P-selectin mediates neutrophil rolling and recruitment in acute pancreatitis
P-selectin mediates neutrophil rolling and recruitment in acute pancreatitis
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DOI：
10.1002/bjs.7775
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发表时间：
2012-02-01
影响因子：
9.6
通讯作者：
Regner, S.
中科院分区：
文献类型：
--
作者：
Hartman, H.;Abdulla, A.;Regner, S.
背景：调节胰腺白细胞-内皮细胞相互作用的粘附机制仍不清楚，但选择素可能发挥作用。本研究探讨了介导白细胞沿着胰腺内皮滚动的分子机制以及靶向滚动粘附相互作用在急性胰腺炎（AP）中的治疗潜力。通过向胰管逆行输注5%牛磺胆酸钠诱导胰腺炎，在C57 BL/6小鼠中重复腹膜内施用雨蛙肽（50 μ g/kg）或腹膜内施用L-精氨酸（4 μ g/kg）。在AP诱导前后给予对照和抗P-选择素单克隆抗体。血清和组织取样，以评估胰腺炎的严重程度，和活体显微镜被用来研究白细胞rolling.Results：牛磺胆酸输注到胰管胰蛋白酶原，胰蛋白酶原激活，胰腺中性粒细胞浸润，巨噬细胞炎性蛋白（MIP）2的形成和组织损伤的血清水平增加。P-选择素的免疫中和作用降低了牛磺胆酸盐诱导的血清胰蛋白酶原升高（中位数（范围）17.35（12.20-30.00）vs 1.55（0.60 -15.70）μ g/l; P = 0.017）、中性粒细胞蓄积（4.00（0.75-4.00）vs 0.60 - 15.70）μ g/l; 63（0-3.25）; P = 0.002）和组织损伤，但对MIP-2的产生没有影响（14.08（1.68-33.38）vs 3.70（0.55-51.80）pg/mg; P = 0.195）或血清胰蛋白酶原激活肽水平（1.10（0.60-1.60）vs.0.45（0-1.80）μ g/l; P = 0.069）。活体荧光显微镜显示，抗P-选择素抗体抑制白细胞滚动完全毛细血管后微静脉的炎症pancreas.Conclusion：抑制P-选择素保护胰腺组织损伤实验性胰腺炎。靶向P-选择素可能是减轻AP炎症的有效策略。
Background: The adhesive mechanisms regulating leucocyte-endothelium interactions in the pancreas remain elusive, but selectins may play a role. This study examined the molecular mechanisms mediating leucocyte rolling along the endothelium in the pancreas and the therapeutic potential of targeting the rolling adhesive interaction in acute pancreatitis (AP).Methods: Pancreatitis was induced by retrograde infusion of 5 per cent sodium taurocholate into the pancreatic duct, repeated intraperitoneal administration of caerulein (50 mu g/kg) or intraperitoneal administration of L-arginine (4 g/kg) in C57BL/6 mice. A control and a monoclonal antibody against P-selectin were administered before and after induction of AP. Serum and tissue were sampled to assess the severity of pancreatitis, and intravital microscopy was used to study leucocyte rolling.Results: Taurocholate infusion into the pancreatic duct increased the serum level of trypsinogen, trypsinogen activation, pancreatic neutrophil infiltration, macrophage inflammatory protein (MIP) 2 formation and tissue damage. Immunoneutralization of P-selectin decreased the taurocholate-induced increase in serum trypsinogen (median (range) 17.35 (12.20-30.00) versus 1.55 (0 .60-15.70) mu g/l; P = 0.017), neutrophil accumulation (4.00 (0.75-4.00) versus 0 . 63 (0-3.25); P = 0.002) and tissue damage, but had no effect on MIP-2 production (14.08 (1.68-33.38) versus 3.70 (0.55-51.80) pg/mg; P = 0.195) or serum trypsinogen activating peptide level (1.10 (0.60-1.60) versus 0.45 (0-1.80) mu g/l; P = 0.069). Intravital fluorescence microscopy revealed that anti-P-selectin antibody inhibited leucocyte rolling completely in postcapillary venules of the inflamed pancreas.Conclusion: Inhibition of P-selectin protected against pancreatic tissue injury in experimental pancreatitis. Targeting P-selectin may be an effective strategy to ameliorate inflammation in AP.