Wu Zengkai, Mulatibieke Tunike, Niu Mengya, Li Bin, Dai Juanjuan, Ye Xin, He Yan, Chen Congying, Wen Li, Hu Guoyong
Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Pancreatic Disease, Institute of Pancreatic Disease, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Gastroenterol Res Pract. 2020 Apr 28;2020:8903610. doi: 10.1155/2020/8903610. eCollection 2020.
AP was induced in Balb/C mice by ten hourly intraperitoneal injections of caerulein (100 g/kg) and LPS (5 mg/kg). The MMP inhibitor, BB-94 (20 mg/kg) was intraperitoneally administered 30 min before AP induction. Pancreatitis was confirmed by histology and serum amylase and lipase. Expression of pancreatic proinflammatory mediators and NF-B activation were assessed. Bone marrow-derived neutrophils (BMDNs) and macrophages (BMDMs) were isolated. BMDNs were activated by phorbol 12-myristate 13-acetate (PMA, 50 ng/ml) and neutrophil reactive oxygen species (ROS) production was recorded. BMDMs were stimulated with 10 ng/ml IFN- and 100 ng/ml LPS to induce M1 macrophage polarization.
Pancreatic MMP-9 was markedly upregulated and serum MMP-9 was increased in caerulein-induced pancreatitis. Inhibition of MMP with BB-94 ameliorated pancreatic tissue damage and decreased the expression of proinflammatory cytokines (TNF and IL-6) or chemokines (CCL2 and CXCL2) and NF-B activation. Furthermore, using isolated BMDNs and BMDMs, we found that inhibition of MMP with BB-94 markedly decreased neutrophil ROS production, inhibited inflammatory macrophage polarization and NF-B activation.
Our results showed that inhibition of MMP with BB-94 protected against pancreatic inflammatory responses in caerulein-induced pancreatitis via modulating neutrophil and macrophage activation.
通过每小时一次腹腔注射蛙皮素（100 μg/kg）和脂多糖（LPS，5 mg/kg），连续注射10次，诱导Balb/C小鼠发生急性胰腺炎（AP）。在诱导AP前30分钟腹腔注射MMP抑制剂BB-94（20 mg/kg）。通过组织学检查以及血清淀粉酶和脂肪酶来确诊胰腺炎。评估胰腺促炎介质的表达和NF-κB的激活情况。分离骨髓来源的中性粒细胞（BMDNs）和巨噬细胞（BMDMs）。用佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA，50 ng/ml）激活BMDNs，并记录中性粒细胞活性氧（ROS）的产生。用10 ng/ml干扰素-γ和100 ng/ml LPS刺激BMDMs以诱导M1巨噬细胞极化。
在蛙皮素诱导的胰腺炎中，胰腺MMP-9明显上调，血清MMP-9升高。用BB-94抑制MMP可改善胰腺组织损伤，并降低促炎细胞因子（TNF和IL-6）或趋化因子（CCL2和CXCL2）的表达以及NF-κB的激活。此外，使用分离的BMDNs和BMDMs，我们发现用BB-94抑制MMP可显著降低中性粒细胞ROS的产生，抑制炎症巨噬细胞极化和NF-κB的激活。
我们的结果表明，用BB-94抑制MMP可通过调节中性粒细胞和巨噬细胞的激活，预防蛙皮素诱导的胰腺炎中的胰腺炎症反应。
