Role of Substance P–Dependent Chemotactic Signaling in Postoperative Adhesion Formation

Academic Article

Abstract

  • Background: Postoperative adhesions are a potentially life-threatening complication of abdominal surgery. We previously showed that substance P (SP), acting through the neurokinin-1 receptor (NK-1R), is an important early mediator of adhesiogenesis through its regulation of the tissue plasminogen activator/plasminogen activator inhibitor-1 (PAI-1) fibrinolytic system. SP also mediates neurogenic inflammation by recruiting inflammatory leukocytes, such as neutrophils and macrophages. Our objective was to determine the role of SP-dependent chemotactic recruitment of these inflammatory cells through the CXCR2 in postsurgical adhesion formation. Materials and methods: A mouse cecal cauterization model was used to generate intra-abdominal adhesions. Protein and mRNA levels of the chemokines CXCL1 and CXCL2 and their receptor CXCR2 were measured at 3 h and 6 h after surgery in peritoneal tissue and in peritoneal lavages in response to antagonists for the SP receptor and CXCR2, and in IFN-γ knockout mice. Results: Postsurgical adhesion formation was inhibited by both an antagonist to NK-1R and an antagonist to CXCR2. Expression levels of neutrophil chemokines and CXCR2 in peritoneal tissue peaked 3-6 h after surgery and partially depended on SP and IFN-γ, one of its downstream mediators. An NK-1R antagonist inhibited SP-mediated increases in the expression of the PAI-1 inhibitory component of the fibrinolytic system, but the CXCR2 antagonist had no effect. Conclusions: Postsurgical adhesiogenesis involves upregulation of chemokine signaling that is partially SP- and IFN-γ–dependent. However, the adhesiogenic properties of chemokine signaling are not mediated through the inhibition of fibrinolysis with PAI-1, as was previously shown for SP.
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    Author List

  • Kosaka H; Kaibori M; Chu DI; Stucchi AF; Sekimoto M
  • Start Page

  • 49
  • End Page

  • 57
  • Volume

  • 270