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1
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Liu P, Liu T, Zhang M, Mo R, Zhou W, Li D, Wu Y. Effects of Avenanthramide on the Small Intestinal Damage through Hsp70-NF-κB Signaling in an Ovalbumin-Induced Food Allergy Model. Int J Mol Sci 2022; 23:ijms232315229. [PMID: 36499554 PMCID: PMC9739943 DOI: 10.3390/ijms232315229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/22/2022] [Accepted: 12/01/2022] [Indexed: 12/11/2022] Open
Abstract
A food allergy is caused by an abnormal immune reaction and can induce serious intestinal inflammation and tissue damage. Currently, the avoidance of food allergens is still the most effective way to prevent or reduce allergic symptoms, so the development of new strategies to treat allergies is important. Avenanthramide (AVA) is a bioactive polyphenol derived from oats with a wide range of biological activities; however, it is still not clear whether or how AVA alleviates intestinal damage under allergic situations. The aim of this study was to explore the effect of AVA on the small intestinal damage in an ovalbumin (OVA)-induced food allergy model and its mechanism. In experiment 1, 10 mg/kg bw and 20 mg/kg bw doses of AVA both decreased the serum levels of OVA-specific IgE, histamine, and prostaglandin D induced by OVA. The AVA administration relieved inflammation indicated by the lower serum concentrations of pro-inflammatory cytokines including interleukin-1β, IL-6, and tumor necrosis factor-α. The levels of tight junction proteins including Claudin-1, ZO-1, and Occludin in the jejunum were elevated after AVA administration, accompanied by the improved intestinal morphology. Furthermore, AVA elevated the protein expression of heat shock protein 70 (Hsp70) and inhibited the phosphorylation of nuclear factor kappa-B (NF-κB), thus the apoptozole, which a Hsp70 inhibitor, was applied in experiment 2 to assess the contribution of Hsp70-NF-κB signaling to the effects of AVA. In the experiment 2, the inhibition of Hsp70 signaling treatment abolished the beneficial effects of AVA on the small intestinal damage and other allergic symptoms in mice challenged with OVA. Taken together, our results indicated that AVA exerted an intestinal protection role in the OVA-induced allergy, the mechanism of which was partly mediated by the Hsp70-NF-κB signaling.
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Affiliation(s)
| | | | | | | | | | | | - Yi Wu
- Correspondence: ; Tel.: +86-6273-3588
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2
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Worm M, Reese I, Ballmer-Weber B, Beyer K, Bischoff SC, Bohle B, Brockow K, Claßen M, Fischer PJ, Hamelmann E, Jappe U, Kleine-Tebbe J, Klimek L, Koletzko B, Lange L, Lau S, Lepp U, Mahler V, Nemat K, Raithel M, Saloga J, Schäfer C, Schnadt S, Schreiber J, Szépfalusi Z, Treudler R, Wagenmann M, Werfel T, Zuberbier T. Update of the S2k guideline on the management of IgE-mediated food allergies. Allergol Select 2021; 5:195-243. [PMID: 34263109 PMCID: PMC8276640 DOI: 10.5414/alx02257e] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 06/21/2021] [Indexed: 01/02/2023] Open
Abstract
Not available.
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Affiliation(s)
- Margitta Worm
- Allergology and Immunology, Department of Dermatology, Venereology, and Allergology, Charité – Universitätsmedizin Berlin, Germany
| | - Imke Reese
- Nutritional Counseling and Therapy, Focus on Allergology, Munich, Germany
| | - Barbara Ballmer-Weber
- University Hospital Zurich, Department of Dermatology, Zurich, Switzerland, and Cantonal Hospital St. Gallen, Department of Dermatology and Allergology, St. Gallen, Switzerland
| | - Kirsten Beyer
- Clinic of Pediatrics m. S. Pneumology, Immunology and Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Germany
| | - Stephan C. Bischoff
- Institute of Nutritional Medicine and Prevention, University of Hohenheim, Stuttgart, Germany
| | - Barbara Bohle
- Institute of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria
| | - Knut Brockow
- Department of Dermatology and Allergology, Biederstein, Klinikum rechts der Isar, Technical University of Munich, Germany
| | - Martin Claßen
- Klinik für Kinder und Jugendmedizin/Päd. Intensivmedizin, Eltern-Kind-Zentrum Prof. Hess Klinikum Bremen-Mitte
| | - Peter J. Fischer
- Practice for Pediatric and Adolescent Medicine m. S. Allergology and Pediatric Pneumology, Schwäbisch Gmünd
| | - Eckard Hamelmann
- University Clinic for Pediatric and Adolescent Medicine, Evangelisches Klinikum Bethel gGmbH, Bielefeld
| | - Uta Jappe
- Research Group Clinical and Molecular Allergology, Research Center Borstel, Airway Research Center North (ARCN), member of the German Center for Lung Research (DZL), Borstel
- Interdisciplinary Allergy Outpatient Clinic, Medical Clinic III, University Hospital Schleswig-Holstein, Lübeck
| | | | | | - Berthold Koletzko
- Pediatric Clinic and Pediatric Polyclinic, Dr. von Haunersches Kinderspital, Department of Metabolic and Nutritional Medicine, Ludwig-Maximilians-University, Munich
| | - Lars Lange
- Pediatric and Adolescent Medicine, St.- Marien-Hospital, Bonn
| | - Susanne Lau
- Clinic of Pediatrics m. S. Pneumology, Immunology and Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Germany
| | - Ute Lepp
- Practice for Pulmonary Medicine and Allergology, Buxtehude
| | | | - Katja Nemat
- Practice for Pediatric Pneumology/Allergology at the Children’s Center Dresden (Kid), Dresen
| | | | - Joachim Saloga
- Department of Dermatology, University Medical Center, Johannes Gutenberg-University Mainz
| | - Christiane Schäfer
- Nutritional Therapy, Focus on Allergology and Gastroenterology, Schwarzenbek, Germany
| | - Sabine Schnadt
- German Allergy and Asthma Association, Mönchengladbach, Germany
| | - Jens Schreiber
- Pneumology, University Hospital of Otto von Guericke University, Magdeburg, Germany
| | - Zsolt Szépfalusi
- University Hospital for Pediatrics and Adolescent Medicine, Medical University of Vienna, Austria
| | - Regina Treudler
- Clinic of Dermatology, Venereology and Allergology, University Medical Center Leipzig, Germany
| | | | - Thomas Werfel
- Clinic of Dermatology, Allergology and Venerology, Hannover Medical School, Germany, and
| | - Torsten Zuberbier
- Department of Dermatology, Venerology and Allergology, Charité – Universitätsmedizin Berlin
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3
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Reyes-Pavón D, Cervantes-García D, Bermúdez-Humarán LG, Córdova-Dávalos LE, Quintanar-Stephano A, Jiménez M, Salinas E. Protective Effect of Glycomacropeptide on Food Allergy with Gastrointestinal Manifestations in a Rat Model through Down-Regulation of Type 2 Immune Response. Nutrients 2020; 12:nu12102942. [PMID: 32992996 PMCID: PMC7601722 DOI: 10.3390/nu12102942] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/15/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
Glycomacropeptide (GMP) is a bioactive peptide derived from milk κ-casein with immune-modulatory and anti-inflammatory properties. Food allergy (FA) is an adverse immune reaction with a broad spectrum of manifestations. Allergen intake induces persistent intestinal inflammation and tissue damage. In this study, the anti-allergic activity of GMP was evaluated using a rat ovalbumin (OVA)-induced FA model with gastrointestinal manifestation. Rats were orally GMP treated from 3 days prior and during FA development. The severity of food anaphylaxis and diarrheal episodes, antibody production and histamine level were measured. Histopathological changes, inflammation and predominant cytokine profile at intestine were analyzed. Oral GMP intake decreased clinical signs and diarrhea severity induced by allergen, with a significant reduction in intestinal edema and expression level of IL-1β and TNF-α. Prophylaxis with GMP also diminished serum anti-OVA IgE and IgG1, and histamine levels. GMP treatment markedly decreased eosinophil infiltration, mast cell and goblet cell hyperplasia, total IgE expression in intestine, and prevented histological changes in villi, crypts and internal muscularis layer. The treatment effectively suppressed IL-5, IL-13 and GATA3 expression and skewed the intestinal cytokine profile toward type 1 and regulatory. These results suggest that GMP may protect against FA through down-regulating the type 2 inflammatory response.
