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Biochimica et Biophysica Acta 01/2012; 1822(1):1. · 4.66 Impact Factor
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Journal of pediatric gastroenterology and nutrition 12/2011; 53 Suppl 2:S34-5. · 2.18 Impact Factor
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ABSTRACT: Cross-talk between the immune- and nervous-system is considered an important biological process in health and disease. Because mast cells are often strategically placed between nerves and surrounding (immune)-cells they may function as important intermediate cells. This review summarizes the current knowledge on bidirectional interaction between mast cells and nerves and its possible relevance in (inflammation-induced) increased nociception. Our main focus is on mast cell mediators involved in sensitization of TRP channels, thereby contributing to nociception, as well as neuron-released neuropeptides and their effects on mast cell activation. Furthermore we discuss mechanisms involved in physical mast cell-nerve interactions. This article is part of a Special Issue entitled: Mast cells in inflammation.
Biochimica et Biophysica Acta 04/2011; 1822(1):74-84. · 4.66 Impact Factor
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ABSTRACT: The autonomous nervous system of the gut is increasingly recognized as an important regulatory factor in intestinal permeability and immune cell activation. Neuropeptides released by neurons -or inflammatory cells- have emerged as neuro-immune modulators that can relay, for instance, stress-induced neuronal activity to immune processes. Such peptides can participate in processes reducing inflammatory responses, or augment resolution of inflammation. Neuropeptides and hormones such as vasoactive intestinal peptide, urocortin, ghrelin, and cortistatin have been shown to modulate the disease activity in a variety of experimental models of inflammatory and autoimmune disease via modulation of immune or neuronal cell activity. We review here the potential of neuropeptide receptor activation to modulate inflammatory diseases of the intestine. We will highlight the role of neuropeptides in gastrointestinal (GI) physiology and immune regulation, and we will speculate on the therapeutic potential of peptides that bind G protein coupled receptors (GPCRs) in the management of inflammation in the GI tract.
Current pharmaceutical design 01/2010; 16(9):1091-105. · 4.41 Impact Factor
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ABSTRACT: Multiple organs are targeted by the stress response, but the focus of this article is on stress-induced activation of visceral afferents in the gut. During recent years it became apparent that mast cells are pivotal in this response. Peripheral corticotrophin releasing factor (CRF) induces their degranulation whereupon mast cell mediators activate visceral afferents. In addition, these mediators are responsible for gut barrier dysfunction and subsequent influx of luminal antigens and bacteria. Some research groups have begun to investigate the possible importance of barrier dysfunction for enhanced visceral sensitivity. After reviewing the current knowledge on CRF-induced mast cell degranulation we will discuss these groundbreaking papers in a more elaborate way. They form the basis for a hypothesis in which not only CRF-induced but also antigen-mediated mast cell degranulation is relevant to stress-related afferent activation. Part of this hypothesis is certainly speculative and needs further investigation. At the end of this article we sum up some of the unanswered questions raised by others and during this review.
Autonomic neuroscience: basic & clinical 09/2009; 153(1-2):99-105. · 1.82 Impact Factor
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ABSTRACT: Although postoperative ileus (POI) is considered multifactorial, intestinal inflammation resulting from manipulation-induced mast cell activation is recognized as an important pathophysiological mechanism. Therefore, mast cell stabilization may represent a new therapeutic approach to shortening POI. The aim of this paper was to study the effect of ketotifen, a mast cell stabilizer, on postoperative gastrointestinal transit in patients who underwent abdominal surgery.
In this pilot study, 60 patients undergoing major abdominal surgery for gynecological malignancy with standardized anesthesia were randomized to treatment with ketotifen (4 or 12 mg) or placebo. Patients were treated for 6 days, starting 3 days before surgery. Gastric emptying of liquids, selected as a primary outcome parameter, was measured 24 h after surgery using scintigraphy. Secondary end points were (scintigraphically assessed) colonic transit, represented as geometrical center of activity (segment 1(cecum) to 7(stool)) and clinical parameters.
Gastric retention 1 h after liquid intake was significantly reduced by 12 mg (median 3% (1-7), P=0.01), but not by 4 mg ketotifen (18% (3-45), P=0.6) compared with placebo (16% (5-75)). Twenty-four hour colonic transit in placebo was 0.8 (0.0-1.1) vs. 1.2 (0.2-1.4) colon segments in the 12 mg ketotifen group (P=0.07). Abdominal cramps were significantly relieved in patients treated with 12 mg ketotifen, whereas other clinical parameters were not affected.
