Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis
Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis
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DOI：
10.1189/jlb.0411195
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发表时间：
2011-11-01
影响因子：
5.5
通讯作者：
Regner, Sara
中科院分区：
文献类型：
--
作者：
Abdulla, Aree;Awla, Darbaz;Regner, Sara
胰腺炎中炎症与蛋白水解激活之间的关系是胰腺病学中尚未解决的问题。本研究的目的是确定中性粒细胞对重症AP胰蛋白酶原激活的影响。通过向C57 BL/6小鼠的胰管中输注牛磺胆酸盐来诱导胰腺炎。对于中性粒细胞耗竭，在胰腺炎诱导前给予抗Gr-1抗体。施用抗Gr-1抗体使循环中性粒细胞减少97%。胰腺TAP和血清淀粉酶水平在诱导胰腺炎后2 h和24 h升高。在胰腺炎诱导后24小时，但在2小时，中性粒细胞耗竭降低胰腺TAP和血清淀粉酶水平。胰腺MPO和中性粒细胞浸润，以及MIP-2水平，增加牛磺胆酸盐输注后24小时。牛磺胆酸盐给药后2小时，未观察到显著的中性粒细胞胰腺浸润。注射抗Gr-1抗体后，24 h胰腺中MPO活性、中性粒细胞聚集和MIP-2水平以及腺泡细胞坏死、出血和水肿消失。此外，牛磺胆酸引起的肺组织损伤和MPO活性通过中性粒细胞耗竭而正常化。活体荧光显微镜检查显示，在施用抗Gr-1抗体后，胰腺微循环中的白细胞减少了97%。我们的数据表明，最初的胰蛋白酶原激活是独立的中性粒细胞，而后来的激活是依赖于中性粒细胞在胰腺。中性粒细胞在介导严重AP的胰腺和肺组织损伤中至关重要。J. Leukoc. 90：975-982; 2011.
The relationship between inflammation and proteolytic activation in pancreatitis is an unresolved issue in pancreatology. The purpose of this study was to define the influence of neutrophils on trypsinogen activation in severe AP. Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. For neutrophil depletion, an anti-Gr-1 antibody was administered before pancreatitis induction. Administration of the anti-Gr-1 antibody reduced circulating neutrophils by 97%. Pancreatic TAP and serum amylase levels increased 2 h and 24 h after induction of pancreatitis. Neutrophil depletion reduced pancreatic TAP and serum amylase levels at 24 h but not at 2 h after pancreatitis induction. Pancreatic MPO and infiltration of neutrophils, as well as MIP-2 levels, were increased 24 h after taurocholate infusion. Two hours after taurocholate administration, no significant pancreatic infiltration of neutrophils was observed. Injection of the anti-Gr-1 antibody abolished MPO activity, neutrophil accumulation, and MIP-2 levels, as well as acinar cell necrosis, hemorrhage, and edema in the pancreas at 24 h. Moreover, taurocholate-provoked tissue damage and MPO activity in the lung were normalized by neutrophil depletion. Intravital fluorescence microscopy revealed a 97% reduction of leukocytes in the pancreatic microcirculation after administration of the anti-Gr-1 antibody. Our data demonstrate that initial trypsinogen activation is independent of neutrophils, whereas later activation is dependent on neutrophils in the pancreas. Neutrophils are critical in mediating pancreatic and lung tissue damage in severe AP. J. Leukoc. Biol. 90: 975-982; 2011.