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Affiliation(s)
- Diana Reyes-Pavón
- Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico; (D.R.-P.); (D.C.-G.); (L.E.C.-D.)
| | - Daniel Cervantes-García
- Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico; (D.R.-P.); (D.C.-G.); (L.E.C.-D.)
- National Council of Science and Technology, 03940 Mexico City, Mexico
| | | | - Laura Elena Córdova-Dávalos
- Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico; (D.R.-P.); (D.C.-G.); (L.E.C.-D.)
| | - Andrés Quintanar-Stephano
- Department of Physiology and Pharmacology, Basic Science Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico;
| | - Mariela Jiménez
- Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico; (D.R.-P.); (D.C.-G.); (L.E.C.-D.)
- Correspondence: (M.J.); (E.S.); Tel.: +52-(449)-910-8424 (E.S.)
| | - Eva Salinas
- Department of Microbiology, Basic Science Center, Autonomous University of Aguascalientes, 20131 Aguascalientes, Mexico; (D.R.-P.); (D.C.-G.); (L.E.C.-D.)
- Correspondence: (M.J.); (E.S.); Tel.: +52-(449)-910-8424 (E.S.)
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4
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Chen X, Churchill MJ, Nagar KK, Tailor YH, Chu T, Rush BS, Jiang Z, Wang EBC, Renz BW, Wang H, Fung MC, Worthley DL, Mukherjee S, Wang TC. IL-17 producing mast cells promote the expansion of myeloid-derived suppressor cells in a mouse allergy model of colorectal cancer. Oncotarget 2016; 6:32966-79. [PMID: 26429861 PMCID: PMC4741743 DOI: 10.18632/oncotarget.5435] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 09/15/2015] [Indexed: 12/11/2022] Open
Abstract
Food allergy can influence the development of colorectal cancer, although the underlying mechanisms are unclear. While mast cells (MC) store and secrete histamine, immature myeloid cells (IMC) are the major site of histidine decarboxylase (HDC) expression, the enzyme responsible for histamine production. From our earlier work, we hypothesized that histamine is central to the association between allergy and colorectal carcinogenesis through its influence on the MC-MDSC axis. Here, we show that in wild type (WT) mice, ovalbumin (OVA) immunization elicits a typical TH2 response. In contrast, in HDC−/− mice, the response to OVA allergy is skewed towards infiltration by IL-17 expressing MCs. This response is inhibited by histamine treatment. The HDC−/− allergic IL-17-expressing MCs promote MDSC proliferation and upregulation of Cox-2 and Arg-1. OVA allergy in HDC−/− mice increases the growth of colon tumor cells in both the MC38 tumor cell implantation model and the AOM/DSS carcinogenesis model. Taken together, our results show that histamine represses IL-17-expressing MCs and their subsequent activation of MDSCs, attenuating the risk of colorectal cancer in the setting of food allergy. Targeting the MC-MDSC axis may be useful for cancer prevention and treatment in patients, particularly in those with food allergy.
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Affiliation(s)
- Xiaowei Chen
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.,Division of Biology, School of Life Science, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China
| | - Michael J Churchill
- Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Karan K Nagar
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Yagnesh H Tailor
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Timothy Chu
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Brittany S Rush
- Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Zhengyu Jiang
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Edwin B C Wang
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Bernhard W Renz
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Hongshan Wang
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Ming Chiu Fung
- Division of Biology, School of Life Science, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, China
| | - Daniel L Worthley
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Siddhartha Mukherjee
- Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
| | - Timothy C Wang
- Division of Digestive and Liver Disease, Columbia University, New York, NY, USA.,Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA
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5
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Pigrau M, Rodiño-Janeiro BK, Casado-Bedmar M, Lobo B, Vicario M, Santos J, Alonso-Cotoner C. The joint power of sex and stress to modulate brain-gut-microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome. Neurogastroenterol Motil 2016; 28:463-86. [PMID: 26556786 DOI: 10.1111/nmo.12717] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/05/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intestinal homeostasis is a dynamic process that takes place at the interface between the lumen and the mucosa of the gastrointestinal tract, where a constant scrutiny for antigens and toxins derived from food and microorganisms is carried out by the vast gut-associated immune system. Intestinal homeostasis is preserved by the ability of the mucus layer and the mucosal barrier to keep the passage of small-sized and antigenic molecules across the epithelium highly selective. When combined and preserved, immune surveillance and barrier's selective permeability, the host capacity of preventing the development of intestinal inflammation is optimized, and viceversa. In addition, the brain-gut-microbiome axis, a multidirectional communication system that integrates distant and local regulatory networks through neural, immunological, metabolic, and hormonal signaling pathways, also regulates intestinal function. Dysfunction of the brain-gut-microbiome axis may induce the loss of gut mucosal homeostasis, leading to uncontrolled permeation of toxins and immunogenic particles, increasing the risk of appearance of intestinal inflammation, mucosal damage, and gut disorders. Irritable bowel syndrome is prevalent stress-sensitive gastrointestinal disorder that shows a female predominance. Interestingly, the role of stress, sex and gonadal hormones in the regulation of intestinal mucosal and the brain-gut-microbiome axis functioning is being increasingly recognized. PURPOSE We aim to critically review the evidence linking sex, and stress to intestinal barrier and brain-gut-microbiome axis dysfunction and the implications for irritable bowel syndrome.
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Affiliation(s)
- M Pigrau
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - B K Rodiño-Janeiro
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Casado-Bedmar
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - B Lobo
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Vicario
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - J Santos
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - C Alonso-Cotoner
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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6
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Mansueto P, D’Alcamo A, Seidita A, Carroccio A. Food allergy in irritable bowel syndrome: The case of non-celiac wheat sensitivity. World J Gastroenterol 2015; 21:7089-109. [PMID: 26109796 PMCID: PMC4476871 DOI: 10.3748/wjg.v21.i23.7089] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 04/04/2015] [Accepted: 05/07/2015] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal disorders, having a prevalence of 12%-30% in the general population. Most patients with IBS attribute their symptoms to adverse food reactions. We review the role of diet in the pathogenesis of IBS and the importance of dietary factors in the management of these patients. The MEDLINE electronic database (1966 to Jan 2015) was searched using the following keywords: "food", "diet", "food allergy", "food hypersensitivity", "food intolerance", "IBS", "epidemiology", "pathogenesis", "pathophysiology", "diagnosis", "treatment". We found 153 eligible papers; 80 were excluded because: not written in English, exclusive biochemical and experimental research, case reports, reviews, and research otherwise not relevant to our specific interest. We selected 73 papers: 43 original papers, 26 reviews and 4 letters to the editor. These papers focused on IBS pathogenesis, the association between IBS and atopy, and between IBS and food allergy, the relationship between IBS and non-celiac wheat sensitivity, the role of diet in IBS. Pending further scientific evidence, a cautious approach is advisable but the concept of food allergy should be included as a possible cause of IBS, and a dietary approach may have a place in the routine clinical management of IBS.
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7
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Rodiño-Janeiro BK, Alonso-Cotoner C, Pigrau M, Lobo B, Vicario M, Santos J. Role of Corticotropin-releasing Factor in Gastrointestinal Permeability. J Neurogastroenterol Motil 2015; 21:33-50. [PMID: 25537677 PMCID: PMC4288093 DOI: 10.5056/jnm14084] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 10/06/2014] [Accepted: 10/07/2014] [Indexed: 12/11/2022] Open
Abstract
The interface between the intestinal lumen and the mucosa is the location where the majority of ingested immunogenic particles face the scrutiny of the vast gastrointestinal immune system. Upon regular physiological conditions, the intestinal micro-flora and the epithelial barrier are well prepared to process daily a huge amount of food-derived antigens and non-immunogenic particles. Similarly, they are ready to prevent environmental toxins and microbial antigens to penetrate further and interact with the mucosal-associated immune system. These functions promote the development of proper immune responses and oral tolerance and prevent disease and inflammation. Brain-gut axis structures participate in the processing and execution of response signals to external and internal stimuli. The brain-gut axis integrates local and distant regulatory networks and super-systems that serve key housekeeping physiological functions including the balanced functioning of the intestinal barrier. Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor. In this review, we describe the role of stress and corticotropin-releasing factor in the regulation of gastrointestinal permeability, and discuss the link to both health and pathological conditions.
