IL-22激活IL-22R1/STAT3通路调控肠Lgr5+干细胞增殖参与损伤肠上皮修复在重症急性胰腺炎合并肠屏障功能障碍中的机制研究

Severe acute pancreatitis (SAP) patients are often associated with intestinal barrier dysfunction." pancreatic-intestinal crosstalk" aggravates the patient's condition. Intestinal Lgr5+ stem cells (ISCs) play a crucial role in regeneration and repair of epithelial cells,thus maintaining the integrity of structure and function of intestinal barrier. Interleukin-22 (IL-22) has a positive effect of promoting intestinal epithelial repair. However, the changes of ISCs and IL-22 in SAP and whether IL-22 can regulate the ISCs involved in the protection of intestinal barrier function have not been studied. Pre-experimental results in this project show that rats with SAP have pathological damage of the Intestinal epithelium and the proliferative activity of ISCs is weakened,combined with increased intestinal permeability. The expression levels of IL-22 in colon tissue are decreased. The following scientific hypothesis is proposed: The lower levels of IL-22 under SAP state had decreased ability of regulating proliferation and differentiation of ISCs, resulting in decreased ability of epithelial injury repair. Expression of Occludin, MUC-2,Reg3β,Reg3γetc are down-regulated and dysbiosis of intestinal flora exists.The IL-22R1/STAT3 pathway plays a key role in the regulation of the proliferative activity of ISCs by IL-22.This study presents new possible mechanisms to elucidate SAP combined with intestinal barrier dysfunction and helps to provide new therapeutic targets for SAP.

重症急性胰腺炎(SAP)患者常合并肠屏障功能障碍，“胰-肠互话”进一步加重患者病情。肠Lgr5+干细胞(ISCs)在肠上皮再生、损伤修复及维持肠屏障结构和功能中起至关重要的作用，白细胞介素-22（IL-22）具有促进肠上皮修复的作用，但在SAP时ISCs及IL-22的变化及IL-22是否能调控ISCs参与肠屏障功能的维护尚无研究。本项目预实验发现SAP大鼠肠上皮存在损伤，ISCs增殖活性减弱，肠粘膜通透性增加，肠组织IL-22产生减少。我们提出如下假说：SAP状态下IL-22调控ISCs增殖分化的能力下降，造成对损伤上皮修复能力下降，Occludin、MUC-2、Reg3β、Reg3γ等表达下降，肠道菌群失调。IL-22R1/STAT3信号通路在IL-22调控ISCs的增殖活性中发挥了关键作用。该研究提出了SAP合并肠屏障功能障碍新的发病机制，有助于为SAP的治疗策略提供新的靶点。

肠屏障功能障碍在重症急性胰腺炎（severe acute pancreatitis, SAP)全身性炎症和胰腺感染性坏死的发病机制和进展中起着重要作用，最终可导致多器官衰竭和死亡，而目前对SAP相关的肠屏障功能障碍的治疗尚缺乏足够的策略。在本研究中，我们设计并制作了一种针对炎症的包含IL-22的纳米颗粒pHA-NCs，它可以聚集在结肠组织上，调节急性坏死性胰腺炎（ANP）小鼠中被破坏的肠道屏障。体外和体内实验均表明，pHA-NCs具有较强的自由基清除能力，在胰腺和结肠的积累水平显著升高，提示pHA-NCs可促进IL-22在炎症组织中的聚集。此外，在小鼠ANP模型中，pHA-NCs显著降低胰腺和结肠的病理评分，降低促炎细胞因子的分泌，增加肠上皮紧密连接分子的表达，显著减轻肠道屏障功能障碍。此外，研究发现包含IL-22的pHA-NCs通过IL-22/STAT3通路调控肠Lgr5干细胞增殖。这一发现为SAP合并肠屏障功能障碍的治疗提供了一个理想的潜在的策略。