guo, Grace L.
影响因子：
29.4
作者：
Kanda, T;Fujii, H;Hatakeyama, K
通讯作者：
Hatakeyama, K
影响因子：
3.7
作者：
Ghebremariam YT;Yamada K;Lee JC;Johnson CL;Atzler D;Anderssohn M;Agrawal R;Higgins JP;Patterson AJ;Böger RH;Cooke JP
通讯作者：
Cooke JP
缺血和再灌注 - 从翻译机构。
影响因子：
82.9
作者：
通讯作者：
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