title: Interferon-gamma is a therapeutic target molecule for prevention of postoperative adhesion formation.
abstract: Intestinal adhesions are bands of fibrous tissue that connect the loops of the intestine to each other, to other abdominal organs or to the abdominal wall. Fibrous tissue formation is regulated by the balance between plasminogen activator inhibitor type 1 (PAI-1) and tissue-type plasminogen activator (tPA), which reciprocally regulate fibrin deposition. Several components of the inflammatory system, including cytokines, chemokines, cell adhesion molecules and neuropeptide substance P, have been reported to participate in adhesion formation. We have used cecal cauterization to develop a unique experimental mouse model of intestinal adhesion. Mice developed severe intestinal adhesion after this treatment. Adhesion development depended upon the interferon-gamma (IFN-gamma) and signal transducer and activator of transcription-1 (STAT1) system. Natural killer T (NKT) cell-deficient mice developed adhesion poorly, whereas they developed severe adhesion after reconstitution with NKT cells from wild-type mice, suggesting that NKT cell IFN-gamma production is indispensable for adhesion formation. This response does not depend on STAT4, STAT6, interleukin-12 (IL-12), IL-18, tumor necrosis factor-alpha, Toll-like receptor 4 or myeloid differentiation factor-88-mediated signals. Wild-type mice increased the ratio of PAI-1 to tPA after cecal cauterization, whereas Ifng(-/-) or Stat1(-/-) mice did not, suggesting that IFN-gamma has a crucial role in the differential regulation of PAI-1 and tPA. Additionally, hepatocyte growth factor, a potent mitogenic factor for hepatocytes, strongly inhibited intestinal adhesion by diminishing IFN-gamma production, providing a potential new way to prevent postoperative adhesions.
authors.affiliation: Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Kosaka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Jiro
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Kenji
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011183:Postoperative Complications / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D058258:Serpin E2; D015843:Serpins / Q000502:physiology; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D000267:Tissue Adhesions / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D010959:Tissue Plasminogen Activator / Q000502:physiology
chemical_list: D050794:STAT1 Transcription Factor; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; C494080:Stat1 protein, mouse; D017228:Hepatocyte Growth Factor; D007371:Interferon-gamma; D010959:Tissue Plasminogen Activator