MECHANISM OF ENDOTOXIN ABSORPTION IN ALCOHOLISM

描述：（改编自研究者摘要）： 酒精性肝病涉及血浆内毒素和内毒素 介导的肝损伤。临床和实验研究的证据表明， 酒精中毒时内毒素水平升高与内毒素过度生长有关 产生细菌并增加肠内毒素的吸收。的 研究人员最近证明，乙醛的氧化产物， 乙醇，已知是在肠道中产生的， Caco-2细胞单层（一种肠上皮模型）中的渗透性。的 乙醛渗透性的增加是由酪氨酸激酶介导的 依赖性机制，并与蛋白酪氨酸的抑制有关 磷酸酶（PTK）和增加的蛋白酪氨酸磷酸化。的 L-谷氨酰胺可抑制乙醛对通透性的影响， 酸被认为对各种胃肠道疾病具有治疗益处 紊乱根据初步结果，假设：1） 乙醛在上皮连接处解离蛋白质复合物， 通过调节PTP 1B（PTP 1B）诱导β-连环蛋白的酪氨酸磷酸化， 和2）L-谷氨酰胺通过以下方式防止乙酰丙酮酸诱导的渗透性增加： 阻断乙醛抑制PTP 1B和增加酪氨酸的能力 β-连环蛋白的磷酸化。利用上述肠粘膜模型， 上皮细胞，研究人员建议确定：a）如果乙醛诱导 闭合蛋白/Z 0 -1和E-钙粘蛋白/β-连环蛋白复合物的解离。B）是否 乙醛诱导β-连环蛋白和特异性酪氨酸磷酸化 残基c）乙醛是否抑制PTP 1B。（3）如果过度表达 PTP 1B延迟乙醛诱导的通透性和磷酸酶表达 失活的PTP 1B突变体降低渗透性，和e）如果L-谷氨酰胺阻止 乙醛抑制β-连环蛋白的PTP 1B酪氨酸磷酸化， E-钙粘蛋白/b-连环蛋白复合物的解离。导出的所述信息 这些研究有可能扩大我们对酒精介导的 通过确定内毒素吸收的一些机制， 乙醛诱导的细胞旁连接的破坏和保护作用 谷氨酰胺

DESCRIPTION: (Adapted from the Investigator's Abstract): The pathogenesis of alcoholic liver disease involves elevated plasma endotoxin and endotoxin mediated liver injury. Evidence from clinical and experimental studies suggests that elevated endotoxin level in alcoholism involves overgrowth of endotoxin producing bacteria and increased intestinal absorption of endotoxin. The investigators recently demonstrated that acetaldehyde the oxidative product of ethanol, known to be generated in the intestine, increases paracellular permeability in Caco-2 cell monolayers, an intestinal epithelial model. The acetaldehyde increase in permeability is mediated by a tyrosine kinase dependent mechanism and is associated with an inhibition of protein tyrosine phosphatase (PTPase) and increased protein tyrosine phosphorylation. The acetaldehyde effects on permeability was inhibited by L-glutamine, an amino acid considered for its therapeutic benefits in various gastrointestinal disorders. On the basis of preliminary results it is hypothesized that: 1) acetaldehyde dissociates protein complexes at the epithelial junctions by inducing tyrosine phosphorylation of b-catenin by regulating PTP1B (a PTPase), and 2) L-glutamine prevents acetaldehyde-induced increase in permeability by blocking the ability of acetaldehyde to inhibit PTP1B and increased tyrosine phosphorylation of b-catenin. Using the above mentioned model of intestinal epithelia, the investigators propose to determine: a) If acetaldehyde induces a dissociation of occludin/Z0-1 and E-Cadherin/b-catenin complexes. b) Whether acetaldehyde induces phosphorylation of b-catenin and specific tyrosine residues. c) Whether acetaldehyde inhibits PTP1B. d) If over expression of PTP1B delays acetaldehyde induced permeability and expression of phosphatase inactive PTP1B mutants decreases permeability, and e) If L-glutamine prevents acetaldehyde inhibition of PTP1B tyrosine phosphorylation of b-catenin and dissociation of E-cadherin/b-catenin complex. The information derived from these studies has the potential to expand our understanding of alcohol mediated increase in endotoxin absorption by identifying some of the mechanisms of acetaldehyde induced disruption of paracellular junctions and protection by L-glutamine.