在酒精性肝病中调控NLRP3炎症复合体活化的机制研究

Alcoholic liver disease is one of the common liver diseases in our country. However, there is no definitive treatment available for any stages of the alcohol-related liver disease. It is important to investigate pathogenic mechanisms that drive the disease progression and clinical outcome of human alcoholic liver disease because we can find the potential target. Inflammasomes are cytosolic multi-protein complexes that are essential effectors for sterile inflammatory response, in which NLRP3 inflammasome is associated with a wide range of diseases including infection, auto-inflammatory and autoimmune disorders. Activation of NLRP3 inflammasome leads pyroptosis and secretion of the important pro-inflammatory cytokines IL-1β and IL-18. NLRP3 inflammasome has been shown to be required for a wide range of liver diseases. However, the characteristic of NLRP3 inflammasome in human alcoholic liver disease remains unclear. Our recent study found that NLRP3 components highly expressed in the livers in the patients with alcoholic hepatitis. Analysis of NLRP3 components documented that a positive association with liver damage and fibrosis. As such, we partially confirm NLRP3 inflammasome is involved in alcoholic liver disease. In this study, we further investigate: (1) the characteristic of NLRP3 inflammasome in disease progression; (2) the upstream mechanisms underling NLRP3 inflammasome activation; (3) disease-related damage-associated molecular patterns

酒精性肝病是我国常见的肝脏疾病之一，治疗上缺少具有明确效果的方法，因此调查影响酒精性肝病疾病进展和预后的致病机制可为将来的治疗提供潜在的干预靶点。炎症复合体是胞浆内一组复杂的多蛋白复合体，是造成无菌性炎症的最基本的效用器，NLRP3炎症复合体是其中被研究最多的一个，其活化后造成细胞死亡并引起IL-1β和IL-18的成熟与释放。动物模型中的研究提示NLRP3炎症复合体在多种肝病中发挥重要作用，但在人酒精性肝病中的特征及功能意义还不完全清楚。我们前期的结果显示，酒精性肝病患者肝内NLRP3炎症复合体显著升高并与肝损伤、肝纤维化指标密切相关。因此，我们推测NLRP3炎症复合体参与并推动着酒精性肝病的疾病进展。在本研究中我们将进一步明确NLRP3炎症复合体与酒精性肝病疾病进展、病理损伤的关系，找到调控NLRP3炎症复合体活化的上游机制和影响疾病进展的内源性损伤相关模式分子