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Affiliation(s)
- Bruno K Rodiño-Janeiro
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - Carmen Alonso-Cotoner
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - Marc Pigrau
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - Beatriz Lobo
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - María Vicario
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
| | - Javier Santos
- Neuro-Immuno-Gastroenterology Group, Digestive Diseases Research Unit, Gastroenterology Department, Hospital Universitari Vall d'Hebron, Vall d' Hebron Research Institute; and Department of Medicine, Universitat Autònoma de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
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8
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Lied GA. Indication of immune activation in patients with perceived food hypersensitivity. Dig Dis Sci 2014; 59:259-66. [PMID: 24185686 DOI: 10.1007/s10620-013-2926-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 10/16/2013] [Indexed: 12/15/2022]
Abstract
Majority of the patients with perceived food hypersensitivity have irritable bowel syndrome (IBS), and a significant proportion of IBS patients also attribute their gastrointestinal complaints to food items. Different factors such as disturbed intestinal fermentation, enteric dysmotility, post-infectious changes and altered microbial flora in the colon as well as psychological disturbances likely play a role in the pathophysiology and symptoms generation in patients with food hypersensitivity. In addition, a number of studies in these patient groups indicate that local, systemic and mucosal immune systems are activated. The question now is no longer intestinal immune activation, but how the immune system is activated in these patients. In the following review, the potential pathogenetic role of the immune system and evidence of immune activation are reported in patients with perceived food hypersensitivity.
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Affiliation(s)
- Gülen Arslan Lied
- Department of Clinical Medicine, University of Bergen, Bergen, Norway,
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9
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Zhang H, Yang H, Ma W, Zhang Z, He S. Modulation of PAR expression and tryptic enzyme induced IL-4 production in mast cells by IL-29. Cytokine 2013; 61:469-77. [PMID: 23218741 DOI: 10.1016/j.cyto.2012.10.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2012] [Revised: 09/17/2012] [Accepted: 10/31/2012] [Indexed: 12/25/2022]
Abstract
Interleukin (IL)-29 is a relatively newly discovered cytokine, which has been shown to be actively involved in the pathogenesis of allergic inflammation. However, little is known of the effects of IL-29 on protease activated receptor (PAR) expression and potential mechanisms of cytokine production in mast cells. In the present study, we examined potential influence of IL-29 on PAR expression and cytokine production in P815 and bone marrow derived mast cells (BMMCs) by using flow cytometry analysis, quantitative real time PCR, and ELISA techniques. The results showed that IL-29 downregulated the expression of PAR-1 by up to 56.2%, but had little influence on the expression of PAR-2, PAR-3 and PAR-4. IL-29 also induced downregulation of expression of PAR-1 mRNA. However, when mast cells were pre-incubated with IL-29, thrombin-, trypsin- and tryptase-induced expression of PAR-2, PAR-3 and PAR-4 was upregulated, respectively. IL-29 provoked approximately up to 1.9-fold increase in IL-4 release when mast cells was challenged with IL-29. Administration of IL-29 blocking antibody, AG490 or LY294002 abolished IL-29-induced IL-4 release from P815 cells. It was found that IL-29 diminished trypsin- and tryptase-induced IL-4 release from P815 cells following 16 h incubation. In conclusion, IL-29 can regulate expression of PARs and tryptase- and trypsin-induced IL-4 production in mast cells, through which participates in the mast cell related inflammation.
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Affiliation(s)
- Huiyun Zhang
- Department of Pathophysiology, Hainan Medical College, Haikou, Hainan 571101, China
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10
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Nagy K, Ramos L, Courtet-Compondu MC, Braga-Lagache S, Redeuil K, Lobo B, Azpiroz F, Malagelada JR, Beaumont M, Moulin J, Acquistapache S, Sagalowicz L, Kussmann M, Santos J, Holst B, Williamson G. Double-balloon jejunal perfusion to compare absorption of vitamin E and vitamin E acetate in healthy volunteers under maldigestion conditions. Eur J Clin Nutr 2012; 67:202-6. [PMID: 23212132 DOI: 10.1038/ejcn.2012.183] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND/OBJECTIVES The vitamin E derivative, α-tocopheryl acetate, is often included in formulations used in enteral nutrition. In this respect, we compared α-tocopherol and α-tocopheryl acetate absorption under 'maldigestion' conditions, such as occurring during enteral tube feeding, using differentially labeled RRR-[5,7-methyl-((2)H(6))]-α-tocopherol and RRR-[5-methyl-(2)H(3)]-α-tocopheryl acetate allowing direct comparison between free and esterified forms. SUBJECTS/METHODS The two derivatives were given together in a single dose to six volunteers directly into the jejunum using a double-balloon perfusion system. Perfusion lasted for 1 h, and the collected blood and effluent samples were analyzed by liquid chromatography-mass spectrometry. RESULTS In the isolated 20-cm length of exposed jejunum, on average ~ 6% of the two vitamin E forms were absorbed >1 h based on subtraction of effluent from influent. There was substantial difference in the absolute absorbed quantity between individuals, but no significant differences were observed in the absorption between the two labeled forms as assessed in the plasma. (2)H(3)-α-tocopherol was not present in the influent, but appeared in the effluent, indicating that the acetylated form of vitamin E is cleaved by brush border enzymes in the small intestine. CONCLUSIONS This study shows that even in the absence of digestive enzymes and bile salts, the appropriately solubilized acetylated form of α-tocopherol exhibits the same bioavailability as free α-tocopherol. This suggests that both forms can be absorbed equally under maldigestion conditions such as present clinically during enteral tube feeding.
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Affiliation(s)
- K Nagy
- Nestlé Research Center, Nestec Ltd, Lausanne, Switzerland
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11
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Lied GA, Lillestøl K, Lind R, Valeur J, Morken MH, Vaali K, Gregersen K, Florvaag E, Tangen T, Berstad A. Perceived food hypersensitivity: a review of 10 years of interdisciplinary research at a reference center. Scand J Gastroenterol 2011; 46:1169-78. [PMID: 21679125 DOI: 10.3109/00365521.2011.591428] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Perceived food hypersensitivity is a prevalent, but poorly understood condition. In this review article, we summarize narratively recent literature including results of our 10 years' interdisciplinary research program dealing with such patients. The patients (more than 400) included in our studies were all adults referred to a university hospital because of gastrointestinal complaints self-attributed to food hypersensitivity. Despite extensive examinations, food allergy was seldom diagnosed. The majority of the patients fulfilled the diagnostic criteria for irritable bowel syndrome. In addition, most suffered from several extra-intestinal health complaints and had considerably impaired quality of life. However, psychological factors could explain only approximately 10% of the variance in the patients' symptom severity and 90% of the variance thus remained unexplained. Intolerance to low-digestible carbohydrates was a common problem and abdominal symptoms were replicated by carbohydrate ingestion. A considerable number of patients showed evidence of immune activation by analyses of B-cell activating factor, dendritic cells and "IgE-armed" mast cells. Multiple factors such as immune activation, disturbed intestinal fermentation, enteric dysmotility, post-infectious changes and "local" allergy in the gut as well as psychological disturbances may play a role in the pathophysiology of perceived food hypersensitivity. Hence, our results support the view that management of these patients should be interdisciplinary.
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12
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Pizzuti D, Senzolo M, Buda A, Chiarelli S, Giacomelli L, Mazzon E, Curioni A, Faggian D, De Lazzari F. In vitro model for IgE mediated food allergy. Scand J Gastroenterol 2011; 46:177-87. [PMID: 21028948 DOI: 10.3109/00365521.2010.525716] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND In intestinal food allergy, the non-specificity of gastrointestinal symptoms and the limited access to the reacting organ are the reasons for the limited understanding of the pathophysiology of this disease and the difficulties in establishing an appropriate diagnosis in the individual patient. OBJECTIVE To develop an in vitro model reproducing pathophysiological mechanisms of IgE mediated food allergy. METHODS Distal duodenum biopsies of nine patients with food allergy and 10 control subjects were cultured for 3 h with medium alone and with 1 mg/ml of peptic-tryptic digest of wheat gliadin, wheat albumins, and apple proteins. Each biopsy was used for conventional histological examination and for immunohistochemical detection of IgE-positive cells. We have also analyzed the expression of tight junction proteins, occludin, claudin-1, and ZO-1 by immunoconfocal microscopy. Histamine and tryptase release were measured in the culture medium and collected at 0, 30 min, and 3 h of culture using an enzyme and radio immunoassay, respectively. RESULTS Exposure of small intestinal biopsy specimens of patients with food allergy to food allergens led to a significative increase of IgE-positive cells with a significative increase of histamine and tryptase release and an altered expression of tight junction proteins. No differences were found in intestinal biopsies of controls, cultured with or without food antigens. CONCLUSIONS Small intestinal organ culture is a functional model of food allergy and could be considered as an in vitro oral food challenge, with evident reduction of costs and risks for the patients.
