Xu Qiushi, Wang Mengfei, Guo Haoya, Liu Huanhuan, Zhang Guixin, Xu Caiming, Chen Hailong
Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China.
Front Pharmacol. 2021 Apr 23;12:655372. doi: 10.3389/fphar.2021.655372. eCollection 2021.
Severe acute pancreatitis (SAP) can lead to acute lung injury (ALI). This study investigated the therapeutic effect of emodin and its molecular mechanisms in a rat model of SAP-ALI. Forty male Sprague-Dawley rats were randomly divided into the groups: Control (CON), SAP (SAP), emodin (EMO), and C23 (C23). The latter three groups of rats were induced for SAP-ALI by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and were treated with vehicle, emodin or C23, respectively. One day post induction, their pancreatic and lung injury was assessed by histology and arterial blood gas analysis. , rat alveolar macrophages (NR8383 cells) were treated with recombinant rat CIRP in the presence or absence of TAK242 (a TLR4 inhibitor), C23 or emodin. The CIRP-mediated activation of the NLRP3/IL-1/CXCL1 signaling in rat lungs and NR8383 cells was determined. Similarly, the role of IL-1 in the CIRP-induced CXCL1 expression was investigated. Emodin treatment significantly reduced inflammation and tissue damages in the pancreatic and lung tissues in rats with SAP-ALI, accompanied by decreasing serum amylase, CIRP and IL-1β levels and improving lung function. Furthermore, emodin significantly mitigated the SAP-up-regulated CIRP expression in the pancreatic islets and lung tissues, and attenuated the SAP-activated NF-κB signaling, NLRP3 inflammasome formation and CXCL1 expression in lung resident macrophages as well as neutrophil infiltration in the lungs of rats. In addition, treatment with CIRP significantly activated the NF-κB signaling and NLRP3 inflammasome formation and induced IL-1β and CXCL1 expression and pyroptosis in NR8383 cells, which were abrogated by TAK242 and significantly mitigated by C23 or emodin. Moreover, CIRP only induced very lower levels of CXCL1 expression in IL-1β-silencing NR8383 cells and treatment with IL-1β induced CXCL1 expression in NR8383 cells in a dose and time-dependent manner. Emodin may inhibit the CIRP-activated NLRP3/IL-1β/CXCL1signaling to decrease neutrophil infiltration and ameliorate the SAP-ALI in rats.
重症急性胰腺炎（SAP）可导致急性肺损伤（ALI）。本研究在SAP-ALI大鼠模型中研究了大黄素的治疗作用及其分子机制。40只雄性Sprague-Dawley大鼠随机分为对照组（CON）、SAP组（SAP）、大黄素组（EMO）和C23组（C23）。后三组大鼠通过向胆胰管逆行注射5%牛磺胆酸钠诱导建立SAP-ALI模型，并分别用溶剂、大黄素或C23进行治疗。诱导后1天，通过组织学和动脉血气分析评估其胰腺和肺损伤情况。此外，大鼠肺泡巨噬细胞（NR8383细胞）在有或无TAK242（一种TLR4抑制剂）、C23或大黄素存在的情况下用重组大鼠CIRP进行处理。测定CIRP介导的大鼠肺和NR8383细胞中NLRP3/IL-1/CXCL1信号通路的激活情况。同样，研究了IL-1在CIRP诱导的CXCL1表达中的作用。大黄素治疗显著减轻了SAP-ALI大鼠胰腺和肺组织的炎症和组织损伤，同时血清淀粉酶、CIRP和IL-1β水平降低，肺功能改善。此外，大黄素显著减轻了SAP上调的胰腺胰岛和肺组织中CIRP的表达，并减弱了SAP激活的NF-κB信号通路、肺驻留巨噬细胞中NLRP3炎性小体的形成以及CXCL1的表达，以及大鼠肺中的中性粒细胞浸润。此外，用CIRP处理显著激活了NR8383细胞中的NF-κB信号通路和NLRP3炎性小体的形成，并诱导了IL-1β和CXCL1的表达以及细胞焦亡，这些作用被TAK242消除，并被C23或大黄素显著减轻。此外，CIRP仅在IL-1β沉默的NR8383细胞中诱导非常低水平的CXCL1表达，并且用IL-1β处理以剂量和时间依赖性方式诱导NR8383细胞中CXCL1的表达。大黄素可能通过抑制CIRP激活的NLRP3/IL-1β/CXCL1信号通路来减少中性粒细胞浸润并改善大鼠的SAP-ALI。
