Lipopolysaccharide Causes an Increase in Intestinal Tight Junction Permeability in Vitro and in Vivo by Inducing Enterocyte Membrane Expression and Localization of TLR-4 and CD14
Lipopolysaccharide Causes an Increase in Intestinal Tight Junction Permeability in Vitro and in Vivo by Inducing Enterocyte Membrane Expression and Localization of TLR-4 and CD14
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DOI：
10.1016/j.ajpath.2012.10.014
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发表时间：
2013-02-01
影响因子：
6
通讯作者：
Ma, Thomas Y.
中科院分区：
文献类型：
--
作者：
Guo, Shuhong;Al-Sadi, Rana;Ma, Thomas Y.
细菌来源的脂多糖(LPS)在炎症性肠病的炎症过程中起着重要作用。肠道紧密连接(TJ)屏障的缺陷是炎症性肠病和其他肠道炎症状态的重要致病因素。尽管内毒素在介导肠道炎症中具有重要作用，但其对肠上皮屏障的生理作用仍不清楚。本研究的主要目的是利用体外(滤器生长的Caco-2单层)和在体(小鼠肠道灌流)肠上皮模型系统，确定生理相关浓度(0~1 ng/mL)的内毒素对肠屏障功能的影响。在生理相关浓度下(0~1 ng/mL)，基底外侧室内的脂多糖可使Caco-2的TJ通透性呈时间依赖性增加，而不会导致细胞死亡。腹腔注射脂多糖(0.1 mg/kg)，导致临床上相关的血浆浓度，也引起体内肠道通透性的时间依赖性增加。内毒素诱导的肠道TJ通透性增加是由肠细胞膜TLR-4表达增加和TLR-4依赖的膜相关蛋白CD14膜共定位增加所介导的。综上所述，这些研究首次表明，内毒素通过TLR-4依赖的CD14膜表达上调的细胞内机制导致肠道通透性增加。(Am J Pathol 2013,182：375-387；http://dx.doi.org/10.1016/j.ajpath.2012.10.014)
Bacterial-derived Lipopolysaccharides (LPS) play an essential role in the inflammatory process of inflammatory bowel disease. A defective intestinal tight junction (TJ) barrier is an important pathogenic factor of inflammatory bowel disease and other inflammatory conditions of the gut. Despite its importance in mediating intestinal inflammation, the physiological effects of LPS on the intestinal epithelial barrier remain unclear. The major aims of this study were to determine the effects of physiologically relevant concentrations of LPS (0 to 1 ng/mL) on intestinal barrier function using an in vitro (filter-grown Caco-2 monolayers) and an in vivo (mouse intestinal perfusion) intestinal epithelial model system. LPS, at physiologically relevant concentrations (0 to 1 ng/mL), in the basolateral compartment produced a time-dependent increase in Caco-2 TJ permeability without inducing cell death. Intraperitoneal injection of LPS (0.1 mg/kg), leading to clinically relevant plasma concentrations, also caused a time-dependent increase in intestinal permeability in vivo. The LPS-induced increase in intestinal TJ permeability was mediated by an increase in enterocyte membrane TLR-4 expression and a TLR-4-dependent increase in membrane colocalization of membrane-associated protein CD14. In conclusion, these studies show for the first time that LPS causes an increase in intestinal permeability via an intracellular mechanism involving TLR-4 dependent up-regulation of CD14 membrane expression. (Am J Pathol 2013, 182:375-387; http://dx.doi.org/10.1016/j.ajpath.2012.10.014)