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Affiliation(s)
- Daniela Pizzuti
- Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy.
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Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol 2009; 124:3-20; quiz 21-2. [PMID: 19560575 PMCID: PMC4266989 DOI: 10.1016/j.jaci.2009.05.038] [Citation(s) in RCA: 1210] [Impact Index Per Article: 75.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2009] [Revised: 05/22/2009] [Accepted: 05/27/2009] [Indexed: 02/08/2023]
Abstract
The intestinal epithelium is a single-cell layer that constitutes the largest and most important barrier against the external environment. It acts as a selectively permeable barrier, permitting the absorption of nutrients, electrolytes, and water while maintaining an effective defense against intraluminal toxins, antigens, and enteric flora. The epithelium maintains its selective barrier function through the formation of complex protein-protein networks that mechanically link adjacent cells and seal the intercellular space. The protein networks connecting epithelial cells form 3 adhesive complexes: desmosomes, adherens junctions, and tight junctions. These complexes consist of transmembrane proteins that interact extracellularly with adjacent cells and intracellularly with adaptor proteins that link to the cytoskeleton. Over the past decade, there has been increasing recognition of an association between disrupted intestinal barrier function and the development of autoimmune and inflammatory diseases. In this review we summarize the evolving understanding of the molecular composition and regulation of intestinal barrier function. We discuss the interactions between innate and adaptive immunity and intestinal epithelial barrier function, as well as the effect of exogenous factors on intestinal barrier function. Finally, we summarize clinical and experimental evidence demonstrating intestinal epithelial barrier dysfunction as a major factor contributing to the predisposition to inflammatory diseases, including food allergy, inflammatory bowel diseases, and celiac disease.
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Affiliation(s)
- Katherine R. Groschwitz
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
- Division of Immunobiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Simon P. Hogan
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH
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14
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Zanconato S, Carraro S, Gottardi G, Rusalen F, Alinovi R, Corradi M, Baraldi E. Dissociation between biological and clinical response to oral challenge in children with food allergy. Allergy 2008; 63:1408-10. [PMID: 18782122 DOI: 10.1111/j.1398-9995.2008.01849.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- S Zanconato
- Department of Pediatrics, Allergy and Respiratory Medicine Unit, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
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15
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Abstract
The association between increased tissue eosinophilia and allergic disease is particularly striking in the case of the gastrointestinal tract. About 80% of individuals with eosinophilic gastrointestinal disorders (EGIDs) are atopic, while half of the patients with gastrointestinal allergy show tissue eosinophilia. The function of eosinophils in gastrointestinal allergic disorders is unclear; however, a proinflammatory action is most likely. Cytokines (interleukins 5 and 3, granulocyte-monocyte colony-stimulating factor) and chemokines (eotaxin, RANTES, etc.) released by Th2 lymphocytes, mast cells and other tissue cells have been identified as major regulators of eosinophil chemotaxis and activation, but a convincing mechanism by which eosinophils are activated in an allergen-dependent manner is still lacking. The diagnostic approach comprises both histological and laboratory methods to assess eosinophilia and eosinophil activation, as well as tools to assess the allergic disease while excluding other gastrointestinal diseases such as food intolerances, infections and tumours. Treatment of allergic EGIDs includes elimination or elemental diets and drug therapy using classical anti-allergic agents such as topical corticosteroids and new approaches such as LTD4 receptor antagonists or antibodies against IL-5 or eotaxin.
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16
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Abstract
Biogenic mono-, di- and poly-amines are widely distributed among living organisms. The amines fulfil many important functions in the human body both in the periphery and brain. Some authors suggest that foods rich in biogenic amines, especially histamine, present high health hazards for consumers. However, this is conditional on a range of other factors. The alimentary tract is well equipped with enzymes that inactivate amines and the blood-brain barrier prevents them entering the brain from the circulation. Oxidative deamination, methylation, acetylation and transglutamylation are the degradation pathways which operate efficiently in the stomach, intestines and liver. Particularly important is oxidative deamination. Food histamine poisoning or cheese reaction, manifested itself in patients treated with drugs that inhibit amine oxidases or in patients showing an enterocytic diamine oxidase deficit. It is rather food allergy, which should worry us more, as endogenous histamine release from mast cells is more dangerous. Preventive measures should be undertaken against increases in food allergies.
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Affiliation(s)
- W A Fogel
- Department of Hormone Biochemistry, Medical University of Lodz, 7/9 Zeligowskiego, 90-752 Lodz, Poland.
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17
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Ramos L, Vicario M, Santos J. [Stress-mast cell axis and regulation of gut mucosal inflammation: from intestinal health to an irritable bowel]. Med Clin (Barc) 2007; 129:61-9. [PMID: 17588364 DOI: 10.1157/13106939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The functional gastrointestinal disorders and the irritable bowel syndrome, in particular, represent one of the commonest causes of medical consultation and the most frequent diagnosis raised by the gastroenterologists. Despite their high prevalence, the aetiology and pathophysiology of these functional digestive disorders remains unclear and specific diagnostic markers and clearly effective therapeutic options are lacking as well. These factors generate an important impairment in the quality of life in these patients and a growing sanitary burden. Recent studies showing the presence of low grade intestinal mucosal inflammation along with mast cell hyperplasia may contribute to the development and perpetuation of visceral hypersensitivity and dismotility patterns and epithelial barrier abnormalities, characteristic of the irritable bowel syndrome. In this article we will review the role of the stress-mast cell axis in the modulation of the gut mucosal inflammation and in the pathophysiology of the irritable bowel syndrome.
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Affiliation(s)
- Laura Ramos
- Unidad de Investigación en Enfermedades Digestivas, Servicio de Aparato Digestivo, Hospital Universitari Vall d'Hebron, Departamento de Medicina, Universitat Autònoma de Barcelona, Barcelona, España
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18
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Gilja OH, Hatlebakk JG, Odegaard S, Berstad A, Viola I, Giertsen C, Hausken T, Gregersen H. Advanced imaging and visualization in gastrointestinal disorders. World J Gastroenterol 2007; 13:1408-21. [PMID: 17457973 PMCID: PMC4146926 DOI: 10.3748/wjg.v13.i9.1408] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Advanced medical imaging and visualization has a strong impact on research and clinical decision making in gastroenterology. The aim of this paper is to show how imaging and visualization can disclose structural and functional abnormalities of the gastrointestinal (GI) tract. Imaging methods such as ultrasonography, magnetic resonance imaging (MRI), endoscopy, endosonography, and elastography will be outlined and visualization with Virtual Reality and haptic methods. Ultrasonography is a versatile method that can be used to evaluate antral contractility, gastric emptying, transpyloric flow, gastric configuration, intragastric distribution of meals, gastric accommodation and strain measurement of the gastric wall. Advanced methods for endoscopic ultrasound, three-dimensional (3D) ultrasound, and tissue Doppler (Strain Rate Imaging) provide detailed information of the GI tract. Food hypersensitivity reactions including gastrointestinal reactions due to food allergy can be visualized by ultrasonography and MRI. Development of multi-parametric and multi-modal imaging may increase diagnostic benefits and facilitate fusion of diagnostic and therapeutic imaging in the future.
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Affiliation(s)
- Odd Helge Gilja
- National Centre for Ultrasound in Gastroenterology, Department of Medicine, Haukeland University Hospital, Bergen N-5021, Norway.
