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Letter
Nature Medicine 14, 437 - 441 (2008)
Published online: 16 March 2008 | doi:10.1038/nm1733
Interferon-
is a therapeutic target molecule for prevention of postoperative adhesion formation
Hisashi Kosaka1,5, Tomohiro Yoshimoto2,3,5, Takayuki Yoshimoto4, Jiro Fujimoto1 & Kenji Nakanishi2,3
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 wall1, 2, 3. 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 cytokines4, chemokines, cell adhesion molecules and neuropeptide substance P, have been reported to participate in adhesion formation4, 5, 6, 7. 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-
(IFN-) 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- production is indispensable for adhesion formation. This response does not depend on STAT4, STAT6, interleukin-12 (IL-12), IL-18, tumor necrosis factor-
, 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- has a crucial role in the differential regulation of PAI-1 and tPA. Additionally, hepatocyte growth factor, a potent mitogenic factor for hepatocytes8, 9, strongly inhibited intestinal adhesion by diminishing IFN- production, providing a potential new way to prevent postoperative adhesions.
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