Specific-size hyaluronan in ALD

 描述(由申请人提供)：酒精性肝病(ALD)在所有酗酒者中约有20%发生，女性患病率较高。越来越多的人认识到，先天性免疫和器官间串扰是酒精性肝损伤的原因。肠道和肝脏之间的相互作用尤为重要。肠屏障功能受损与酒精性肝损伤的进展有关。慢性乙醇期间，Kupffer细胞，驻留在肝脏的巨噬细胞，暴露于肠道来源的内毒素，激活了TLR4依赖的炎症介质的产生。慢性酒精暴露还会使库普弗细胞对脂多糖敏感，导致炎性介质的产生增加。因此，改善肠道健康和使库普弗细胞对激活的敏感性正常化的治疗策略在ALD的治疗中可能是有用的。透明质酸(HA)是一种丰富的细胞外基质成分，是由重复的D-葡萄糖醛酸和N-乙酰氨基葡萄糖组成的直链聚合物。在急慢性炎症或组织损伤过程中，活性氧物种和特定的酶(透明质酸酶1和2)会增加HA的周转，导致不同分子量的HA片段在局部和全身积累。事实上，几十年来，HA一直被用作肝损伤的指标；然而，尚不清楚HA是否与慢性酒精性肝损伤的病理生理学有关。透明质酸通过至少四种信号受体与多种类型的细胞进行大小特异性的通讯，包括CD44、RHAMM(HA介导的运动性受体)和Toll样受体(Toll-like Receptor，TLR)模式识别分子TLR4和TLR2。在病理炎症环境下，HA起到募集和激活白细胞的作用，现在HA被列入天然免疫中公认的损伤相关分子模式分子(DAMP)之一。尽管HA具有刺激炎症反应的强大能力，但越来越多的证据表明，特定大小的HA片段既可以促炎，也可以抗炎。在初步实验中，我们发现一种特定大小的HA在慢性乙醇暴露后使Kupffer细胞中TLR4介导的信号正常化，并保护小鼠免受慢性乙醇诱导的肝损伤。在这里，我们将检验两个互补的假设，即特定大小的HA在慢性酒精暴露后将Kupffer细胞信号转导的调节恢复到正常，以及特定大小的HA保护乙醇诱导的肠道和肝脏损伤。这些研究的结果将被用来指导制定治疗策略，以治疗和预防特定大小的HA的ALD。

 DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) develops in approximately 20% of all alcoholics with a higher prevalence in females. There is a growing appreciation that innate immunity and inter-organ cross talk contribute to ethanol-induced liver injury. Interactions between the intestine and liver are of particular importance. Impairment of intestinal barrier function is associated with the progression of ethanol-induced liver injury. Increased exposure of Kupffer cells, the resident hepatic macrophages, to gut-derived LPS during chronic ethanol activates TLR4- dependent production of inflammatory mediators. Chronic ethanol exposure also sensitizes Kupffer cells to LPS, resulting in increased production of inflammatory mediators. Thus, therapeutic strategies to improve intestinal health and normalize Kupffer cell sensitivity to activation will likely be useful in treatment of ALD. Hyaluronan (HA), an abundant extracellular matrix component, is produced as a straight chain polymer strictly composed of repeating disaccharides of D-glucuronic acid and N-acetylglucosamine. During acute and chronic inflammation or tissue injury, reactive oxygen species and specific enzymes (hyaluronidases 1 and 2) increase HA turnover, resulting in the local and systemic accumulation of HA fragments of different molecular weights. Indeed, HA has been used as an indicator of liver injury for decades; however, it is not known if HA contributes to the pathophysiology of chronic ethanol-induced liver injury. HA communicates with many cell types in a size-specific manner, using at least four signaling receptors including CD44, RHAMM (receptor for HA mediated motility) and toll-like receptor (TLR) pattern recognition molecules TLR4 and TLR 2. HA acts to recruit and activate leukocytes under pathological inflammatory settings and HA is now included among the damage associated molecular pattern molecules (DAMPs) recognized in innate immunity. Despite the potent ability of HA to stimulate inflammatory responses, growing evidence indicates that specific-sized HA fragments can be either pro-inflammatory or anti-inflammatory. In pilot experiments, we have discovered that a specific-sized HA normalizes TLR4-mediated signaling in Kupffer cells after chronic ethanol exposure and also protects mice from chronic ethanol-induced liver injury. Here we will test two complementary hypotheses that specific-sized HA restores regulation of Kupffer cell signal transduction to normal after chronic ethanol exposure and that specific-sized HA protects from ethanol-induced gut and liver injury. Results from these studies will be used to guide the development of therapeutic strategies for the treatment and prevention of ALD with specific- sized HA.