title: Inhibition of spleen tyrosine kinase as treatment of postoperative ileus.
abstract: OBJECTIVE
  Intestinal inflammation resulting from manipulation-induced mast cell activation is a crucial mechanism in the pathophysiology of postoperative ileus (POI). Recently it has been shown that spleen tyrosine kinase (Syk) is involved in mast cell degranulation. Therefore, we have evaluated the effect of the Syk-inhibitor GSK compound 143 (GSK143) as potential treatment to shorten POI.
  
  
  METHODS
  In vivo: in a mouse model of POI, the effect of the Syk inhibitor (GSK143) was evaluated on gastrointestinal transit, muscular inflammation and cytokine production. In vitro: the effect of GSK143 and doxantrazole were evaluated on cultured peritoneal mast cells (PMCs) and bone marrow derived macrophages.
  
  
  RESULTS
  In vivo: intestinal manipulation resulted in a delay in gastrointestinal transit at t=24 h (Geometric Center (GC): 4.4 ± 0.3). Doxantrazole and GSK143 significantly increased gastrointestinal transit (GC doxantrazole (10 mg/kg): 7.2 ± 0.7; GSK143 (1 mg/kg): 7.6 ± 0.6), reduced inflammation and prevented recruitment of immune cells in the intestinal muscularis. In vitro: in PMCs, substance P (0-90 μM) and trinitrophenyl (0-4 μg/ml) induced a concentration-dependent release of β-hexosaminidase. Pretreatment with doxantrazole and GSK143 (0.03-10 μM) concentration dependently blocked substance P and trinitrophenyl induced β-hexosaminidase release. In addition, GSK143 was able to reduce cytokine expression in endotoxin-treated bone marrow derived macrophages in a concentration-dependent manner.
  
  
  CONCLUSIONS
  The Syk inhibitor GSK143 reduces macrophage activation and mast cell degranulation in vitro. In addition, it inhibits manipulation-induced intestinal muscular inflammation and restores intestinal transit in mice. These findings suggest that Syk inhibition may be a new tool to shorten POI.
authors.affiliation: Department of Gastroenterology and Hepatology, Tytgat Institute of Liver and Intestinal Research, Academic Medical Center, , Amsterdam, The Netherlands.
authors.forename: Sjoerd H W
authors.initials: SH
authors.lastname: van Bree
authors.forename: Pedro Julian
authors.initials: PJ
authors.lastname: Gomez-Pinilla
authors.forename: Fleur Suzanne
authors.initials: FS
authors.lastname: van de Bovenkamp
authors.forename: Martina
authors.initials: M
authors.lastname: Di Giovangiulio
authors.forename: Giovanna
authors.initials: G
authors.lastname: Farro
authors.forename: Andrea
authors.initials: A
authors.lastname: Nemethova
authors.forename: Cathy
authors.initials: C
authors.lastname: Cailotto
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: de Jonge
authors.forename: Kevin
authors.initials: K
authors.lastname: Lee
authors.forename: Cesar
authors.initials: C
authors.lastname: Ramirez-Molina
authors.forename: Dave
authors.initials: D
authors.lastname: Lugo
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Skynner
authors.forename: Guy E E
authors.initials: GE
authors.lastname: Boeckxstaens
authors.forename: Gianluca
authors.initials: G
authors.lastname: Matteoli
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005772:Gastrointestinal Transit / Q000187:drug effects; D045823:Ileus / Q000503:physiopathology / Q000517:prevention & control*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008262:Macrophage Activation / Q000187:drug effects; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D011183:Postoperative Complications / Q000503:physiopathology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000072377:Syk Kinase; D013892:Thioxanthenes / Q000627:therapeutic use; D044004:Xanthones / Q000627:therapeutic use
chemical_list: D000814:Aniline Compounds; D016207:Cytokines; C585067:GSK143; D047908:Intracellular Signaling Peptides and Proteins; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013892:Thioxanthenes; D044004:Xanthones; C038600:trinitrophenyl-ovalbumin; D013373:Substance P; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C010134:doxantrazole