PO Box 2345, Beijing 100023, China World J Gastroenterol 2005;11(19):2851-2857 www.wjgnet.com World Journal of Gastroenterology ISSN 1007-9327 [email protected] © 2005 The WJG Press and Elsevier Inc. All rights reserved. ELSEVIER • REVIEW • Roles of histamine and its receptors in allergic and inflammatory bowel diseases Hua Xie, Shao-Heng He Hua Xie, Shao-Heng He, Allergy and Inflammation Research these diseases. The prevalence of allergy has shown an Institute, Shantou University Medical College, Shantou 515031, increase in the last few years. At present it affects about Guangdong Province, China 30-40% of world population and has become one of the Supported by the Li Ka Shing Foundation, Hong Kong, China, No. st C0200001; the Planned Science and Technology Project of Guangdong three key diseases in the 21 century. Province, China, No. 2003B31502 Since last two decades, inflammation has been known Correspondence to: Professor Shao-Heng He, Allergy and as the main pathophysiological characteristics of allergy. Inflammation Research Institute, Shantou University Medical Mast cells are major participants of allergic reactions, and College, 22 Xin-Ling Road, Shantou 515031, Guangdong Province, their activation may be all that is sufficient and necessary China. [email protected] for the rapid development of microvascular leakage and Telephone: +86-754-8900405 Fax: +86-754-8900192 tissue edema in sensitized subjects exposed to allergen. Received: 2004-04-30 Accepted: 2004-07-15 Mast cell is a key source of potent mediators of allergic inflammation including histamine, neutral proteinases, proteoglycans, prostaglandin D2, leukotriene C4 and certain [1] Abstract cytokines . Among them, histamine is the first mediator implicated in the pathophysiological changes of asthma when Mast cell has a long history of being recognized as an it was found to mimic several features of the disease, and important mediator-secreting cell in allergic diseases, and James received the Nobel Prize for medicine in 1988 for has been discovered to be involved in IBD in last two decades. Histamine is a major mediator in allergic diseases, his outstanding achievements in histamine research. Recently, and has multiple effects that are mediated by specific some novel findings concerning histamine, mast cell and surface receptors on target cells. Four types of histamine allergy or IBD have been reported and are summarized receptors have now been recognized pharmacologically herein. and the first three are located in the gut. The ability of histamine receptor antagonists to inhibit mast cell THE ROLES OF MAST CELLS IN ALLERGIC degranulation suggests that they might be developed as a group of mast cell stabilizers. Recently, a series of DISEASES experiments with dispersed colon mast cells suggested Mast cell has a long history of being recognized as an that there should be at least two pathways in man for important mediator-secreting cell in allergic diseases. It has mast cells to amplify their own activation-degranulation a high capacity to release an array of both preformed and signals in an autocrine or paracrine manner. In a word, histamine is an important mediator in allergic diseases newly generated mediators in response to environmental and IBD, its antagonists may be developed as a group of stimuli, especially allergen exposure. Cross linkage of IgE mast cell stabilizers to treat these diseases. bound to high affinity receptors on mast cells not only results in the rapid release of autacoid mediators, but also the © 2005 The WJG Press and Elsevier Inc. All rights reserved. sustained synthesis and release of cytokines, chemokines and growth factors. Key words: Allergic diseases; Immunoglobulin Mature mast cells are ubiquitous in human tissues and can thus participate in the processes of inflammation at Xie H, He SH. Roles of histamine and its receptors in allergic different sites. Systemic anaphylaxis, a life-threatening disease, and inflammatory bowel diseases. World J Gastroenterol involves mast cell activation in multiple organs. In bronchial 2005; 11(19): 2851-2857 asthma, a disease characterized by widespread but potentially http://www.wjgnet.com/1007-9327/11/2851.asp reversible bronchial obstruction, there are increased numbers of mast cells and a greater degree of continuous mast cell degranulation in bronchoalveolar lavage fluid from asthmatics compared with normal controls. Increased mast cell numbers INTRODUCTION and evidence for continuous degranulation of mast cells Allergic diseases including allergic asthma, allergic rhinitis, have been observed also in nasal lavage fluid and the nasal food allergy, drug allergy, and allergic atopic eczema/dermatitis epithelium of the patients with allergic rhinitis. syndrome, etc. are a group