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ISSN 1007-9327 CN 14-1219/R  World J Gastroenterol  2007 June 14;13(22): 3027-3030

Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: Stress, intestinal hyperpermeability and inflammation

Ashkan Farhadi, Jeremy Z Fields, Ali Keshavarzian

 

 


 


 

Ashkan Farhadi, Jeremy Z Fields, Ali Keshavarzian, Division of Digestive disease and Nutrition, Rush University Medical Center, Chicago, IL, United States

Correspondence to: Ashkan Farhadi, MD, MS, FACG, Section  of Gastroenterology and Nutrition, 1725 W. Harrison Street, Suite  206, Professional Building, Rush University Medical Center, Chicago, IL 60612,

United States. ashkan_farhadi@rush.edu

Telephone: +1-312-9425861  Fax: +1-312-5633883

Received: 2007-03-15          Accepted: 2007-04-26

  

Abstract

Mast cells (MC) are pivotal elements in several physiological and immunological functions of the gastro-intestinal (GI) tract. MC translate the stress signals that has been transmitted through brain gut axis into release of proinflammatory mediators that can cause stimulation of nerve endings that could affect afferent nerve terminals and change their perception, affect intestinal motility, increase intestinal hyperpermeability and, in susceptible individuals, modulate the inflammation. Thus, it is not surprising that MC are an important element in the pathogenesis of inflammatory bowel disease and non inflammatory GI disorders such as IBS and mast cell enterocolitis.

 

2007 The WJG Press. All rights reserved.

 

Key words: Mast cells; Intestinal permeability; Stress, Inflammatory bowel disease; Irritable bowel syndrome; Intestinal barrier

 

Farhadi A, Fields JZ, Keshavarzian A. Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: Stress, intestinal hyperpermeability and inflammation. World J Gastroenterol 2007; 13(22): 3027-3030

 

 http://www.wjgnet.com/1007-9327/13/3027.asp

  

Mast cells (MC) of the intestinal mucosa are key elements in several biological processes. For example, they are an important component in allergic responses to exogenous antigens and they act in concert with IgE to increase the release of MC mediators in allergic reactions. Recently the role of MC in non-allergic phenomena has been getting more attention. In fact, MC are an important component of the mucosal innate immune response[1]. Thus, it is not surprising that these cells are involved in several inflammatory disease processes such as bronchiectasis[2], idiopathic pulmonary fibrosis[3], bronchiolitis obliterans with organizing pneumonia[4], sarcoidosis[5], glomerulonephritis[6] and rheumatoid arthritis[7]. In the gastrointestinal (GI) tract, similar to other mucosal surfaces, Mast cells are part of the allergic response to luminal antigens and of protective innate immune responses.

Mast cells in the GI tract also serve as end effectors of the brain-gut axis (BGA). The BGA is composed of main regulatory cores in the central nervous system that are connected to peripheral (enteric and autonomic) nervous systems through a series of networks of afferent and efferent nerves. One role of the BGA is to transmit information from the brain to the GI tract regarding the perception and/or experience of stressful events.

Upon activation of the BGA by stress, Mast cells release a wide range of neurotransmitters and other proinflammatory molecules. These mediators include histamine, heparin, chondroitin sulfate, chymase, carboxypeptidase, tryptase, platelet activating factor, prostagalanin (PGD2), leukotriene (LTC4) and a variety of interleukins such as IL-1b, IL-3,  IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-13, IL-16, IL-18, IL-25, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), stem cell factor, macrophage chemotactic peptide (MCP)-1, 3&4, regulated on activation of normal T cell-expressed and secreted protein (RANTES), and eotaxin[8].

The release of these mediators can profoundly affect GI physiology. For example, tryptase can activate PAR-2 receptors on epithelial cells, resulting in modulation of tight junction proteins and increases in permeability through paracellular pathways in the intestinal epithelium[9]. Such increases expose the submucosal immune system to lumen-derived food antigens and bacterial by-products, which will result in immune system activation[10,11]. This is clinically important because an increased mucosal permeability and activation of the mucosal immune system are the two major players in mucosal inflammation in inflammatory bowel disease (IBD). PAR-2 receptors are not limited to epithelial cells and the presence of this receptor on afferent nerve terminals and MC themselves has been shown. Thus, activation of PAR-2, can result in release of proinflammatory mediators from nerve endings which may cause neurogenic inflammation[12] or even potentiate MC release by creating a positive feedback loop[13,14].

