title: Mast cells play no role in the pathogenesis of postoperative ileus induced by intestinal manipulation.
abstract: BACKGROUND
  Intestinal manipulation (IM) during abdominal surgery results in intestinal inflammation leading to hypomotility or ileus. Mast cell activation is thought to play a crucial role in the pathophysiology of postoperative ileus (POI). However, this conclusion was mainly drawn using mast cell-deficient mouse models with abnormal Kit signaling. These mice also lack interstitial cells of Cajal (ICC) resulting in aberrant gastrointestinal motility even prior to surgery, compromising their use as model to study POI. To avoid these experimental weaknesses we took advantage of a newly developed knock-in mouse model, Cpa3(Cre/+) , devoid of mast cells but with intact Kit signaling.
  
  
  METHODS
  The role of mast cells in the development of POI and intestinal inflammation was evaluated assessing gastrointestinal transit and muscularis externa inflammation after IM in two strains of mice lacking mast cells, i.e. Kit(W-sh/W-sh) and Cpa3(Cre/+) mice, and by use of the mast cell stabilizer cromolyn.
  
  
  RESULTS
  Kit(W-sh/W-sh) mice lack ICC networks and already revealed significantly delayed gastrointestinal transit even before surgery. IM did not further delay intestinal transit, but induced infiltration of myeloperoxidase positive cells, expression of inflammatory cytokines and recruitment of monocytes and neutrophils into the muscularis externa. On the contrary, Cpa3(Cre/+) mice have a normal network of ICC and normal gastrointestinal. Surprisingly, IM in Cpa3(Cre/+) mice caused delay in gut motility and intestinal inflammation as in wild type littermates mice (Cpa3(+/+) ). Furthermore, treatment with the mast cell inhibitor cromolyn resulted in an inhibition of mast cells without preventing POI.
  
  
  CONCLUSIONS
  Here, we confirm that IM induced mast cell degranulation. However, our data demonstrate that mast cells are not required for the pathogenesis of POI in mice. Although there might be species differences between mouse and human, our results argue against mast cell inhibitors as a therapeutic approach to shorten POI.
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Gomez-Pinilla
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Farro
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
authors.forename: Martina
authors.initials: M
authors.lastname: Di Giovangiulio
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Stakenborg
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
authors.forename: Andrea
authors.initials: A
authors.lastname: Némethova
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
authors.forename: Annick
authors.initials: A
authors.lastname: de Vries
authors.affiliation: Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium ; Autoimmune Genetics Laboratory, Vlaams Instituut voor Biotechnologie (VIB), Leuven, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.affiliation: Division for Cellular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Thorsten B
authors.initials: TB
authors.lastname: Feyerabend
authors.forename: Hans-Reimer
authors.initials: HR
authors.lastname: Rodewald
authors.affiliation: Division for Cellular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hans-Reimwer
authors.initials: HR
authors.lastname: Rodewald
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Boeckxstaens
authors.affiliation: Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Matteoli
mesh_terms: D000818:Animals; D043422:Carboxypeptidases A / Q000235:genetics / Q000378:metabolism; D015550:Cell Degranulation; D002465:Cell Movement; D004205:Cromolyn Sodium / Q000494:pharmacology; D013505:Digestive System Surgical Procedures / Q000009:adverse effects*; D004195:Disease Models, Animal; D005772:Gastrointestinal Transit; D015870:Gene Expression; D006801:Humans; D045823:Ileus / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D056885:Interstitial Cells of Cajal / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011183:Postoperative Complications / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D043422:Carboxypeptidases A; C503326:Cpa3 protein, mouse; D004205:Cromolyn Sodium