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.
Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. The long-term goals of this research project are to identify therapeutic agents that will prevent ethanol-induced injury to intestine and liver. Previous work has identified inflammatory responses as critical contributors to disease progression. Increased intestinal permeability and changes in bacterial microflora result in elevated levels of bacterial products in alcoholic patients and animal models of ALD. Lipopolysaccharide (LPS) recognition by Toll-like receptor 4 (TLR4) on Kupffer cells, the resident hepatic macrophages, releases inflammatory cytokines that impact the functions of hepatocytes and stellate cells. Specific-sized hyaluronan fragments have the potential to normalize sensitivity of Kupffer cells to activation and decrease inflammation in both intestine and liver. Understanding the complex interactions between specific-sized HA and alcohol-induced injury in liver and intestine will provide the foundation for the future development of rationally designed therapeutic interventions to slow and/or reverse alcoholic liver disease.
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