Moriez Raphaël, Salvador-Cartier Christel, Theodorou Vassilia, Fioramonti Jean, Eutamene Helene, Bueno Lionel
Institut National de la Recherche Agronomique, Neuro-Gastroenterology and Nutrition Unit, 180 Chemin de Tournefeuille, BP.3, 31931 Toulouse Cedex 9, France.
Am J Pathol. 2005 Oct;167(4):1071-9. doi: 10.1016/S0002-9440(10)61196-0.
Sepsis is associated with bacterial translocation (BT) and changes in colonic paracellular permeability (CPP), but the link between these effects is unknown. The present study aimed to identify whether changes in CPP after lipopolysaccharide (LPS) administration triggers BT, colonic inflammation, visceral pain, and sickness behavior and to evaluate the role of myosin light chain kinase (MLCK) in colonocyte cytoskeleton contraction. Rats received the MLCK inhibitor ML-7 alone or combined with LPS. CPP was measured for 6 hours after administration. Visceral pain, food intake, BT, electron microscopy of tight junctions of colonocytes, cytokine levels, and Western blotting of phosphorylated MLC from colonic mucosa were assessed in a time range of 0 to 3 hours after treatment. Sepsis increased CPP at 0 to 6 hours after LPS and associated with tight junction morphological changes, increased MLC phosphorylation, and mucosal release of proinflammatory cytokines. Massive BT, visceral hyperalgesia, and reduced food intake were also observed. Addition of ML-7 prevented all LPS-induced effects, except for changes in food intake. In conclusion, LPS-mediated effects on CPP include gut inflammation, BT, and visceral hyperalgesia. Inhibition of MLCK-dependent colonocyte cytoskeleton contraction by ML-7 prevents the LPS-induced alterations of CPP and its subsequent effects.
脓毒症与细菌易位(BT)及结肠细胞旁通透性(CPP)变化有关,但这些效应之间的联系尚不清楚。本研究旨在确定脂多糖(LPS)给药后CPP的变化是否会引发BT、结肠炎症、内脏疼痛和疾病行为,并评估肌球蛋白轻链激酶(MLCK)在结肠细胞骨架收缩中的作用。大鼠单独接受MLCK抑制剂ML-7或与LPS联合使用。给药后6小时测量CPP。在治疗后0至3小时的时间范围内评估内脏疼痛、食物摄入量、BT、结肠细胞紧密连接的电子显微镜检查、细胞因子水平以及结肠黏膜磷酸化MLC的蛋白质印迹分析。脓毒症在LPS后0至6小时增加CPP,并与紧密连接形态变化、MLC磷酸化增加和促炎细胞因子的黏膜释放有关。还观察到大量BT、内脏痛觉过敏和食物摄入量减少。添加ML-7可预防所有LPS诱导的效应,但食物摄入量变化除外。总之,LPS对CPP的介导效应包括肠道炎症、BT和内脏痛觉过敏。ML-7抑制MLCK依赖性结肠细胞骨架收缩可预防LPS诱导的CPP改变及其后续效应。