Merza Mohammed, Rahman Milladur, Zhang Songen, Hwaiz Rundk, Regner Sara, Schmidtchen Artur, Thorlacius Henrik
Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, Sweden;
Department of Clinical Sciences, Section of Dermatology and Venereology, Lund, Lund University, Sweden; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
Am J Physiol Gastrointest Liver Physiol. 2014 Nov 1;307(9):G914-21. doi: 10.1152/ajpgi.00237.2014. Epub 2014 Sep 11.
Severe acute pancreatitis (AP) is characterized by leukocyte infiltration and tissue injury. Herein, we wanted to examine the potential effects of thrombin-derived host defense peptides (TDPs) in severe AP. Pancreatitis was provoked by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of l-arginine in C57BL/6 mice. Animals were treated with the TDPs GKY20 and GKY25 or a control peptide WFF25 30 min before induction of AP. TDPs reduced blood amylase levels, neutrophil infiltration, hemorrhage, necrosis, and edema formation in the inflamed pancreas. Treatment with TDPs markedly attenuated the taurocholate-induced increase in plasma levels of CXCL2 and interleukin-6. Moreover, administration of TDPs decreased histone 3, histone 4, and myeloperoxidase levels in the pancreas in response to taurocholate challenge. Interestingly, administration of TDPs abolished neutrophil expression of Mac-1 in mice with pancreatitis. In addition, TDPs inhibited CXCL2-induced chemotaxis of isolated neutrophils in vitro. Fluorescent-labeled TDP was found to directly bind to isolated neutrophils. Finally, a beneficial effect of TDPs was confirmed in l-arginine-induced pancreatitis. Our novel results demonstrate that TDPs exert protective effects against pathological inflammation and tissue damage in AP. These findings suggest that TDPs might be useful in the management of patients with severe AP.
重症急性胰腺炎（AP）的特征是白细胞浸润和组织损伤。在此，我们想要研究凝血酶衍生的宿主防御肽（TDPs）在重症AP中的潜在作用。通过向C57BL/6小鼠的胰管内注入牛磺胆酸盐或腹腔注射L-精氨酸来诱发胰腺炎。在诱导AP前30分钟，用TDPs GKY20和GKY25或对照肽WFF25对动物进行治疗。TDPs降低了炎症胰腺中的血淀粉酶水平、中性粒细胞浸润、出血、坏死和水肿形成。TDPs治疗显著减轻了牛磺胆酸盐诱导的血浆CXCL2和白细胞介素-6水平的升高。此外，给予TDPs可降低牛磺胆酸盐刺激后胰腺中组蛋白3、组蛋白4和髓过氧化物酶的水平。有趣的是，给予TDPs可消除胰腺炎小鼠中性粒细胞上Mac-1的表达。此外，TDPs在体外抑制CXCL2诱导的分离中性粒细胞的趋化作用。发现荧光标记的TDP可直接与分离的中性粒细胞结合。最后，在L-精氨酸诱导的胰腺炎中证实了TDPs的有益作用。我们的新结果表明，TDPs对AP中的病理性炎症和组织损伤具有保护作用。这些发现提示TDPs可能对重症AP患者的治疗有用。
