title: Effects of nerve growth factor antagonist K252a on peritoneal mast cell degranulation: implications for rat postoperative ileus.
abstract: Stabilization of mast cell (MC) degranulation has been proposed to prevent postoperative ileus (POI). Nerve growth factor (NGF) mediates MC degranulation. The aim of the study was to evaluate whether NGF receptor antagonist K252a acts as a MC stabilizer in vitro and in vivo model of POI. Peritoneal mast cells (PMCs) were obtained from Sprague-Dawley rats and were incubated with K252a and exposed to NGF or Compound 48/80 (C48/80). MC degranulation was assessed by β-hexosaminidase assay. POI was induced in rats by intestinal manipulation (IM). Rats were pretreated with K252a (100 μg/kg sc) 20 min prior to POI induction. At 20 min after IM, release of rat mast cell protease 6 (RMCP-6) was evaluated in peritoneal lavage. At 24 h, intestinal transit (IT) and gastric emptying (GE) were evaluated. Ileal inflammation was assessed by myeloperoxidase (MPO) activity, expression of IL-6, NGF, TrkA, RMCP-2 and 6, and MC density within the full-thickness ileum. C48/80 and NGF evoked degranulation of PMCs in a dose-dependent manner. K252a prevented NGF-evoked, but not C48/80-evoked, MC degranulation. IM evoked the release of peritoneal RMCP-6 and subsequently delayed IT and GE. IM increased MPO activity and expression of IL-6. In IM rats, K252a prevented upregulation of IL-6 expression and reduced TrkA. IT, GE, and inflammation were not affected by K252a. K252a inhibited NGF-evoked degranulation of PMCs in vitro. In vivo, K252a decreased IL-6 and PMC degranulation. This may be of relevance for the development of new therapeutic targets for POI.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Veterinary School, Autonomous University of Barcelona, Barcelona, Spain; Neuroscience Institute, Autonomous University of Barcelona, Barcelona, Spain; and.
authors.forename: Sergio
authors.initials: S
authors.lastname: Berdún
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Veterinary School, Autonomous University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain.
authors.forename: Jakub
authors.initials: J
authors.lastname: Rychter
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Veterinary School, Autonomous University of Barcelona, Barcelona, Spain; Neuroscience Institute, Autonomous University of Barcelona, Barcelona, Spain; and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain patri.vergara@uab.cat.
authors.forename: Patri
authors.initials: P
authors.lastname: Vergara
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects*; D004195:Disease Models, Animal; D016903:Drug Monitoring; D005746:Gastric Emptying / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D045823:Ileus / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D026121:Indole Alkaloids / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism; D011183:Postoperative Complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D053802:Tryptases / Q000378:metabolism; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D005765:Gastrointestinal Agents; D026121:Indole Alkaloids; D015850:Interleukin-6; D020800:Receptor, Nerve Growth Factor; D003189:p-Methoxy-N-methylphenethylamine; D020932:Nerve Growth Factor; C049985:staurosporine aglycone; C509221:Tpsb2 protein, rat; D053802:Tryptases
keywords: gastrointestinal motility; mast cells; nerve growth factor; postoperative ileus