IBD is believed to result from an abnormal responses to normal pro-inflammatory factors in the gut lumen in a susceptible individual with immune dysregulation[15]. The origins of this disease are probably multi-factorial, with interplay between genetic and environmental factors[15,16]. This interplay results in initiation of inflammatory processes and creation of vicious cycles (involving positive feedback loops) that cause sustained, uncontrolled inflammation and tissue damage. However, for luminal factors such as bacterial antigens to initiate an inflammatory cascade, they must be able to bypass the intestinal barrier[17,18]. Indeed, as suggestive above, a decreased intestinal barrier integrity (leaky gut) has been implicated in the pathogenesis of IBD[17-20]. In fact, activation of the BGA by stressful situations and by the associated degranulation of MC in the gut mucosa can result in intestinal hyperpermeability and activation of the mucosal immune function.

Nevertheless, the mechanisms through which MC play a role in the pathogenesis of IBD are not well known. For example, there is a wide variation in the number of MC in IBD in different reports. A few studies have shown a mild to marked increase in the number of MC in subjects with active IBD[21-23]. King et al and other researchers reported that MC number was not different between controls and subjects with inactive IBD[24-26]. Surprisingly, in the report by King et al the number of MC increased in the area of demarcation between involved and non-involved colon and the number of MC dropped significantly in areas of active inflammation. In our own recent study, we did not find any significant differences in the number of MC in subjects with IBD compared to healthy controls. In addition we showed that there was no increase in the number of MC after stress in human subjects[27]. This contrasts with animal studies in which the number of MC increased after stress[28].

Although there is controversy regarding the number of intestinal MC in IBD, there is consensus that there is a close association among stress, BGA activation, and MC mediated mechanisms in IBD[21,29-35]. For example, studies in animal models of IBD showed that stress results in increased intestinal permeability and worsening of hapten-induced colitis in rats[36]. Stress did not affect gut permeability in MC-deficient rats and failed to cause epithelial mitochondrial damage in a rat model, indicating that stress-induced intestinal hyperpermeability is MC-dependent[28]. In human studies, stress [modeled using cold pressor test (CPT)] in healthy subjects caused activation of mucosal mast cells and release of proinflammatory mediators in the jejunum[37]. This study reaffirmed the finding that was previously showed in animal studies and reaffirmed the BGA activation in humans activates MC in GI mucosa in healthy subjects. Finally, we recently showed that stress (CPT) caused more pronounced MC activation and degranulation in patients with inactive IBD than in healthy controls. The activation of mucosal MC was associated with mucosal oxidative damage[27]. The mechanism for the exaggerated MC response to stress in IBD patients is not known but could be one of the important factors involved in IBD flare up. In fact, it remains to be seen, whether the exaggerated response of mucosal MC to stress in IBD subjects is a primary phenomenon due to an inherently abnormal MC or whether it is a secondary phenomenon due to the inflammatory environment of the MC. After further investigation we recently reported that MC in the intestinal mucosa of patients with IBD have reduced immunostaining of c-kit receptors compared to MC from healthy controls[38,39]. Mucosal MC are identified in intestinal tissues by antibodies against the CD117 (c-kit) antigen[29]. C-kit is a transmembrane, tyrosine kinase containing, growth factor receptor expressed by MC, and its presence on MC membranes represents maturity of the cells[30-32]. In our report, we compared the results of immunostaining with markers of mast cell degranulation (using electron microscopy) and observed that a lack of c-kit immunostaining is not associated with MC activity and degranulation. Whether this MC abnormality underlies MC overactivity in IBD requires further investigation.

