NLRP3炎性体在胰腺纤维化中的作用及其调控机制

Fibrosis is the main reason causing continuous and permanent dysfunction of pancreas. Once activated by LPS, etc., the NLRP3 inflammasome play an imperative role in tissue fibrogenesis via regulating the function of hepatic stellate cells and fibroblasts. However, the role and the mechanism of NLRP3 inflammasome in regulating pancreatic fibrogenesis needs to be further clarified. According to our previous work, the inflammasome associated expression of caspase-1 and IL-1β is involved in necro-inflammatory response in pancreatitis model induced by LPS combining alcohol, accompanied with the activation of pancreatic stellate cells and early formation of peri-acini fibrosis. Taken the “Necrosis-Fibrosis Sequence” theory into account, we postulate that NLRP3 inflammasome promotes the pancreatic fibrogenesis by directly modulating the function of pancreatic stellate cells when activated by LPS, etc., and by generating endogenous danger signals that required for activation of pancreatic stellate cells via accelerating necrosis-inflammation response. To prove this hypothesis, the expression of NLRP3 inflammasome in pancreatic stellate cells as well as it’s mechanism in modulating the biological function of pancreatic stellate cells and tissue necrosis-fibrosis response will be studied in vitro and in vivo. This study aims to clarify the pleiotropic role of intracellular activation of NLRP3 inflammasome in pancreatic fibrogenesis and to figure out the therapeutic targets against pancreatic fibrosis.

胰腺纤维化是导致胰腺组织和功能持续性、永久性损伤的重要原因。研究发现NLRP3炎性体受LPS等因素活化后，通过调节肝星状细胞及成纤维细胞活性促进组织纤维化，然而NLRP3炎性体在胰腺纤维化中的作用及其调控机制仍待阐明。课题组前期研究发现在LPS联合酒精诱导的胰腺炎模型中炎性体效应分子caspase-1、IL-1β参与胰腺坏死-炎症反应，并伴有胰腺星状细胞活化及早期纤维化形成。结合“坏死-纤维化”学说，我们推测：胰腺星状细胞受LPS等因素激活后高表达NLRP3炎性体，后者通过其效应分子在调控胰腺星状细胞合成细胞外基质同时，促进坏死-炎症反应，并介导释放胰腺星状细胞活化所需的信号，从而直接和间接地调控胰腺纤维化。为证实该假说，本课题将对NLRP3炎性体在胰腺星状细胞中的表达及其在体、内外实验中对胰腺星状细胞生物学特性和胰腺坏死-纤维化的影响及机制进行研究。希望为治疗胰腺纤维化提供新思路。