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Inhibition of spleen tyrosine kinase as treatment of postoperative ileus
  1. Sjoerd H W van Bree1,
  2. Pedro Julian Gomez-Pinilla2,
  3. Fleur Suzanne van de Bovenkamp1,
  4. Martina Di Giovangiulio2,
  5. Giovanna Farro2,
  6. Andrea Nemethova2,
  7. Cathy Cailotto1,
  8. Wouter J de Jonge1,
  9. Kevin Lee3,
  10. Cesar Ramirez-Molina3,
  11. Dave Lugo3,
  12. Michael J Skynner3,
  13. Guy E E Boeckxstaens1,2,
  14. Gianluca Matteoli2
  1. 1Department of Gastroenterology and Hepatology, Tytgat Institute of Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
  2. 2Department of Clinical and Experimental Medicine, University Hospital Leuven, University of Leuven, Leuven, Belgium
  3. 3Immunoinflammation Therapy Area, GlaxoSmithKline Research and Development Ltd, Stevenage, UK
  1. Correspondence to Dr Gianluca Matteoli, Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Herestraat 49, O&N1 bus 701, Leuven 3000, Belgium; gianluca.matteoli{at}med.kuleuven.be

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.

Design 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.

  • Abdominal Surgery
  • Mast Cells
  • Macrophages
  • Inflammation
  • Intestinal Motility

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