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19
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Cattaruzza F, Cenac N, Barocelli E, Impicciatore M, Hyun E, Vergnolle N, Sternini C. Protective effect of proteinase-activated receptor 2 activation on motility impairment and tissue damage induced by intestinal ischemia/reperfusion in rodents. THE AMERICAN JOURNAL OF PATHOLOGY 2006; 169:177-88. [PMID: 16816371 PMCID: PMC1698753 DOI: 10.2353/ajpath.2006.051098] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
We hypothesized that proteinase-activated receptor-2 (PAR(2)) modulates intestinal injuries induced by ischemia/reperfusion. Ischemia (1 hour) plus reperfusion (6 hours) significantly delayed gastrointestinal transit (GIT) compared with sham operation. Intraduodenal injection of PAR(2)-activating peptide SLIGRL-NH(2) significantly accelerated transit in ischemia/reperfusion but not in sham-operated rats. GIT was significantly delayed in ischemia/reperfusion and sham-operated PAR(2)(-/-) mice compared with PAR(2)(+/+). SLIGRL-NH(2) significantly accelerated transit in ischemia/reperfusion in PAR(2)(+/+) but not in PAR(2)(-/-) mice. Prevention of mast cell degranulation with cromolyn, ablation of visceral afferents with capsaicin, and antagonism of calcitonin gene-related peptide (CGRP) and neurokinin-1 receptors with CGRP(8-37) and RP67580, respectively, abolished the SLIGRL-NH(2)-induced stimulatory effect on transit in ischemia/reperfusion. Tissue damage was significantly reduced by SLIGRL-NH(2); this effect was not observed in cromolyn-, capsaicin-, or RP67580-treated rats but was detected following CGRP(8-37). Intestinal PAR(2) mRNA levels were not affected by SLIGRL-NH(2) in ischemia/reperfusion. We propose that PAR(2) modulates GIT and tissue damage in intestinal ischemia/reperfusion by a mechanism dependent on mast cells and visceral afferents. PAR(2) effect on transit might be mediated by CGRP and substance P, whereas the effect on tissue damage appears to involve substance P but not CGRP. PAR(2) might be a signaling system in the neuroimmune communication in intestinal ischemia/reperfusion.
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Affiliation(s)
- Fiore Cattaruzza
- Center for Ulcer Research and Education, Digestive Diseases Research Center, Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, USA
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20
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Raithel M, Weidenhiller M, Abel R, Baenkler HW, Hahn EG. Colorectal mucosal histamine release by mucosa oxygenation in comparison with other established clinical tests in patients with gastrointestinally mediated allergy. World J Gastroenterol 2006; 12:4699-705. [PMID: 16937442 PMCID: PMC4087836 DOI: 10.3748/wjg.v12.i29.4699] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: This study evaluated colorectal mucosal histamine release in response to blinded food challenge-positive and -negative food antigens as a new diagnostic procedure.
METHODS: 19 patients suffering from gastrointestinally mediated allergy confirmed by blinded oral provocation were investigated on grounds of their case history, skin prick tests, serum IgE detection and colorectal mucosal histamine release by ex vivo mucosa oxygenation. Intact tissue particles were incubated/stimulated in an oxygenated culture with different food antigens for 30 min. Specimens challenged with anti-human immunoglobulin E and without any stimulus served as positive and negative controls, respectively. Mucosal histamine release (% of total biopsy histamine content) was considered successful (positive), when the rate of histamine release from biopsies in response to antigens reached more than twice that of the spontaneous release. Histamine measurement was performed by radioimmunoassay.
RESULTS: The median (range) of spontaneous histamine release from colorectal mucosa was found to be 3.2 (0.1%-25.8%) of the total biopsy histamine content. Food antigens tolerated by oral provocation did not elicit mast cell degranulation 3.4 (0.4%-20.7%, P = 0.4), while anti-IgE and causative food allergens induced a significant histamine release of 5.4 (1.1%-25.6%, P = 0.04) and 8.1 (1.5%-57.9%, P = 0.008), respectively. 12 of 19 patients (63.1%) showed positive colorectal mucosal histamine release in accordance with the blinded oral challenge responding to the same antigen (s), while the specificity of the functional histamine release to accurately recognise tolerated foodstuffs was found to be 78.6%. In comparison with the outcome of blinded food challenge tests, sensitivity and specificity of history (30.8% and 57.1%), skin tests (47.4% and 78.6%) or antigen-specific serum IgE determinations (57.9% and 50%) were found to be of lower diagnostic accuracy in gastrointestinally mediated allergy.
CONCLUSION: Functional testing of the reactivity of colorectal mucosa upon antigenic stimulation in patients with gastrointestinally mediated allergy is of higher diagnostic efficacy.
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Affiliation(s)
- M Raithel
- Functional Tissue Diagnostics, Gastroenterology, Department of Medicine I, University Erlangen-Nuremberg, Ulmenweg 18, Erlangen 91054, Germany.
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21
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Leszczyńska J, Łącka A, Bryszewska M. The use of transglutaminase in the reduction of immunoreactivity of wheat flour. FOOD AGR IMMUNOL 2006. [DOI: 10.1080/09540100600870279] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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22
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Prescott VE, Hogan SP. Genetically modified plants and food hypersensitivity diseases: usage and implications of experimental models for risk assessment. Pharmacol Ther 2005; 111:374-83. [PMID: 16364445 DOI: 10.1016/j.pharmthera.2005.10.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2005] [Accepted: 10/13/2005] [Indexed: 10/25/2022]
Abstract
The recent advances in biotechnology in the plant industry have led to increasing crop production and yield that in turn has increased the usage of genetically modified (GM) food in the human food chain. The usage of GM foods for human consumption has raised a number of fundamental questions including the ability of GM foods to elicit potentially harmful immunological responses, including allergic hypersensitivity. To assess the safety of foods derived from GM plants including allergenic potential, the US FDA, Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO), and the EU have developed approaches for evaluation assessment. One assessment approach that has been a very active area of research and debate is the development and usage of animal models to assess the potential allergenicity of GM foods. A number of specific animal models employing rodents, pigs, and dogs have been developed for allergenicity assessment. However, validation of these models is needed and consideration of the criteria for an appropriate animal model for the assessment of allergenicity in GM plants is required. We have recently employed a BALB/c mouse model to assess the potential allergenicity of GM plants. We have been able to demonstrate that this model is able to detect differences in antigenicity and identify aspects of protein post-translational modifications that can alter antigenicity. Furthermore, this model has also enabled us to examine the usage of GM plants as a therapeutic approach for the treatment of allergic diseases. This review discusses the current approaches to assess the allergenic potential of GM food and particularly focusing on the usage of animal models to determine the potential allergenicity of GM foods and gives an overview of our recent findings and implications of these studies.
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Affiliation(s)
- Vanessa E Prescott
- Division of Molecular Bioscience, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
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23
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Abstract
The prevalence of food allergy reaches 3% in the adult population. Chronic gastrointestinal allergy is a rare entity: 4.2% of food allergies in adults, and represents 3.2% of all intestinal disorders. Non-specific symptoms are the rule but eosinophilic gastrointestinal disorders are the subject of much interest. Endoscopy and biopsies of the gastrointestinal tract help the differential diagnoses. Food allergy is suspected from the patient's history leading to skin tests and laboratory tests identifying a sensitization but allergy is only confirmed by standardized challenges or eviction diets over a sufficiently long period. New types of investigations coupling oral challenges to foods to gastroenterological techniques should be studied further.
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24
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Abstract
Food allergies are increasing in incidence, and the variety of triggering antigens is widening. There is also an increased recognition of the breadth of immunologically mediated responses to dietary antigens; the area of non-IgE-mediated food allergy is belatedly acquiring scientific respectability, aided by improved clinical recognition and basic scientific studies. The role of mucosal mast cells and eosinophils in intestinal allergic responses is now better recognized, and conditions such as eosinophilic oesophagitis are more prevalent than previously thought. However, the diagnostic difficulties of non-IgE-mediated allergies remain challenging.
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Affiliation(s)
- Simon H Murch
- Warwick Medical School, Clinical Sciences Research Institute, Coventry, UK.
