Hmgb1 In Acute Liver Injury And Its Mechanism

High mobility group box 1 protein (HMGB1) was discovered as a nonhistone intranuclear architectural protein more than 30 years ago . Nuclear HMGB1 has been known as a DNA-binding protein that can participate in DNA recombination,repair,reproduction and gene transcription. Recent studies identify that HMGB1 can be released and extracellar HMGB1 triggers an inflammatory response as a late potent proinflammatory mediator .It was demonstrated that HMGB1 was not only actively secrected by macrophages/ monocytes in response to several proinflammatory stimuli such as LPS,TNF-α,IL-1,γ-IFN, was but also passively released by necrotic cells. Thus, extracellar HMGB1 appears to be a danger singal of"tissue and cell damage or necrotization". Since necrotic cells of HMGB1-/- animal did not release HMGB1, the inflammatory response caused by HMGB1-/- animal necrotic cells is mild.The mechanism of inflammation induced by HMGB1 was not claritied,but HMGB1 has demonstrated to be a late mediator initiating inflammatory responses, which included signal transduction, the production of multiple cytokines such as TNF-α, induction of vascular adhesion molecules,chemoattraction of certain stem cells and impaired function of intestinal epithelial cells. HMGB1 has a stronger binding to DNA in apopotic cells, not released, even when apopotic cells were eliminated by macrophages.The affinity of HMGB1 for DNA is dependent on the acetylation degree of HMGB1. If apopotic cells were treated with the deacetylase inhibitor, HMGB1 detached from condensed chromosomes, diffused to the cytoplasm and was released .Interestingly, many studies identified that HMGB1 production was significantly delayed and maintain longer time compared with LPS-induced other cytokines production,apart from study in hepatic injury after murine liver ischemia-reperfusion. Anti-HMGB1 antibody or antagonist of HMGB1 can reduce inflammation and improve survival in experimental animals. HMGB1-targeted therapy is to be an important anti-inflammatory strategy.More recently, scholars pay attention to the"secordary liver injury"induced by intestinal endotoxemia(IETM). As being shown in many studies, the various primary liver injury resulted in IETM, then IETM active the Kupffer cells to secrete TNF-αand accelerate the development of liver injury. Fang and Sass et al demonstrated hepatic HMGB1 concentration were remarkably increased in system sepsis and endotoxemia, we propose a key link between liver up-regulated HMGB1 and acute liver injury(ALI). The aim of this study was to account for HMGB1 expression in hepatocytes and Kupffer cells and to test the hypothesis that HMGB1 is an late mediator of inflammation and cell injury after acute liver injury. This thesis includes three parts:Part I: High Mobility Group Box-1 expression and release in hepatocytes and Kupffer cells...