Considering MC as the end effector of the BGA, it is not surprising that MC have an important role in the pathogenesis of other stress-related GI disorders such as irritable bowel syndrome (IBS). Barbara showed that the number of MC in ileum of subjects with IBS is increased[40,41]. He also showed that there is a close proximity of the nerve ending and mucosal MC[42]. He noted that MC activation and the close proximity of MC to nerve fibers are correlated with the severity of perceived abdominal painful sensations. The mediators released from MC interact with nerves supplying the gut leading to altered gut physiology and increased sensory perception. This proposes the notion of nerve↔MC activation in stressful situations. In fact, abnormal intestinal perme-ability has been reported in at least one subgroup of diarrhea -predominant IBS patients[43]. Although, there is a lack of clear histological inflammation in IBS, the apparent presence of a biochemical inflammatory process in IBS is an emerging topic. An abnormal proinflammatory cytokine profile has been reported in subjects with IBS[44,45]. Some researcher have also connected MC and functional bowel disorders such as IBS through allergic responses to food antigens and food intolerance[46]. MC enterocolitis is a new term that was coined by our group and includes a subgroup of IBS with intractable diarrhea who have normal routine histology but an increased number of MC [more than 20 per high power field (HPF)] in special staining for MC. These patients respond well to medicine that curbs the release of proinflammatory MC mediators such as histamine typeand blockers[47]. Thus, it is not surprising that researchers are now proposing the possibility of using, in management of IBS, drugs that have the potential to control MC[41].

In conclusion, MC is an important component of gastrointestinal tract physiological and immunological functions. As the end effector of the BGA, MC translate the stress signals into release of proinflammatory mediators that can stimulate gastrointestinal nerve endings and affect its perception, change intestinal motility, cause intestinal hyperpermeability and, in susceptible individuals-those with hyperreactive intestinal immune systems modify the inflammation. Despite the apparent importance of this element in the pathogenesis of several inflammatory and non-inflammatory GI disorders, our knowledge about the role of MC in these disorders is only rudimentary. Further research that more precisely characterizes the role of MC in these diseases could open new doors toward new therapies for IBD and other common GI ailments.

 

REFERENCES

1      Dror Y, Leaker M, Caruana G, Bernstein A, Freedman MH. Mastocytosis cells bearing a c-kit activating point mutation
        are characterized by hypersensitivity to stem cell factor and increased apoptosis. Br J Haematol 2000; 108: 729-736

        PubMed

2      Sepper R, Konttinen YT, Kemppinen P, Sorsa T, Eklund KK. Mast cells in bronchiectasis. Ann Med 1998; 30: 307-315

        PubMed

3      Hunt LW, Colby TV, Weiler DA, Sur S, Butterfield JH. Immunofluorescent staining for mast cells in idiopathic pulmonary
        fibrosis: quantification and evidence for extracellular release of mast cell tryptase. Mayo Clin Proc 1992; 67: 941-948

        PubMed

4      Pesci A, Majori M, Piccoli ML, Casalini A, Curti A, Franchini D, Gabrielli M. Mast cells in bronchiolitis obliterans organizing
        pneumonia. Mast cell hyperplasia and evidence for extracellular release of tryptase. Chest 1996; 110: 383-391

        PubMed

5      Flint KC, Leung KB, Hudspith BN, Brostoff J, Pearce FL, Geraint-James D, Johnson NM. Bronchoalveolar mast cells in
        sarcoidosis: increased numbers and accentuation of mediator release. Thorax 1986; 41: 94-99   PubMed

6      Toth T, Toth-Jakatics R, Jimi S, Ihara M, Urata H, Takebayashi S. Mast cells in rapidly progressive glomerulonephritis. J
        Am Soc Nephrol 1999; 10: 1498-1505   PubMed

7      Godfrey HP, Ilardi C, Engber W, Graziano FM. Quantitation of human synovial mast cells in rheumatoid arthritis and
        other rheumatic diseases. Arthritis Rheum 1984; 27: 852-856   PubMed

8      He SH. Key role of mast cells and their major secretory products in inflammatory bowel disease. World J Gastroenterol
        2004; 10: 309-318   PubMed

9      Cenac N, Chin AC, Garcia-Villar R, Salvador-Cartier C, Ferrier L, Vergnolle N, Buret AG, Fioramonti J, Bueno L. PAR2
        activation alters colonic paracellular permeability in mice via IFN-gamma-dependent and -independent pathways. J
        Physiol 2004; 558: 913-925   PubMed

10    Anton PA. Stress and mind-body impact on the course of inflammatory bowel diseases. Semin Gastrointest Dis 1999;
        10: 14-19   PubMed

11    Levenstein S, Prantera C, Varvo V, Scribano ML, Andreoli A, Luzi C, Arca M, Berto E, Milite G, Marcheggiano A. Stress
        and exacerbation in ulcerative colitis: a prospective study of patients enrolled in remission. Am J Gastroenterol 2000;
        95: 1213-1220   PubMed

