TLRs信号负性调控因子SIGIRR对重症急性胰腺炎肠屏障功能障碍的作用及机制

Severe acute pancreatitis (SAP), is associated with high morbidity mostly because of systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF).It is generally agreed that the excessive activation of TLRs signaling pathway induced by secondary bacterial translocation of intestinal barrier dysfunction plays significant role in SAP. It has been shown that negative regulatory factor SIGIRR of TLRs signal had protective effects in many inflammatory diseases such as sepsis. Our previous study has found that SAP patients with ascites would experience more serious inflammatory response mediated by excessive activation of TLRS signal on account of the inhibition of the expression of SIGIRR in macrophages, which could be reversed by applying exogenous SIGIRR gene. Another study confirmed that SIGIRR could alleviate the pathological damage and inflammatory response of intestinal mucosa in mice with colitis. However, the role of SIGIRR in intestinal barrier dysfunction mediated by TLRS signaling pathway in SAP remains unknown. Our present study intends to study the protective effect of SIGIRR in intestinal barrier dysfunction mediated by TLRs signaling pathway with SAP in vitro and in vivo respectively. This study is aimed to outline the potential mechanism and highlight the clinical treatment of SAP.

重症急性胰腺炎(SAP)死亡率高，全身炎症反应综合征（SIRS）及多脏器功能衰竭（MOF）是其致死的重要原因，肠屏障功能障碍继发细菌易位所诱导的TLRs信号通路过度激活在其中起重要作用。研究表明TLRs信号负性调控因子SIGIRR在脓毒症等许多疾病的炎症反应中具有保护作用。我们前期研究发现SAP患者腹水可抑制巨噬细胞SIGIRR表达，使TLRs信号过度激活，加剧炎症反应，而给予外源性SIGIRR基因能抑制这一过程。我们另一研究证实SIGIRR能减轻小鼠结肠炎肠黏膜的病理损伤和炎症反应。那么，在SAP中SIGIRR可否通过负性调控TLRs信号改善肠屏障功能减轻或阻止SIRS及MOF的发生目前尚不清楚。为此本项目拟分别在细胞和转基因动物中研究TLRs信号通路对SAP的肠屏障功能的影响，以及SIGIRR对TLRs信号的负性调控作用是否可保护SAP的肠屏障功能，以期为SAP的诊治提供新途径。

重症急性胰腺炎(SAP)是一种严重的炎症性疾病，肠屏障功能障碍继发细菌易位所诱导的TLRs信号通路过度激活在其中起重要作用。研究表明SIGIRR参与了TLRs信号通路的调控，然而在SAP中SIGIRR可否通过负性调控TLRs信号改善肠屏障功能减轻SAP目前尚不清楚。为此，本项目进行了以下研究：TLRs信号对SAP肠屏障功能的影响；SIGIRR在SAP肠上皮屏障表达的变化；SIGIRR 对重症急性胰腺炎和肠屏障功能的影响及机制。结果表明：①LPS和SAP患者腹水刺激后肠上皮细胞屏障功能被破坏；②肠上皮细胞出现TLRS通路的过度激活和SIGIRR表达减少；③过表达肠道SIGIRR可改善SAP小鼠的肠屏障功能，进而减轻胰腺的炎症程度，敲减SIGIRR使小鼠的肠屏障功能和胰腺炎症明显加重。以上结果提示：SIGIRR参与了急性胰腺炎发病，其机制可能与SIGIRR负性调控TLRs信号加重肠屏障功能有关，这为以SIGIRR为靶点治疗SAP提供了实验和理论依据。