Department of Medicine/Gastroenterology, University of Pittsburgh, Pittsburgh, PA, USA.
Neurogastroenterol Motil. 2010 Mar;22(3):232-45. doi: 10.1111/j.1365-2982.2009.01464.x.
Our bacterial residents are deadly Janus-faced indwellers that can lead to a sepsis-induced systemic inflammatory response syndrome and multiple organ failure. Over half of ICU patients suffer from infections and sepsis remains one of the top 10 causes of death worldwide. Severe ileus frequently accompanies sepsis setting up an insidious cycle of gut-derived microbial translocation and the copious intestinal production of potent systemic inflammatory mediators. Few therapeutic advances have occurred to prevent/treat the sequelae of sepsis. Here, we selectively review studies on cellular membrane-bound Toll-like receptor (TLR) mechanisms of ileus. Virtually, no data exist on Gram-positive/TLR2 signaling mechanisms of ileus; however, TLR2 is highly inducible by numerous inflammatory mediators and studies using clinically relevant scenarios of Gram-positive sepsis are needed. Specific Gram-negative/TLR4 signaling pathways are being elucidated using a 'reverse engineering' approach, which has revealed that endotoxin-induced ileus is dually mediated by classical leukocyte signaling and by a MyD88-dependent non-bone marrow-derived mechanism, but the specific roles of individual cell populations are still unknown. Like TLR2, little is also know of the role of flagellin/TLR5 signaling in ileus. But, much can be learned by understanding TLR signaling in other systems. Clearly, the use of polymicrobial models provides important clinical relevancy, but the simultaneous activation of virtually all pattern recognition receptors makes it impossible to discretely study specific pathways. We believe that the dissection of individual TLR pathways within the gastrointestinal tract, which can then be intelligently reassembled in a meaningful manner, will provide insight into treatments for sepsis.
我们的细菌居民是两面派的常驻者，它们可能导致脓毒症引起的全身炎症反应综合征和多器官衰竭。超过一半的 ICU 患者受到感染的困扰，而脓毒症仍然是全球十大死亡原因之一。严重的肠梗阻常伴随脓毒症，从而形成一个隐蔽的肠道微生物易位和大量肠道产生强效全身炎症介质的恶性循环。尽管脓毒症的后续治疗取得了一些进展，但很少有治疗方法可以预防/治疗其后果。在这里，我们选择性地回顾了关于细胞表面 Toll 样受体 (TLR) 机制与肠梗阻的研究。实际上，关于革兰氏阳性菌/TLR2 信号机制与肠梗阻的研究还很少；然而，TLR2 可被许多炎症介质高度诱导，并且需要使用临床相关的革兰氏阳性菌脓毒症场景进行研究。使用“反向工程”方法阐明了特定的革兰氏阴性/TLR4 信号通路，该方法表明内毒素诱导的肠梗阻是由经典白细胞信号和 MyD88 依赖性非骨髓来源机制双重介导的，但特定细胞群体的具体作用仍不清楚。与 TLR2 一样，关于鞭毛蛋白/TLR5 信号在肠梗阻中的作用也知之甚少。但是，通过了解其他系统中的 TLR 信号，可以获得很多信息。显然，使用多微生物模型提供了重要的临床相关性，但实际上所有模式识别受体的同时激活使得不可能单独研究特定途径。我们相信，在胃肠道内对单个 TLR 途径进行剖析，然后以有意义的方式进行智能重组，将为脓毒症的治疗提供深入的见解。