12    Steinhoff M, Vergnolle N, Young SH, Tognetto M, Amadesi S, Ennes HS, Trevisani M, Hollenberg MD, Wallace JL,
        Caughey GH, Mitchell SE, Williams LM, Geppetti P, Mayer EA, Bunnett NW. Agonists of proteinase-activated receptor 2
        induce inflammation by a neurogenic mechanism. Nat Med 2000; 6: 151-158   PubMed

13    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. Am J Pathol 2002; 161: 1903-1915   PubMed

14    He SH, He YS, Xie H. Activation of human colon mast cells through proteinase activated receptor-2. World J
        Gastroenterol 2004; 10: 327-331   PubMed

15    Papadakis KA, Targan SR. Current theories on the causes of inflammatory bowel disease. Gastroenterol Clin North Am
        1999; 28: 283-296   PubMed

16    Bjarnason I, MacPherson A, Hollander D. Intestinal permeability: an overview. Gastroenterology 1995; 108: 1566-1581

        PubMed

17    Hollander D. Permeability in Crohn's disease: altered barrier functions in healthy relatives? Gastroenterology 1993;
        104: 1848-1851   PubMed

18    Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients
        with Crohn's disease and their relatives.
A possible etiologic factor. Ann Intern Med 1986; 105: 883-885   PubMed

19    Hilsden RJ, Meddings JB, Sutherland LR. Intestinal permeability changes in response to acetylsalicylic acid in relatives of
        patients with Crohn's disease. Gastroenterology 1996; 110: 1395-1403   PubMed

20    May GR, Sutherland LR, Meddings JB. Is small intestinal permeability really increased in relatives of patients with
        Crohn's disease? Gastroenterology 1993; 104: 1627-1632   PubMed

21    Nolte H, Spjeldnaes N, Kruse A, Windelborg B. Histamine release from gut mast cells from patients with inflammatory
        bowel diseases. Gut 1990; 31: 791-794   PubMed

22    Dvorak AM, Monahan RA, Osage JE, Dickersin GR. Crohn's disease: transmission electron microscopic studies. II.
        Immunologic inflammatory response. Alterations of mast cells, basophils, eosinophils, and the microvasculature. Hum
        Pathol 1980; 11: 606-619   PubMed

23    Lloyd G, Green FH, Fox H, Mani V, Turnberg LA. Mast cells and immunoglobulin E in inflammatory bowel disease. Gut
        1975; 16: 861-865   PubMed

24    Sarin SK, Malhotra V, Sen Gupta S, Karol A, Gaur SK, Anand BS. Significance of eosinophil and mast cell counts in rectal
        mucosa in ulcerative colitis. A prospective controlled study. Dig Dis Sci 1987; 32: 363-367   PubMed

25    Bischoff SC, Wedemeyer J, Herrmann A, Meier PN, Trautwein C, Cetin Y, Maschek H, Stolte M, Gebel M, Manns MP.
        Quantitative assessment of intestinal eosinophils and mast cells in inflammatory bowel disease. Histopathology 1996;
        28: 1-13   PubMed

26    King T, Biddle W, Bhatia P, Moore J, Miner PB Jr. Colonic mucosal mast cell distribution at line of demarcation of active
        ulcerative colitis. Dig Dis Sci 1992; 37: 490-495   PubMed

27    Farhadi A, Keshavarzian A, Van de Kar LD, Jakate S, Domm A, Zhang L, Shaikh M, Banan A, Fields JZ. Heightened
        responses to stressors in patients with inflammatory bowel disease. Am J Gastroenterol 2005; 100: 1796-1804

        PubMed

28    Santos J, Yang PC, Soderholm JD, Benjamin M, Perdue MH. Role of mast cells in chronic stress induced colonic
        epithelial barrier dysfunction in the rat. Gut 2001; 48: 630-636   PubMed

29    Levenstein S, Prantera C, Varvo V, Scribano ML, Berto E, Andreoli A, Luzi C. Psychological stress and disease activity in
        ulcerative colitis: a multidimensional cross-sectional study. Am J Gastroenterol 1994; 89: 1219-1225   PubMed

