Honjo Kumpei, Munakata Shinya, Tashiro Yoshihiko, Salama Yousef, Shimazu Hiroshi, Eiamboonsert Salita, Dhahri Douaa, Ichimura Atsuhiko, Dan Takashi, Miyata Toshio, Takeda Kazuyoshi, Sakamoto Kazuhiro, Hattori Koichi, Heissig Beate
Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University, Tokyo, Japan.
FASEB J. 2017 Jun;31(6):2625-2637. doi: 10.1096/fj.201600871RR. Epub 2017 Mar 7.
Adhesive small bowel obstruction remains a common problem for surgeons. After surgery, platelet aggregation contributes to coagulation cascade and fibrin clot formation. With clotting, fibrin degradation is simultaneously enhanced, driven by tissue plasminogen activator-mediated cleavage of plasminogen to form plasmin. The aim of this study was to investigate the cellular events and proteolytic responses that surround plasminogen activator inhibitor (PAI-1; ) inhibition of postoperative adhesion. Peritoneal adhesion was induced by gauze deposition in the abdominal cavity in C57BL/6 mice and those that were deficient in fibrinolytic factors, such as and In addition, C57BL/6 mice were treated with the novel PAI-1 inhibitor, TM5275. Some animals were treated with clodronate to deplete macrophages. Epidermal growth factor (EGF) experiments were performed to understand the role of macrophages and how EGF contributes to adhesion. In the early phase of adhesive small bowel obstruction, increased PAI-1 activity was observed in the peritoneal cavity. Genetic and pharmacologic PAI-1 inhibition prevented progression of adhesion and increased circulating plasmin. Whereas Serpine1 mice showed intra-abdominal bleeding, mice that were treated with TM5275 did not. Mechanistically, PAI-1, in combination with tissue plasminogen activator, served as a chemoattractant for macrophages that, in turn, secreted EGF and up-regulated the receptor, HER1, on peritoneal mesothelial cells, which led to PAI-1 secretion, further fueling the vicious cycle of impaired fibrinolysis at the adhesive site. Controlled inhibition of PAI-1 not only enhanced activation of the fibrinolytic system, but also prevented recruitment of EGF-secreting macrophages. Pharmacologic PAI-1 inhibition ameliorated adhesion formation in a macrophage-dependent manner.-Honjo, K., Munakata, S., Tashiro, Y., Salama, Y., Shimazu, H., Eiamboonsert, S., Dhahri, D., Ichimura, A., Dan, T., Miyata, T., Takeda, K., Sakamoto, K., Hattori, K., Heissig, B. Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice.
粘连性小肠梗阻仍是外科医生面临的常见问题。手术后，血小板聚集促进凝血级联反应和纤维蛋白凝块形成。随着凝血过程，组织纤溶酶原激活物介导纤溶酶原裂解形成纤溶酶，同时增强纤维蛋白降解。本研究的目的是调查纤溶酶原激活物抑制剂（PAI-1）抑制术后粘连周围的细胞事件和蛋白水解反应。通过在C57BL/6小鼠腹腔内放置纱布诱导腹膜粘连，以及在缺乏纤溶因子（如 和 ）的小鼠中诱导粘连。此外，用新型PAI-1抑制剂TM5275处理C57BL/6小鼠。一些动物用氯膦酸盐处理以耗尽巨噬细胞。进行表皮生长因子（EGF）实验以了解巨噬细胞的作用以及EGF如何促进粘连。在粘连性小肠梗阻的早期阶段，观察到腹腔内PAI-1活性增加。基因和药物抑制PAI-1可阻止粘连进展并增加循环纤溶酶。Serpine1基因敲除小鼠出现腹腔内出血，而用TM5275处理的小鼠则未出现。从机制上讲，PAI-1与组织纤溶酶原激活物结合，作为巨噬细胞的趋化因子，巨噬细胞进而分泌EGF并上调腹膜间皮细胞上的受体HER1，导致PAI-1分泌，进一步加剧粘连部位纤维蛋白溶解受损的恶性循环。对PAI-1的可控抑制不仅增强了纤溶系统的激活，还阻止了分泌EGF的巨噬细胞的募集。药物抑制PAI-1以巨噬细胞依赖的方式改善粘连形成。-本庄健、宗方聪、田代洋、萨拉马·亚、岛津浩、埃亚姆布恩瑟特·斯、达赫里·达、市村明、丹田、宫田哲、武田康、坂本健、服部克、海西格·B。纤溶酶原激活物抑制剂-1通过增强小鼠中的EGF-HER1信号传导调节巨噬细胞依赖性术后粘连 。