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25
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Berstad A, Arslan G, Lind R, Florvaag E. Food hypersensitivity-immunologic (peripheral) or cognitive (central) sensitisation? Psychoneuroendocrinology 2005; 30:983-9. [PMID: 15979811 DOI: 10.1016/j.psyneuen.2005.04.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2004] [Revised: 03/30/2005] [Accepted: 04/01/2005] [Indexed: 01/01/2023]
Abstract
Patients with food hypersensitivity suffer poor quality of life and several unexplained health complaints, both abdominal and extra-abdominal. Part of the suffering is due to healthcare providers' neglect and poor insight, allowing a strong position for alternative medicine. Distinguishing food allergy from functional and organic disorders can be extremely difficult. We have found examination of faecal calprotectin and gut permeability to be useful for excluding organic disease, whilst conventional provocation tests for positive diagnosis of food hypersensitivity are cumbersome. Our new ultrasound provocation test has been promising, but we acknowledge that much work remains to be done before its sensitivity and specificity can be finally established. The majority of patients with self-reported food hypersensitivity have a non-allergic hypersensitivity disorder. We suggest that cognitive-emotional sensitisation at the brain level, and not peripheral (immunological) sensitisation, is a major pathogenetic mechanism by which the patients' various abdominal and extra-abdominal health complaints are generated. Extensive activation of cognitive networks might be triggered by peripheral sensory mechanisms, often misinterpreted as 'food allergy'. Clearly, the approach to patients with food hypersensitivity should be interdisciplinary.
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Affiliation(s)
- Arnold Berstad
- Division of Gastroenterology, Institute of Medicine, Haukeland University Hospital, 5021 Bergen, Norway.
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26
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Abstract
Mast cells (MCs) are major effector cells of immunoglobulin E (IgE)-mediated allergic inflammation. However, it has become increasingly clear that they also play important roles in diverse physiological and pathological processes. Recent advances have focused on the importance of MCs in both innate and adaptive immune responses and have fostered studies of MCs beyond the myopic focus on allergic reactions. MCs possess a variety of surface receptors and may be activated by inflammatory mediators, IgE, IgG, light chains, complement fragments, proteases, hormones, neuropeptides, and microbial products. Following activation, they produce a plethora of pro-inflammatory mediators and participate in inflammatory reactions in many organs. This review focuses on the role of MCs in inflammatory reactions in mucosal surfaces with particular emphasis on their role in respiratory and gastrointestinal inflammatory conditions.
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Affiliation(s)
- Harissios Vliagoftis
- Department of Medicine, Pulmonary Research Group, University of Alberta, Edmonton, Alberta, Canada
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27
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Jacob C, Yang PC, Darmoul D, Amadesi S, Saito T, Cottrell GS, Coelho AM, Singh P, Grady EF, Perdue M, Bunnett NW. Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins. J Biol Chem 2005; 280:31936-48. [PMID: 16027150 DOI: 10.1074/jbc.m506338200] [Citation(s) in RCA: 252] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Tight junctions between intestinal epithelial cells prevent ingress of luminal macromolecules and bacteria and protect against inflammation and infection. During stress and inflammation, mast cells mediate increased mucosal permeability by unknown mechanisms. We hypothesized that mast cell tryptase cleaves protease-activated receptor 2 (PAR2) on colonocytes to increase paracellular permeability. Colonocytes expressed PAR2 mRNA and responded to PAR2 agonists with increased [Ca2+]i. Supernatant from degranulated mast cells increased [Ca2+]i in colonocytes, which was prevented by a tryptase inhibitor, and desensitized responses to PAR2 agonist, suggesting PAR2 cleavage. When applied to the basolateral surface of colonocytes, PAR2 agonists and mast cell supernatant decreased transepithelial resistance, increased transepithelial flux of macromolecules, and induced redistribution of tight junction ZO-1 and occludin and perijunctional F-actin. When mast cells were co-cultured with colonocytes, mast cell degranulation increased paracellular permeability of colonocytes. This was prevented by a tryptase inhibitor. We determined the role of ERK1/2 and of beta-arrestins, which recruit ERK1/2 to PAR2 in endosomes and retain ERK1/2 in the cytosol, on PAR2-mediated alterations in permeability. An ERK1/2 inhibitor abolished the effects of PAR2 agonist on permeability and redistribution of F-actin. Down-regulation of beta-arrestins with small interfering RNA inhibited PAR2-induced activation of ERK1/2 and suppressed PAR2-induced changes in permeability. Thus, mast cells signal to colonocytes in a paracrine manner by release of tryptase and activation of PAR2. PAR2 couples to beta-arrestin-dependent activation of ERK1/2, which regulates reorganization of perijunctional F-actin to increase epithelial permeability. These mechanisms may explain the increased epithelial permeability of the intestine during stress and inflammation.
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Affiliation(s)
- Claire Jacob
- Department of Surgery, University of California, San Francisco, California 94143, USA
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Bischoff S, Crowe SE. Gastrointestinal food allergy: new insights into pathophysiology and clinical perspectives. Gastroenterology 2005; 128:1089-113. [PMID: 15825090 DOI: 10.1053/j.gastro.2004.08.015] [Citation(s) in RCA: 179] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Adverse reactions to food that result in gastrointestinal symptoms are common in the general population; while only a minority of such individuals will have symptoms due to immunologic reactions to foods, gastrointestinal food allergies do exist in both children and adults. These immune reactions are mediated by immunoglobulin E-dependent and -independent mechanisms involving mast cells, eosinophils, and other immune cells, but the complexity of the underlying mechanisms of pathogenesis have yet to be fully defined. Knowledge of the spectrum of adverse reactions to foods that affect the digestive system, including gastrointestinal food allergy, is essential to correctly diagnose and manage the subset of patients with immunologically mediated adverse reactions to foods. Potentially fatal reactions to food necessitate careful instruction and monitoring on the part of health care workers involved in the care of individuals at risk of anaphylaxis. New methods of diagnosis and novel strategies for treatment, including immunologic modulation and the development of hypoallergenic foods, are exciting developments in the field of food allergy.
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Affiliation(s)
- Stephan Bischoff
- Department of Gastroenterology, University Medical School of Hannover, Germany
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Santos J, Guilarte M, Alonso C, Malagelada JR. Pathogenesis of irritable bowel syndrome: the mast cell connection. Scand J Gastroenterol 2005; 40:129-40. [PMID: 15764142 DOI: 10.1080/00365520410009410] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Javier Santos
- Digestive Diseases Research Unit, Hospital General Vall d'Hebron, Autonomous University of Barcelona, ES-08035 Barcelona, Spain.
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30
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Saito T, Bunnett NW. Protease-activated receptors: regulation of neuronal function. Neuromolecular Med 2005; 7:79-99. [PMID: 16052040 DOI: 10.1385/nmm:7:1-2:079] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2004] [Revised: 02/13/2005] [Accepted: 02/17/2005] [Indexed: 12/20/2022]
Abstract
Certain serine proteases from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast-cell tryptase, neutrophil proteinase 3), and from many other cell types (e.g., trypsins) can specifically signal to cells by cleaving protease-activated receptors (PARs), a family of four G protein-coupled receptors. Proteases cleave PARs at specific sites within the extracellular amino-terminus to expose amino-terminal tethered ligand domains that bind to and activate the cleaved receptors. The proteases that activate PARs are often generated and released during injury and inflammation, and activated PARs orchestrate tissue responses to injury, including hemostasis, inflammation, pain, and repair. This review concerns protease and PAR signaling in the nervous system. Neurons of the central and peripheral nervous systems express all four PARs. Proteases that may derive from the circulation, inflammatory cells, or neural tissues can cleave PARs on neurons and thereby activate diverse signaling pathways that control survival, morphology, release of neurotransmitters, and activity of ion channels. In this manner proteases and PARs regulate neurodegeneration, neurogenic inflammation, and pain transmission. Thus, PARs may participate in disease states and PAR antagonists or agonists may be useful therapies for certain disorders.
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Affiliation(s)
- Toshiyuki Saito
- Department of Surgery, University of California, San Francisco, CA, USA
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31
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Vergnolle N. Modulation of visceral pain and inflammation by protease-activated receptors. Br J Pharmacol 2004; 141:1264-74. [PMID: 15051630 PMCID: PMC1574902 DOI: 10.1038/sj.bjp.0705750] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2004] [Revised: 02/19/2004] [Accepted: 02/19/2004] [Indexed: 12/15/2022] Open
Abstract
The gastrointestinal (GI) tract is exposed to a large array of proteases, under both physiological and pathophysiological conditions. The discovery of G protein-coupled receptors activated by proteases, the protease-activated receptors (PARs), has highlighted new signaling functions for proteases in the GI tract, particularly in the domains of inflammation and pain mechanisms. Activation of PARs by selective peptidic agonists in the intestine or the pancreas leads to inflammatory events and changes in visceral nociception, suggesting that PARs could be involved in the modulation of visceral pain and inflammation. PARs are present in most of the cells that are potentially actors in the generation of irritable bowel syndrome (IBS) symptoms. Activation of PARs interferes with several pathophysiological factors that are involved in the generation of IBS symptoms, such as altered motility patterns, inflammatory mediator release, altered epithelial functions (immune, permeability and secretory) and altered visceral nociceptive functions. Although definitive studies using genetically modified animals, and, when available, pharmacological tools, in different IBS and inflammatory models have not yet confirmed a role for PARs in those pathologies, PARs appear as promising targets for therapeutic intervention in visceral pain and inflammation processes.