30    Robertson DA, Ray J, Diamond I, Edwards JG. Personality profile and affective state of patients with inflammatory
        bowel disease. Gut 1989; 30: 623-626   PubMed

31    Raithel M, Schneider HT, Hahn EG. Effect of substance P on histamine secretion from gut mucosa in inflammatory bowel
        disease. Scand J Gastroenterol 1999; 34: 496-503   PubMed

32    Knutson L, Ahrenstedt O, Odlind B, Hallgren R. The jejunal secretion of histamine is increased in active Crohn's disease.
        Gastroenterology 1990; 98: 849-854   PubMed

33    Fox CC, Lazenby AJ, Moore WC, Yardley JH, Bayless TM, Lichtenstein LM. Enhancement of human intestinal mast cell
        mediator release in active ulcerative colitis. Gastroenterology 1990; 99: 119-124   PubMed

34    Bjorck S, Dahlstrom A, Ahlman H. Topical treatment of ulcerative proctitis with lidocaine. Scand J Gastroenterol 1989;
        24: 1061-1072   PubMed

35    Bjorck S, Dahlstrom A, Ahlman H. Treatment of distal colitis with local anaesthetic agents. Pharmacol Toxicol 2002; 90:
        173-180   PubMed

36    Qiu BS, Vallance BA, Blennerhassett PA, Collins SM. The role of CD4+ lymphocytes in the susceptibility of mice to stress-
        induced reactivation of experimental colitis. Nat Med 1999; 5: 1178-1182   PubMed

37    Santos J, Saperas E, Nogueiras C, Mourelle M, Antolin M, Cadahia A, Malagelada JR. Release of mast cell mediators
        into the jejunum by cold pain stress in humans. Gastroenterology 1998; 114: 640-648   PubMed

38    Farhadi A, Keshavarzian A, Fields JZ, Sheikh M, Banan A. Resolution of common dietary sugars from probe sugars for
        test of intestinal permeability using capillary column gas chromatography. J Chromatogr B Analyt Technol Biomed Life Sci
        2006; 836: 63-68   PubMed

39    Farhadi A, Keshavarzian A, Van de Kar LD, Jakate S, Domm A, Zhang L, Shaikh M, Banan A, Fields JZ. Heightened
        responses to stressors in patients with inflammatory bowel disease. Am J Gastroenterol 2005; 100: 1796-1804

        PubMed

40    Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B, Corinaldesi R. New pathophysiological mechanisms in
        irritable bowel syndrome. Aliment Pharmacol Ther 2004; 20 Suppl 2: 1-9   PubMed

41    Barbara G, Stanghellini V, De Giorgio R, Corinaldesi R. Functional gastrointestinal disorders and mast cells: implications
        for therapy. Neurogastroenterol Motil 2006; 18: 6-17   PubMed

42    Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, Pasquinelli G, Morselli-Labate AM, Grady EF,
        Bunnett NW, Collins SM, Corinaldesi R. Activated mast cells in proximity to colonic nerves correlate with abdominal pain
        in irritable bowel syndrome. Gastroenterology 2004; 126: 693-702   PubMed

43    Dunlop SP, Hebden J, Campbell E, Naesdal J, Olbe L, Perkins AC, Spiller RC. Abnormal intestinal permeability in
        subgroups of diarrhea-predominant irritable bowel syndromes. Am J Gastroenterol 2006; 101: 1288-1294   PubMed

44    O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, O'Sullivan GC, Kiely B, Collins JK, Shanahan F, Quigley EM.
        Lactobacillus and bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles.
        Gastroenterology 2005; 128: 541-551   PubMed

45    van der Veek PP, van den Berg M, de Kroon YE, Verspaget HW, Masclee AA. Role of tumor necrosis factor-alpha and
        interleukin-10 gene polymorphisms in irritable bowel syndrome. Am J Gastroenterol 2005; 100: 2510-2516   PubMed

46    Zar S, Kumar D, Kumar D. Role of food hypersensitivity in irritable bowel syndrome. Minerva Med 2002; 93: 403-412

        PubMed

47    Jakate S, Demeo M, John R, Tobin M, Keshavarzian A. Mastocytic enterocolitis: increased mucosal mast cells in chronic
        intractable diarrhea. Arch Pathol Lab Med 2006; 130: 362-367   PubMed

 

                                                            S- Editor  Liu Y    E- Editor  Lu W

 


 

 

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