Ketotifen significantly improves gastric emptying after abdominal surgery and warrants further exploration of mast cell stabilizers as putative therapy for POI.
The American Journal of Gastroenterology 07/2009; 104(9):2257-66. · 7.28 Impact Factor
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Journal of Pediatric Gastroenterology and Nutrition 10/2005; 41 Suppl 1:S36-7. · 2.30 Impact Factor
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Journal of Pediatric Gastroenterology and Nutrition 10/2005; 41 Suppl 1:S10-1. · 2.30 Impact Factor
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Journal of Pediatric Gastroenterology and Nutrition 08/2005; 41:S10-S11. · 2.30 Impact Factor
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ABSTRACT: Inflammation of the intestinal muscularis following manipulation during surgery plays a crucial role in the pathogenesis of postoperative ileus. Here, we evaluate the role of mast cell activation in the recruitment of infiltrates in a murine model.
Twenty-four hours after control laparotomy or intestinal manipulation, gastric emptying was determined. Mast cell degranulation was determined by measurement of mast cell protease-I in peritoneal fluid. Intestinal inflammation was assessed by determination of tissue myeloperoxidase activity and histochemical staining.
Intestinal manipulation elicited a significant increase in mast cell protease-I levels in peritoneal fluid and resulted in recruitment of inflammatory infiltrates to the intestinal muscularis. This infiltrate was associated with a delay in gastric emptying 24 hours after surgery. Pretreatment with mast cell stabilizers ketotifen (1 mg/kg, p.o.) or doxantrazole (5 mg/kg, i.p.) prevented both manipulation-induced inflammation and gastroparesis. Reciprocally, in vivo exposure of an ileal loop to the mast cell secretagogue compound 48/80 (0.2 mg/mL for 1 minute) induced muscular inflammation and delayed gastric emptying. The manipulation-induced inflammation was dependent on the presence of mast cells because intestinal manipulation in mast cell-deficient Kit/Kitv mice did not elicit significant leukocyte recruitment. Reconstitution of Kit/Kitv mice with cultured bone marrow-derived mast cells from congenic wild types restored the manipulation-induced inflammation.
Our results show that degranulation of connective tissue mast cells is a key event for the establishment of the intestinal infiltrate that mediates postoperative ileus following abdominal surgery.
Gastroenterology 08/2004; 127(2):535-45. · 11.68 Impact Factor
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ABSTRACT: Postoperative ileus after abdominal surgery largely contributes to patient morbidity and prolongs hospitalization. We aimed to study its pathophysiology in a murine model by determining gastric emptying after manipulation of the small intestine.
Gastric emptying was determined at 6, 12, 24, and 48 hours after abdominal surgery by using scintigraphic imaging. Intestinal or gastric inflammation was assessed by immune-histochemical staining and measurement of tissue myeloperoxidase activity. Neuromuscular function of gastric and intestinal muscle strips was determined in organ baths.
Intestinal manipulation resulted in delayed gastric emptying up to 48 hours after surgery; gastric half-emptying time 24 hours after surgery increased from 16.0 +/- 4.4 minutes after control laparotomy to 35.6 +/- 5.4 minutes after intestinal manipulation. The sustained delay in gastric emptying was associated with the appearance of leukocyte infiltrates in the muscularis of the manipulated intestine, but not in untouched stomach or colon. The delay in postoperative gastric emptying was prevented by inhibition of intestinal leukocyte recruitment. In addition, postoperative neural blockade with hexamethonium (1 mg/kg intraperitoneally) or guanethidine (50 mg/kg intraperitoneally) normalized gastric emptying without affecting small-intestinal transit. The appearance of intestinal infiltrates after intestinal manipulation was associated with increased c-fos protein expression in sensory neurons in the lumbar spinal cord.
Sustained postoperative gastroparesis after intestinal manipulation is mediated by an inhibitory enterogastric neural pathway that is triggered by inflammatory infiltrates recruited to the intestinal muscularis. These findings show new targets to shorten the duration of postoperative ileus pharmacologically.
Gastroenterology 11/2003; 125(4):1137-47. · 11.68 Impact Factor
