Specific-size hyaluronan in ALD

 描述（由申请人提供）：酒精性肝病（ALD）在所有酗酒者中约占20%，女性患病率较高。越来越多的人认识到先天免疫和器官间串扰有助于乙醇诱导的肝损伤。肠道和肝脏之间的相互作用特别重要。肠屏障功能受损与乙醇诱导的肝损伤的进展相关。在慢性乙醇过程中，枯否细胞（常驻肝巨噬细胞）暴露于肠源性LPS的增加激活了TLR 4依赖性炎症介质的产生。慢性乙醇暴露也使枯否细胞对LPS敏感，导致炎症介质的产生增加。因此，改善肠道健康和使枯否细胞对活化的敏感性正常化的治疗策略可能在ALD的治疗中有用。透明质酸（HA）是一种丰富的细胞外基质成分，是由D-葡萄糖醛酸和N-乙酰葡糖胺重复二糖组成的直链聚合物。在急性和慢性炎症或组织损伤期间，活性氧和特异性酶（透明质酸酶1和2）增加HA周转，导致不同分子量的HA片段的局部和全身蓄积。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是否有助于慢性乙醇诱导的肝损伤的病理生理学。HA以大小特异性方式与许多细胞类型通信，使用至少四种信号传导受体，包括CD 44、RHAMM（HA介导的运动性受体）和Toll样受体（TLR）模式识别分子TLR 4和TLR 2。HA在病理性炎症环境下起募集和激活白细胞的作用，并且HA现在被包括在先天免疫中识别的损伤相关分子模式分子（DAMP）中。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片段可以是促炎性的或抗炎性的。在初步实验中，我们发现特定大小的HA在慢性乙醇暴露后使Kupffer细胞中TLR 4介导的信号正常化，并且还保护小鼠免受慢性乙醇诱导的肝损伤。在这里，我们将测试两个互补的假设，即特定大小的HA恢复库普弗细胞信号转导的调节正常后，慢性乙醇暴露和特定大小的HA保护乙醇诱导的肠道和肝脏损伤。这些研究的结果将用于指导使用特定大小的HA治疗和预防ALD的治疗策略的开发。

 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.