of common disorders which are Recent population surveys have estimated rates of regarded to be mediated by immunoglobulin (Ig) E. People prevalence of perceived food hypersensitivity of 12-20% at all ages in countries throughout the world suffer from in adults though this rate varied largely across different 2852 ISSN 1007-9327 CN 14-1219/ R World J Gastroenterol May 21, 2005 Volume 11 Number 19 countries (e.g. Spain, 4.6%; Australia, 19.1%) despite a histamine metabolism was found in collagenous colitis and common standardized methodology[2]. Intestinal mast cells, food allergy[8], and increased level of N-methylhistamine, a as well as eosinophils, have been shown to be involved in stable metabolite of the mast cell mediator histamine, was the pathogenesis of food-allergy-related enteropathy. detected in the urine of patients with active Crohn’s Adverse drug reactions are common, but only 6-10% disease or ulcerative colitis[9,10]. Since increased level of N- are immunologically mediated[3]. Although allergic drug methylhistamine was significantly correlated to clinical disease reactions are just one type of adverse reactions to medications, activity, the above findings further strongly suggest the active they are clinically very important because of the morbidity involvement of histamine in the pathogenesis of these diseases. and mortality they cause. Allergic drug reactions may result Interestingly, mast cells originated from the resected in anaphylaxis, urticaria, bronchospasm and angioedema. colon of active Crohn’s disease or ulcerative colitis were During these reactions, allergic drugs cause direct histamine able to release more histamine than those from normal release from mast cells. colon when being stimulated with an antigen, colon-derived murine epithelial cell-associated compounds[11]. Similarly, cultured colorectal endoscopic samples from patients with THE ROLES OF HISTAMINE IN ALLERGIC IBD secreted more histamine towards substance P alone DISEASE or substance P with anti-IgE than the samples from normal control subjects under the same stimulation[12]. In a guinea Since its discovery in 1911, histamine has been recognized pig model of intestinal inflammation induced by cow’s milk as a major mediator in allergic diseases. Histamine is a proteins and trinitrobenzene sulfonic acid, both IgE titers primary amine synthesized from histidine in the Golgi and histamine levels were higher than normal control apparatus, from where it is transported to the granule for animals[13]. storage in ionic association with the acidic residues of the As a proinflammatory mediator, histamine is selectively glycosaminoglycans side chains of heparin and with located in the granules of human mast cells and basophils proteinases. The histamine content of mast cells dispersed and released from these cells upon degranulation. To date, from human lung and skin is similar at 2-5 pg/cell, and the a total of three histamine receptors H1, H2 and H3 have histamine stored ranges from 10 to 12 µg/g in both tissues. been discovered in human gut[14,15]. It proves that there are Following mast cell activation, histamine is rapidly dissociated some specific targets that histamine can work on in intestinal from the granule matrix by exchange with sodium ions in tract. Histamine was found to cause a transient concentration- the extracellular environment. Proteoglycans comprise the dependent increase in short-circuit current, a measure of total major supporting matrix of the mast cell granule with the ion transport across the epithelial tissue in the gut[16]. This sulfate groups binding to histamine, proteinases and acid could be due to that histamine interacts with H1 receptors hydrolases. As only mast cells and basophils contain to increase the secretion of Na and Cl ions from epithelium[17]. histamine in man (apart from histaminergic nerve), and there The finding that H1-receptor antagonist pyrilamine was are few basophils in human tissues, histamine can be used able to inhibit anti-IgE induced histamine release and ion as a marker of mast cell degranulation. transport[18] suggested further that histamine is a crucial The allergic process is believed to consist of two phases: mediator responsible for diarrhea in IBD and food allergy. early and late. The early phase reaction is mainly induced The ability of SR140333, a potent NK1 antagonist in reducing by histamine released from mast cells. Histamine is a potent mucosal ion transport, was most likely due to its inhibitory vasoactive agent, bronchial smooth muscle constrictor, and actions on histamine release from colon mast cells[19]. stimulant of nociceptive itch nerves. In addition to its known effects on glands, vessels and sensory nerves, recent data have provided further evidence of