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Affiliation(s)
- Nathalie Vergnolle
- Department of Pharmacology and Therapeutics, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N4N1.
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Abstract
Proteases acting at the surface of cells generate and destroy receptor agonists and activate and inactivate receptors, thereby making a vitally important contribution to signal transduction. Certain serine proteases that derive from the circulation (e.g., coagulation factors), inflammatory cells (e.g., mast cell and neutrophil proteases), and from multiple other sources (e.g., epithelial cells, neurons, bacteria, fungi) can cleave protease-activated receptors (PARs), a family of four G protein-coupled receptors. Cleavage within the extracellular amino terminus exposes a tethered ligand domain, which binds to and activates the receptors to initiate multiple signaling cascades. Despite this irreversible mechanism of activation, signaling by PARs is efficiently terminated by receptor desensitization (receptor phosphorylation and uncoupling from G proteins) and downregulation (receptor degradation by cell-surface and lysosomal proteases). Protease signaling in tissues depends on the generation and release of proteases, availability of cofactors, presence of protease inhibitors, and activation and inactivation of PARs. Many proteases that activate PARs are produced during tissue damage, and PARs make important contributions to tissue responses to injury, including hemostasis, repair, cell survival, inflammation, and pain. Drugs that mimic or interfere with these processes are attractive therapies: selective agonists of PARs may facilitate healing, repair, and protection, whereas protease inhibitors and PAR antagonists can impede exacerbated inflammation and pain. Major future challenges will be to understand the role of proteases and PARs in physiological control mechanisms and human diseases and to develop selective agonists and antagonists that can be used to probe function and treat disease.
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Brandt EB, Strait RT, Hershko D, Wang Q, Muntel EE, Scribner TA, Zimmermann N, Finkelman FD, Rothenberg ME. Mast cells are required for experimental oral allergen-induced diarrhea. J Clin Invest 2004; 112:1666-77. [PMID: 14660743 PMCID: PMC281649 DOI: 10.1172/jci19785] [Citation(s) in RCA: 307] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Gastrointestinal allergic disorders represent a diverse spectrum of inflammatory diseases that are occurring with increasing incidence and severity. An essential question concerning these disorders is to determine the specific cells and mediators responsible for specific clinical manifestations. With this in mind, we developed a murine model of oral allergen-induced intestinal inflammation accompanied by strong Th2-associated humoral and cellular responses and focused on the immunopathogenesis of allergic diarrhea. Exposure of OVA/alum-sensitized mice to repeated doses of intragastric OVA induced genetically restricted, dose-dependent, acute diarrhea associated with increased intestinal permeability, eosinophilia, and mastocytosis. Mice developed limited systemic manifestations of anaphylaxis, even though they developed marked intestinal mucosal mast cell degranulation. Notably, experiments involving mast cell depletion (with anti-c-kit mAb), anti-IgE treatment, and Fc epsilon RI-deficient mice indicated a critical effector role for mast cells in mediating allergic diarrhea. Furthermore, allergic diarrhea was dependent upon synergistic signaling induced by serotonin and platelet-activating factor (PAF), but not histamine. These results demonstrate that oral allergen-induced diarrhea associated with experimental Th2 intestinal inflammation is largely mast cell, IgE, serotonin, and PAF dependent.
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Affiliation(s)
- Eric B Brandt
- Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA
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34
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Cenac N, Coelho AM, Nguyen C, Compton S, Andrade-Gordon P, MacNaughton WK, Wallace JL, Hollenberg MD, Bunnett NW, Garcia-Villar R, Bueno L, Vergnolle N. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. THE AMERICAN JOURNAL OF PATHOLOGY 2002. [PMID: 12414536 DOI: 10.1016/s0002-944010)64466-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Proteinase-activated receptor (PAR)-2, a G-protein-coupled receptor for trypsin and mast cell tryptase, is highly expressed in the intestine. Luminal trypsin and tryptase are elevated in the colon of inflammatory bowel disease patients. We hypothesized that luminal proteinases activate PAR-2 and induce colonic inflammation. Mice received intracolonically PAR-2 agonists (trypsin, tryptase, and a selective PAR-2-activating peptide) or control drugs (boiled enzymes, inactive peptide) and inflammatory parameters were followed at various times after this treatment. Colonic administration of PAR-2 agonists up-regulated PAR-2 expression and induced an inflammatory reaction characterized by granulocyte infiltration, increased wall thickness, tissue damage, and elevated T-helper cell type 1 cytokine. The inflammation was maximal between 4 and 6 hours and was resolved 48 hours after the intracolonic administration. PAR-2 activation also increased paracellular permeability of the colon and induced bacterial trans-location into peritoneal organs. These proinflammatory and pathophysiological changes observed in wild-type mice were not detected in PAR-2-deficient mice. Luminal proteinases activate PAR-2 in the mouse colon to induce inflammation and disrupt the integrity of the intestinal barrier. Because trypsin and tryptase are found at high levels in the colon lumen of patients with Crohn's disease or ulcerative colitis, our data may bear directly on the pathophysiology of human inflammatory bowel diseases.
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Affiliation(s)
- Nicolas Cenac
- Neuro-Gastroenterology and Nutrition Unit, Institut National de la Recherche Agronomique, Toulouse, France
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Larsen P, Schleihauf E, Yu H, Prior T, Rangachari PK. Calcium-stimulated short-circuit currents in the canine proximal colonic epithelium: effects of DK-PGD2, a metabolite of prostaglandin D2. Can J Physiol Pharmacol 2002; 80:1085-94. [PMID: 12489928 DOI: 10.1139/y02-139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Prostaglandin D2 (PGD2) has marked inhibitory effects on the canine proximal colonic epithelium set up in Ussing chambers. These effects involved a receptor that is pharmacologically distinct from the classical DP, presumably the recently identified CRTH2/DP2 variety. The mechanism underlying these effects was studied using 13,14-dihydro-15-keto-PGD2 (DK-PGD2), a stable metabolite of the parent prostanoid. The metabolite quickly reversed short circuit currents (I(sc)) stimulated by diverse agonists. Greater inhibitory effects were seen with stimulants such as carbachol and cyclopiazonic acid (CPA) rather than with forskolin or protein kinase A activators. Since the same stimulants were differentially affected by removal and replacement of serosal Ca2+, we tested the possibility that the prostanoid inhibited basolateral Ca2+ entry. In the absence of serosal Ca2+, tissues primed with CPA demonstrated concentration-dependent increases in I(sc), to cumulative additions of Ca2+ or Sr2+, though the former was more potent. Cl- removal and pretreatment with bumetanide virtually abolished responses, suggesting that the increase in I(sc) reflected Ca2+ dependent Cl- secretion. Though responses were insensitive to the L-type channel antagonist, verapamil, a marked inhibition was seen in the presence of metal cations (Gd3+, Cd2+, and La3+). Pretreatment with DK-PGD2 inhibited responses to Ca2+ in CPA-primed tissues. Thus, basolateral Ca2+ entry via store-operated Ca2+ channels may be the locus for the inhibitory effects of PGD2 in this tissue. These results could indicate a potential transduction mechanism for the novel DP receptor variously called CRTH2 or DP2.
