title: Effects of macrophage-dependent peroxisome proliferator-activated receptor γ signalling on adhesion formation after abdominal surgery in an experimental model.
abstract: BACKGROUND
  The pathophysiology of adhesion formation after abdominal and pelvic surgery is still largely unknown. The aim of the study was to investigate the role of macrophage polarization and the effect of peroxisome proliferator-activated receptor (PPAR) γ stimulation on adhesion formation in an animal model.
  
  
  METHODS
  Peritoneal adhesion formation was induced by the creation of ischaemic buttons within the peritoneal wall and the formation of a colonic anastomosis in wild-type, interleukin (IL) 10-deficient (IL-10(-/-) ), IL-4-deficient (IL-4(-/-) ) and CD11b-Cre/PPARγ(fl) (/fl) mice. Adhesions were assessed at regular intervals, and cell preparations were isolated from ischaemic buttons and normal peritoneum. These samples were analysed for macrophage differentiation and its markers, and expression of cytokines by quantitative PCR, fluorescence microscopy, arginase activity and pathological examination. Some animals underwent pioglitazone (PPAR-γ agonist) or vehicle treatment to inhibit adhesion formation. Anastomotic healing was evaluated by bursting pressure measurement and collagen gene expression.
  
  
  RESULTS
  Macrophage M2 marker expression and arginase activity were raised in buttons without adhesions compared with buttons with adhesions. IL-4(-/-) and IL-10(-/-) mice were not affected, whereas CD11b-Cre/PPARγ(fl) (/fl) mice showed decreased arginase activity and increased adhesion formation. Perioperative pioglitazone treatment increased arginase activity and decreased adhesion formation in wild-type but not CD11b-Cre/PPARγ(fl) (/fl) mice. Pioglitazone had no effect on anastomotic healing.
  
  
  CONCLUSIONS
  Endogenous macrophage-specific PPAR-γ signalling affected arginase activity and macrophage polarization, and counter-regulated peritoneal adhesion manifestation. Pharmacological PPAR-γ agonism induced a shift towards macrophage M2 polarization and ameliorated adhesion formation in a macrophage-dependent manner. Surgical relevance Postoperative adhesion formation is frequently seen after abdominal surgery and occurs in response to peritoneal trauma. The pathogenesis is still unknown but includes an imbalance in fibrinolysis, collagen production and inflammatory mechanisms. Little is known about the role of macrophages during adhesion formation. In an experimental model, macrophage M2 marker expression was associated with reduced peritoneal adhesion formation and involved PPAR-γ-mediated arginase activity. Macrophage-specific PPAR-γ deficiency resulted in reduced arginase activity and aggravated adhesion formation. Pioglitazone, a PPAR-γ agonist, induced M2 polarization and reduced postoperative adhesion formation without compromising anastomotic healing in mice. Pioglitazone ameliorated postoperative adhesion formation without compromising intestinal wound healing. Therefore, perioperative PPAR-γ agonism might be a promising strategy for prevention of adhesion formation after abdominal surgery.
authors: Department of Surgery, University Hospital of Bonn, Bonn, Germany.
authors: G-S
authors: GS
authors: Hong
authors: Department of Surgery, University Hospital of Bonn, Bonn, Germany.
authors: T
authors: T
authors: Schwandt
authors: Department of Surgery, University Hospital of Bonn, Bonn, Germany.
authors: K
authors: K
authors: Stein
authors: Department of Surgery, University Hospital of Bonn, Bonn, Germany.
authors: B
authors: B
authors: Schneiker
authors: Clinical Neurosciences Unit, University Hospital of Bonn, Bonn, Germany.
authors: M P
authors: MP
authors: Kummer
authors: Clinical Neurosciences Unit, University Hospital of Bonn, Bonn, Germany.
authors: M T
authors: MT
authors: Heneka
authors: Department of Surgery, University Hospital of Bonn, Bonn, Germany.|Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: K
authors: K
authors: Kitamura
authors: Department of Surgery, University Hospital of Bonn, Bonn, Germany.
authors: J C
authors: JC
authors: Kalff
authors: Department of Surgery, University Hospital of Bonn, Bonn, Germany.|Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, Amsterdam, The Netherlands.
authors: S
authors: S
authors: Wehner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007813:Laparotomy / Q000009:adverse effects; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D047495:PPAR gamma / Q000096:biosynthesis / Q000235:genetics*; D010532:Peritoneal Diseases / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics*; D015398:Signal Transduction; D000267:Tissue Adhesions / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D047495:PPAR gamma; D012313:RNA