Nod2-Rip2信号通路在短肽载体PepT1介导的细菌产物引发小肠黏膜炎性损伤中的作用

Effect of Nod2-Rip2 signaling pathway on the PepT1-mediated MDP transport induces intestinal and systemic inflammation in rat

目的:探讨Nod2-Rip2-NF-κB信号通路在PepT1转运细菌产物酰基二肽(MDP)诱导小肠黏膜炎性损伤中的作用。方法:将80只大鼠随机分为正常组、实验对照组、MDP灌注组和PepT1竞争抑制组,每组20只。正常组大鼠不作处理,其余三组分别给予Krebs-Ringer缓冲液、加细菌产物MDP的缓冲液、加MDP和Gly-Gly的缓冲液灌注4 h。大鼠处死后采集小肠标本,检测小肠组织的病理变化和黏膜中Nod2和Rip2 mRNA表达、NF-κB活性和炎性因子,如肿瘤坏死因子α(TNF-α)、白细胞介素8(IL-8)、髓过氧化物酶(MPO)水平。结果:小肠组织病理学表明,MDP可引起炎性细胞的聚集和肠黏膜损伤。大鼠小肠内灌注MDP后,其黏膜中Nod2与Rip2mRNA的表达、NF-κB的结合活性以及炎性物质MPO、IL-8、TNF-α的表达均较正常组和实验对照组明显升高。上述表现被营养性二肽Gly-Gly明显抑制。结论:Nod2-Rip2-NF-κB信号通路在PepT1转运细菌产物并激活肠道炎性反应中发挥着重要作用。

Objective： To explore the effect of Nod2-Rip2 signaling pathway on the PepTl-mediated MDP transport induing intestinal inflammation. Methods： SD rats （n = 80） were randomly divided into normal group, the experimental control group, MDP perfusion group and PepT1 competitive inhibition group. Normal group had not any treatment, and the remaining three groups received intestinal perfusion. MDP or vehicle was added to the Krebs-Ringer buffer and perfused for 4 hours. For the competition studies, Gly-Gly was added to the buffer before addition of MDP. The expression of Nod2 and Rip2mRNA, the activation state of nuclear factor kappa B （NF-KB） , the production of cytokines [ tumor necrosis alpha （TNF）, interleukin-8 （IL-8） ], myeloperoxidase （MPO） activity, and histological analysis were determined. Results： Nod2 and Rip2mRNA were constitutively expressed in gut, and MDP elicited a robust activation of NF-KB and induced significant production of the different cytokines evaluated. These performances were inhibited by Gly-Gly significantly. Conclusion： This report showed the implication of a membrane transporter （ PepT1 ） in intestinal inflammation. PepTl-mediated transport of MDP and the Nod2-Rip2 signaling pathway might play an important role in this inflammation.