1 Inhibition of spleen tyrosine kinase as treatment of postoperative ileus Sjoerd H.W. van Bree 1 , Pedro J. Gomez-Pinilla 2 , Fleur S. van de Bovenkamp 1 , Martina Di Giovangiulio 2 , Giovanna Farro 2 , Andrea Nemethova 2 , Cathy Cailotto 1 , Wouter J. de Jonge 1 , Kevin Lee 3 , Cesar Ramirez- Molina 3 , Dave Lugo 3 , Michael Skynner 3 , Guy E.E. Boeckxstaens 1,2 , Gianluca Matteoli 2 . 1 Tytgat institute of Liver and Intestinal Research, Department of Gastroenterology&Hepatology, Academic Medical Center, Amsterdam, the Netherlands . 2 Department of Clinical and Experimental Medicine, University Hospital Leuven, University of Leuven, Leuven, Belgium. 3 GlaxoSmithKline, Gunnel's wood road, Stevenage, United Kingdom. Key words: spleen tyrosine kinase, inflammation, leukocytes, mast cells, postoperative ileus Corresponding author: Dr. Gianluca Matteoli, DVM, PhD Department of Clinical and Experimental Medicine Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Herestraat 49, O&N1 bus 701 3000 Leuven, Belgium email: [email protected]Tel.: +32 16 330238/ +32-16-330671 (secr) Disclosure: All authors concur with the submission. The authors state that there is no conflicting financial interest. The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article to be published in Gut editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our licence. Word count: 4678 Grant support: G. Boeckxstaens and S. van Bree (VICI) and W. de Jonge (VIDI) were supported by governmental grants from the Netherlands Organization for Scientific Research (NWO). G. Matteoli and P.J. Gomez-Pinilla were supported by governmental fellowships of the Flemish “Fonds Wetenschappelijk Onderzoek” (FWO). G. Boeckxstaens was supported by a governmental grant (Odysseus program, G.0905.07) of the FWO. Abbreviations: POI – postoperative ileus SYK – spleen tyrosine kinase GI – gastrointestinal IM – intestinal manipulation GC – geometric center L – laparotomy GSK143 – GSK compound143 SP – substance P TNP – trinitrophenyl DOX – doxantrazole PMC – peritoneal mast cell SCF – Stem cell factor PBS – phosphate buffered saline i.p. – intraperitoneal FITC – fluorescein isothiocyanate 4-MUG – 4-methylumbelliferyl glucosaminide HPF – high power field DMSO – dimethyl sulphoxide
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Inhibition of spleen tyrosine kinase as treatment of postoperative ileus
Sjoerd H.W. van Bree1, Pedro J. Gomez-Pinilla2, Fleur S. van de Bovenkamp1, Martina Di Giovangiulio2, Giovanna Farro2, Andrea Nemethova2, Cathy Cailotto1, Wouter J. de Jonge1, Kevin Lee3, Cesar Ramirez-Molina3, Dave Lugo3, Michael Skynner3, Guy E.E. Boeckxstaens1,2, Gianluca Matteoli2.
1Tytgat institute of Liver and Intestinal Research, Department of Gastroenterology&Hepatology, Academic Medical Center, Amsterdam, the Netherlands. 2 Department of Clinical and Experimental Medicine, University Hospital Leuven, University of Leuven, Leuven, Belgium. 3GlaxoSmithKline, Gunnel's wood road, Stevenage, United Kingdom.
Corresponding author: Dr. Gianluca Matteoli, DVM, PhD Department of Clinical and Experimental Medicine Translational Research Center for Gastrointestinal Disorders (TARGID) University of Leuven Herestraat 49, O&N1 bus 701 3000 Leuven, Belgium email: [email protected] Tel.: +32 16 330238/ +32-16-330671 (secr)
Disclosure: All authors concur with the submission. The authors state that there is no conflicting financial interest. The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article to be published in Gut editions and any other BMJPGL products to exploit all subsidiary rights, as set out in our licence. Word count: 4678 Grant support: G. Boeckxstaens and S. van Bree (VICI) and W. de Jonge (VIDI) were supported by governmental grants from the Netherlands Organization for Scientific Research (NWO). G. Matteoli and P.J. Gomez-Pinilla were supported by governmental fellowships of the Flemish “Fonds Wetenschappelijk Onderzoek” (FWO). G. Boeckxstaens was supported by a governmental grant (Odysseus program, G.0905.07) of the FWO.
Abbreviations: POI – postoperative ileus SYK – spleen tyrosine kinase GI – gastrointestinal IM – intestinal manipulation GC – geometric center L – laparotomy GSK143 – GSK compound143 SP – substance P TNP – trinitrophenyl DOX – doxantrazole PMC – peritoneal mast cell SCF – Stem cell factor PBS – phosphate buffered saline i.p. – intraperitoneal FITC – fluorescein isothiocyanate 4-MUG – 4-methylumbelliferyl glucosaminide HPF – high power field DMSO – dimethyl sulphoxide
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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 GSKcompound143 (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 and
bone marrow derived macrophages.
Results In vivo: Intestinal manipulation resulted in a delay of gastrointestinal transit at t=24h
(Geometric Center (GC): 4.4±0.3). Doxantrazole and GSK143 significantly increased gastrointestinal
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