MECHANISM OF ENDOTOXIN ABSORPTION IN ALCOHOLISM

描述：(改编自《调查者摘要》)： 酒精性肝病涉及血浆内毒素和内毒素升高 介导性肝损伤。来自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，增加肠道对内毒素的吸收。这个 研究人员最近证明，乙醛是一种氧化产物 已知在肠道中产生的乙醇会增加细胞旁细胞 肠上皮模型Caco-2细胞单层的通透性。这个 乙醛的通透性增加是由酪氨酸激酶介导的 依赖机制，并与抑制蛋白质酪氨酸有关 磷酸酶(PTPase)和蛋白质酪氨酸磷酸化增加。这个 L-谷氨酰胺抑制乙醛对通透性的影响 被认为对各种胃肠道有治疗作用的酸 精神错乱。根据初步结果，假设：1) 乙醛通过以下途径解离上皮连接处的蛋白质复合体 通过调节PTP1B(A PTPase)诱导b-连环蛋白酪氨酸磷酸化， L-谷氨酰胺通过以下途径拮抗乙醛引起的通透性增加 阻断乙醛抑制PTP1B和增加酪氨酸的能力 B-连环蛋白的磷酸化。使用上述肠道模型 对于上皮细胞，研究人员建议确定：a)乙醛是否诱导 阻滞素/Z0-1和E-钙粘附素/b-连环蛋白复合体的解离。B)是否 乙醛诱导b-连环蛋白和特异性酪氨酸的磷酸化 残留物。C)乙醛是否抑制PTP1B。D)如果过度表达 PTP1B延缓乙醛诱导的细胞通透性和磷酸酶表达 失活的PTP1B突变体降低通透性，e)如果L-谷氨酰胺阻止 乙醛抑制PTP1B酪氨酸磷酸化b-连环蛋白和 E-钙粘蛋白/b-连环蛋白复合体的解离。派生自 这些研究有可能扩大我们对酒精中介的理解。 通过确定一些机制来增加内毒素的吸收 乙醛诱导的细胞旁连接中断及乙醛的保护作用 L-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.