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Affiliation(s)
- P Larsen
- Royal Danish School of Pharmacy, Universitetsparken 2, DK 2100, Copenhagen, Denmark
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36
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Cenac N, Coelho AM, Nguyen C, Compton S, Andrade-Gordon P, MacNaughton WK, Wallace JL, Hollenberg MD, Bunnett NW, Garcia-Villar R, Bueno L, Vergnolle N. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. THE AMERICAN JOURNAL OF PATHOLOGY 2002; 161:1903-15. [PMID: 12414536 PMCID: PMC1850779 DOI: 10.1016/s0002-9440(10)64466-5] [Citation(s) in RCA: 290] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Proteinase-activated receptor (PAR)-2, a G-protein-coupled receptor for trypsin and mast cell tryptase, is highly expressed in the intestine. Luminal trypsin and tryptase are elevated in the colon of inflammatory bowel disease patients. We hypothesized that luminal proteinases activate PAR-2 and induce colonic inflammation. Mice received intracolonically PAR-2 agonists (trypsin, tryptase, and a selective PAR-2-activating peptide) or control drugs (boiled enzymes, inactive peptide) and inflammatory parameters were followed at various times after this treatment. Colonic administration of PAR-2 agonists up-regulated PAR-2 expression and induced an inflammatory reaction characterized by granulocyte infiltration, increased wall thickness, tissue damage, and elevated T-helper cell type 1 cytokine. The inflammation was maximal between 4 and 6 hours and was resolved 48 hours after the intracolonic administration. PAR-2 activation also increased paracellular permeability of the colon and induced bacterial trans-location into peritoneal organs. These proinflammatory and pathophysiological changes observed in wild-type mice were not detected in PAR-2-deficient mice. Luminal proteinases activate PAR-2 in the mouse colon to induce inflammation and disrupt the integrity of the intestinal barrier. Because trypsin and tryptase are found at high levels in the colon lumen of patients with Crohn's disease or ulcerative colitis, our data may bear directly on the pathophysiology of human inflammatory bowel diseases.
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Affiliation(s)
- Nicolas Cenac
- Neuro-Gastroenterology and Nutrition Unit, Institut National de la Recherche Agronomique, Toulouse, France
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Arslan G, Ødegaard S, Elsayed S, Florvaag E, Berstad A. Food allergy and intolerance: response to intestinal provocation monitored by endosonography. EUROPEAN JOURNAL OF ULTRASOUND : OFFICIAL JOURNAL OF THE EUROPEAN FEDERATION OF SOCIETIES FOR ULTRASOUND IN MEDICINE AND BIOLOGY 2002; 15:29-36. [PMID: 12044850 DOI: 10.1016/s0929-8266(02)00004-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVE Objective assessment of adverse reactions to food is a long-felt want. We report our preliminary experience with a new endosonographic allergen provocation test. METHODS Twenty patients were examined, seven patients having food allergy and 13 having food intolerance. The duodenal mucosa was challenged with allergen extracts via a nasoduodenal tube. The responses were recorded using a miniprobe for endosonography through the tube. Thereafter, intestinal lavage was performed by giving 2 l PEG solution containing micro Ci (51)CrEDTA. The gut lavage fluid and urine for 5 h were collected. RESULTS Increased mucosal thickness in response to provocation was recorded in 11 patients, but not more often or pronounced in the allergic than in the intolerance group. Interestingly, increased mucosal thickness associated with a new echogenic layer was seen in two patients and a sustained duodenal contraction, lasting 15-20 min associated with pain, in another two. Intestinal permeability and inflammatory mediators were not significantly different in the two groups. CONCLUSION In patients with self-reported adverse reactions to food abnormal responses to duodenal provocation may be recognised by endosonography. However, neither endosonography nor intestinal permeability or faecal calprotectin responses were able to distinguish between food allergy and intolerance. Sustained duodenal contractions in response to food might be a cause of abdominal pain.
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Affiliation(s)
- Gülen Arslan
- gulen.Medical Department, Division of Gastroenterology, Institute of Medicine, Haukeland University Hospital, University of Bergen, N-5021, Bergen, Norway.
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38
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Vergara P, Saavedra Y, Juanola C. Neuroendocrine control of intestinal mucosal mast cells under physiological conditions. Neurogastroenterol Motil 2002; 14:35-42. [PMID: 11874552 DOI: 10.1046/j.1365-2982.2002.00300.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Mast cells are involved in the pathogenesis of both allergies to food and inflammatory bowel disorders. In addition, there are several lines of evidence suggesting that mucosal mast cells also respond to intraluminal stimuli. Our aim was to identify neuroendocrine stimuli that could modify mucosal mast cell activity in the rat. Anaesthetized rats were prepared for duodenal perfusion and mast cell activation was measured by analysis of RMCP II concentration in the duodenal perfusate. Either buffered saline solution or a 5% ovalbumin hydrolysate (OVH) solution was infused into the duodenum. Subdiaphragmatic vagotomy or afferent ablation by intraluminal treatment with capsaicin diminished RMCP II concentration in basal conditions and significantly reduced the response to OVH, which in control animals induced a three-fold increase of the protease. The noradrenergic blockers phentholamine and propranolol significantly diminished RMCP II concentration in basal conditions and completely blocked the response to OVH. Intravenous infusion of cholecystokinin-related peptides also induced a response of mast cells. However, the response was different depending on the peptide. CCK-8 induced a slight increase of RMCP II, whereas both CCK-33 and gastrin induced a significant decrease in mast cell activity. These results show that intraluminal content modulates mucosal mast cell activity by complex mechanisms involving both nervous and endocrine pathway.
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Affiliation(s)
- P Vergara
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Spain.
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Poonyachoti S, Brown DR. delta-opioid receptors inhibit neurogenic intestinal secretion evoked by mast cell degranulation and type I hypersensitivity. J Neuroimmunol 2001; 112:89-96. [PMID: 11108937 DOI: 10.1016/s0165-5728(00)00387-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Histamine and the mast cell degranulator, compound 48/80 produced elevations in short-circuit current, an electrical measure of active anion secretion, across porcine ileal mucosa sheets mounted in Ussing chambers. Luminally-applied beta-lactoglobulin produced similar effects in mucosal sheets from cow's milk-sensitized pigs. Their secretory effects were attenuated by blockers of H(1)-histamine receptors, neuronal conduction or epithelial Na(+)/K(+)/Cl(-) cotransport. The delta-opioid agonist [D-Pen(2), D-Pen(5)]enkephalin suppressed mucosal responses to these substances in a naltrindole-reversible manner. Furthermore, submucosal mast cells and delta-opioid receptor-immunoreactive nerve fibers were observed in close juxtaposition. Intestinal neural pathways linking immediate hypersensitivity to secretory host defense appear to express inhibitory delta-opioid receptors.
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Affiliation(s)
- S Poonyachoti
- Department of Veterinary PathoBiology, University of Minnesota Academic Health Center, 1988 Fitch Avenue, St. Paul, Minneapolis, MN 55108-6010, USA
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40
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Abstract
There has been considerable recent broadening of basic concepts of intestinal food allergy, in particular the importance of non-IgE-mediated mechanisms. The traditional emphasis on IgE-mediated allergy now appears inappropriate in light of current studies of the basic mechanisms of oral tolerance to dietary antigen and of increasing recognition of the requirement for early infectious challenge in the prevention of allergic sensitization. This major change in emphasis has been forced both by basic scientific studies and by recognition of novel patterns of food allergic disease within the pediatric population, in which rapid increase in food-allergic sensitization has been noted in the last decade and previously rare phenomena such as multiple food allergies and sensitization of exclusively breast-fed infants to antigens eaten by the mother have become commonplace. It is thus emerging that the possession of exaggerated IgE responses may not be the direct cause of food allergic sensitization but may ensure that such sensitization is clinically obvious. Those without such immediate responses have a complex of symptoms, including diet-responsive eczema and a marked disturbance of intestinal motility. The clear demographic links with socioeconomic privilege and relative protection from gastrointestinal infarctions concord with recent murine data suggesting an obligatory input from innate immune responses to the gut flora in the establishment of oral tolerance.
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Affiliation(s)
- S H Murch
- Royal Free and University College School of Medicine, London, UK.
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41
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Abstract
Food allergy or hypersensitivity is defined as an adverse reaction to food protein which is immune mediated. Without standard definitions and reliable tests for many forms of allergic disease of the bowel, studies are difficult to interpret. The proceedings of a recent workshop on the classification of adverse immunologic reactions to foods provide the framework for this review. Recent studies have helped define the clinical spectrum and natural history of IgE and non-IgE-mediated food allergy, and provide insight into underlying pathophysiology and dietary management.
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Affiliation(s)
- C J Justinich
- Department of Pediatrics, University of Connecticut School of Medicine, Connecticut Children's Medical Center, Hartford 06106, USA.
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