Differential effects of hyaluronan synthase 3 deficiency after acute vs chronic liver injury in mice

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author's publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background Hyaluronan (HA) is a ubiquitous extracellular matrix (ECM) glycosaminoglycan synthesized by three different enzymes, hyaluronan synthase (HAS)1, 2, and 3. HA synthesis mediated by HAS3 promotes inflammation and is pathogenic in animal models of human lung and intestinal disease. Liver fibrosis is a common endpoint to chronic liver injury and inflammation for which there is no cure. Although plasma HA is a commonly used biomarker for liver disease, if and how HA contributes to disease pathogenesis remains unclear. Here, we tested the hypothesis that HA synthesized by HAS3 enhances inflammation and fibrosis. To test this hypothesis, we exposed wild-type or Has3−/− mice to carbon tetrachloride (CCl4) once (acute) or ten (chronic) times. Results HAS3-deficient mice exhibited increased hepatic injury and inflammatory chemokine production 48 h after acute CCl4; this was associated with a threefold reduction in plasma HA levels and alterations in the proportions of specific molecular weight HA polymer pools. Hepatic accumulation of fibrosis-associated transcripts was also greater in livers from HAS3-deficient mice compared to controls after acute CCl4 exposure. Surprisingly, fibrosis was not different between genotypes. Hepatic matrix metalloproteinase (MMP)13 mRNA and MMP13 activity was greater in livers from Has3-null mice after chronic CCl4; this was prevented by a MMP13-specific inhibitor. Collectively, these data suggest that Has3, or more likely HA produced by HAS3, limits hepatic inflammation after acute injury and attenuates MMP13-mediated matrix metabolism after chronic injury. Conclusions These data suggest that HA should be investigated further as a novel therapeutic target for acute and chronic liver disease. Electronic supplementary material The online version of this article (doi:10.1186/s13069-016-0041-5) contains supplementary material, which is available to authorized users

Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice

Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24–96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure