Blockage of protease‐activated receptor 1 ameliorates heat‐stress induced intestinal high permeability and bacterial translocation
Blockage of protease‐activated receptor 1 ameliorates heat‐stress induced intestinal high permeability and bacterial translocation
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DOI：
10.1002/cbin.10408
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发表时间：
2015-04
影响因子：
3.9
通讯作者：
Qiu-lin Xu;Xiao-hua Guo;Jingxian Liu;Bin Chen;Zhi-Feng Liu;L. Su
中科院分区：
文献类型：
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作者：
Qiu-lin Xu;Xiao-hua Guo;Jingxian Liu;Bin Chen;Zhi-Feng Liu;L. Su
越来越多的证据表明肠道病变在中暑发病中起重要作用。然而，热应激引起肠道屏障功能障碍和细菌移位的潜在机制仍不清楚。在这项研究中，我们研究了蛋白酶激活受体1（PAR 1）在热应激诱导的肠道高通透性和细菌移位中的作用。通过灌胃乳果糖/甘露醇（L/M）溶液，测定血浆内毒素浓度和尿中L/M比值，评价热应激小鼠肠道通透性。采集静脉血、肝、脾和肠系膜淋巴结组织进行细菌负荷试验。采用真实的时间PCR检测回肠PAR 1 mRNA的表达。在体外研究中，通过测定人肠Caco-2细胞系中的跨上皮电阻（TEER）来评估渗透性。RWJ-58259是一种PAR 1的选择性拮抗剂，在体内和体外研究中均使用。结果表明，热应激可使回肠PAR 1 mRNA水平、尿液L/M比值、血浆内毒素浓度以及血液、脾脏和肠系膜淋巴结中细菌负荷增加。RWJ-58259（10 mg/kg）预处理阻断PAR 1可显著减轻热应激诱导的上述变化，但对PAR 1 mRNA水平无作用。在Caco-2细胞中，RWJ-58259（5-20 µmol/L）也可降低热应激诱导的高渗透性。综上所述，我们的研究结果表明，PAR 1信号通路可能在热应激诱导的肠道通透性升高、细菌移位和内毒素血症的发生中起重要作用。
Accumulated evidences indicate intestinal lesions play an important role in the pathogenesis of heatstroke. However, the underlying mechanisms by which heat stress causes intestinal barrier dysfunction and bacterial translocation remain unclear. In this study, we investigated the role of protease‐activated receptor 1 (PAR1) in heat stress‐induced intestinal hyper‐permeability and bacterial translocation. Intestinal permeability in heat stressed mouse was evaluated by determining plasma endotoxin concentration and urinal lactulose/mannitol (L/M) ratio with gastric administration of L/M solution. Venous blood, liver, spleen and mesenteric lymph node tissues were collected for bacterial load test. Real time PCR was used to determine ileum PAR1 mRNA expression. In vitro study, permeability was assessed by determining trans‐epithelial electrical resistance (TEER) in human intestinal Caco‐2 cell line. RWJ‐58259, a selective antagonist of PAR1, was used both in vivo and in vitro studies. The results showed that heat stress could increase ileum PAR1 mRNA level, urinal L/M ratio, plasma endotoxin concentration and bacterial load in the blood, spleen and mesenteric lymph nodes. Blocking PAR1 with RWJ‐58259 (10 mg/kg) pretreatment could significantly reduce heat stress‐induced above changes, but have no role to PAR1 mRNA level. In Caco‐2 cells, heat stress‐induced high permeability could also be reduced by RWJ‐58259 (5–20 µmol/L). In summary, our results demonstrated that PAR1 signaling pathway may play an important role in the heat stress‐induced elevation of intestinal permeability, bacterial translocation and the occurrence of endotoxemia.