An-Najah Staff

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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; Serpine1 ) 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 Plat2/2 and Serpine12/2 . 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 Serpine12/2 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

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