title: Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice.
abstract: 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 asPlat-/-andSerpine1-/-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.
authors.affiliation: 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.
authors.forename: Kumpei
authors.initials: K
authors.lastname: Honjo
authors.affiliation: 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.
authors.forename: Shinya
authors.initials: S
authors.lastname: Munakata
authors.affiliation: 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.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tashiro
authors.affiliation: Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Salama
authors.affiliation: Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimazu
authors.affiliation: Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Salita
authors.initials: S
authors.lastname: Eiamboonsert
authors.affiliation: Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Douaa
authors.initials: D
authors.lastname: Dhahri
authors.affiliation: United Centers for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Ichimura
authors.affiliation: United Centers for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Dan
authors.affiliation: United Centers for Advanced Research and Translational Medicine, Graduate School of Medicine, Tohoku University, Sendai, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Department of Immunology and Atopy Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.|Center for Genomic and Regenerative Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hattori
authors.affiliation: Division of Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; heissig@ims.u-tokyo.ac.jp.|Department of Immunology and Atopy Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Beate
authors.initials: B
authors.lastname: Heissig
mesh_terms: D000818:Animals; D039481:CD11b Antigen; D054443:Cell Migration Assays; D002465:Cell Movement / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology; D004815:Epidermal Growth Factor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000627:therapeutic use*; D011183:Postoperative Complications / Q000517:prevention & control; D000067996:RAW 264.7 Cells; D058258:Serpin E2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000267:Tissue Adhesions / Q000378:metabolism / Q000473:pathology*; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D062366:para-Aminobenzoates / Q000627:therapeutic use*
chemical_list: C549556:5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate; D039481:CD11b Antigen; D010879:Piperazines; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D062366:para-Aminobenzoates; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D010959:Tissue Plasminogen Activator; D000068818:Cetuximab
keywords: PAI-1; epidermal growth factor; mesothelial cell; plasminogen activator; small bowel obstruction