The role of the mast cell in the pathophysiology of asthma
2006; Elsevier BV; Volume: 117; Issue: 6 Linguagem: Inglês
10.1016/j.jaci.2006.02.039
ISSN1097-6825
AutoresPeter Bradding, Andrew F. Walls, Stephen T. Holgate,
Tópico(s)Allergic Rhinitis and Sensitization
ResumoThere is compelling evidence that human mast cells contribute to the pathophysiology of asthma. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis, a factor likely to be important in determining the asthmatic phenotype. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis, and several mast cell mediators have profound effects on airway smooth muscle function. The autacoids are established as potent bronchoconstrictors, whereas the proteases tryptase and chymase are being demonstrated to have a range of actions consistent with key roles in inflammation, tissue remodeling, and bronchial hyperresponsiveness. IL-4 and IL-13, known mast cell products, also induce bronchial hyperresponsiveness in the mouse independent of the inflammatory response and enhance the magnitude of agonist-induced intracellular Ca2+ responses in cultured human airway smooth muscle. There are therefore many pathways by which the close approximation of mast cells with airway smooth muscle cells might lead to disordered airway smooth muscle function. Mast cells also infiltrate the airway mucous glands in subjects with asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing the airway lumen, suggesting that mast cells play an important role in regulating mucous gland secretion. The development of potent and specific inhibitors of mast cell secretion, which remain active when administered long-term to asthmatic airways, should offer a novel approach to the treatment of asthma. There is compelling evidence that human mast cells contribute to the pathophysiology of asthma. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with asthma but not in normal subjects or those with eosinophilic bronchitis, a factor likely to be important in determining the asthmatic phenotype. The mechanism of mast cell recruitment by asthmatic airway smooth muscle involves the CXCL10/CXCR3 axis, and several mast cell mediators have profound effects on airway smooth muscle function. The autacoids are established as potent bronchoconstrictors, whereas the proteases tryptase and chymase are being demonstrated to have a range of actions consistent with key roles in inflammation, tissue remodeling, and bronchial hyperresponsiveness. IL-4 and IL-13, known mast cell products, also induce bronchial hyperresponsiveness in the mouse independent of the inflammatory response and enhance the magnitude of agonist-induced intracellular Ca2+ responses in cultured human airway smooth muscle. There are therefore many pathways by which the close approximation of mast cells with airway smooth muscle cells might lead to disordered airway smooth muscle function. Mast cells also infiltrate the airway mucous glands in subjects with asthma, showing features of degranulation, and a positive correlation with the degree of mucus obstructing the airway lumen, suggesting that mast cells play an important role in regulating mucous gland secretion. The development of potent and specific inhibitors of mast cell secretion, which remain active when administered long-term to asthmatic airways, should offer a novel approach to the treatment of asthma. Mast cells are resident in all normal tissues, where they are believed to play an important role in tissue homeostasis, wound healing, and host defense, particularly bacterial infection (see review1Bradding P. Holgate S.T. Immunopathology and human mast cell cytokines.Crit Rev Oncol Haematol. 1999; 31: 119-133Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). Chronic mast cell activation contributes to the pathophysiology of many diverse diseases through the synthesis and release of numerous proinflammatory mediators and cytokines, the pattern of which varies depending on the stimulus.2Okumura S. Kashiwakura J. Tomita H. Matsumoto K. Nakajima T. Saito H. et al.Identification of specific gene expression profiles in human mast cells mediated by Toll-like receptor 4 and FcεRI.Blood. 2003; 102: 2547-2554Crossref PubMed Scopus (136) Google Scholar It is beyond our scope to review in detail all of the evidence implicating mast cells in the pathophysiology of asthma, and for further information, the reader is referred to references.3Bradding P. Mast cells in asthma.in: Busse W.W. Holgate S.T. Asthma & rhinitis. Blackwell Scientific Publications, Inc, Boston2000: 319-338Google Scholar, 4Bradding P. The role of the mast cell in asthma: a reassessment.Curr Opin Allergy Clin Immunol. 2003; 3: 45-50Crossref PubMed Scopus (75) Google Scholar We therefore focus on important recent advances in this field. Mast cells secrete the autacoid mediators histamine, prostaglandin (PG) D2, and leukotriene (LT) C4, which are capable of inducing bronchoconstriction, mucus secretion, and mucosal edema, all features of asthma. This is particularly evident during experimental allergen challenge, in which blockade of these mediators attenuates the early fall in lung function (see review3Bradding P. Mast cells in asthma.in: Busse W.W. Holgate S.T. Asthma & rhinitis. Blackwell Scientific Publications, Inc, Boston2000: 319-338Google Scholar). However, mast cells also synthesize and secrete a large number of proinflammatory cytokines (including IL-4, IL-5, and IL-13), which regulate both IgE synthesis and the development of eosinophilic inflammation, and several profibrogenic cytokines, including TGF-β and basic fibroblast growth factor (FGF-2).1Bradding P. Holgate S.T. Immunopathology and human mast cell cytokines.Crit Rev Oncol Haematol. 1999; 31: 119-133Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 3Bradding P. Mast cells in asthma.in: Busse W.W. Holgate S.T. Asthma & rhinitis. Blackwell Scientific Publications, Inc, Boston2000: 319-338Google Scholar The serine proteases tryptase, chymase, and carboxy-peptidase are major secretory products of human mast cells that can interact with various cell types via protease activated receptors (PARs) and by other processes to alter their behavior profoundly.3Bradding P. Mast cells in asthma.in: Busse W.W. Holgate S.T. Asthma & rhinitis. Blackwell Scientific Publications, Inc, Boston2000: 319-338Google Scholar Importantly, bronchial mucosal mast cells in subjects with asthma exhibit features of chronic ongoing activation3Bradding P. Mast cells in asthma.in: Busse W.W. Holgate S.T. Asthma & rhinitis. Blackwell Scientific Publications, Inc, Boston2000: 319-338Google Scholar (Fig 1). Although most of these studies have been performed in atopic individuals, similar evidence has been obtained to support a role for ongoing mast cell secretory activity in both nonatopic and occupational asthma.3Bradding P. Mast cells in asthma.in: Busse W.W. Holgate S.T. Asthma & rhinitis. Blackwell Scientific Publications, Inc, Boston2000: 319-338Google Scholar Although, in general, total mast cell numbers appear not to be increased in the bronchial mucosa of subjects with asthma compared with normal subjects, this inadequately describes the complexity, because it is evident that they localize to 3 key sites: the airway smooth muscle (ASM), the airway mucous glands, and the bronchial epithelium. It is a widely held view that the disordered airway physiology and airway wall remodeling characteristic of asthma are consequences of the inflammatory process, but there are examples where this relationship is weak. This is most evident in patients with eosinophilic bronchitis (EB), a condition that accounts for about 15% of cases of cough referred to respiratory specialists. It is characterized by corticosteroid responsive cough and the presence of a sputum eosinophilia occurring in the absence of variable airflow obstruction or bronchial hyperresponsiveness (BHR).5Brightling C.E. Ward R. Goh K.L. Wardlaw A.J. Pavord I.D. Eosinophilic bronchitis is an important cause of chronic cough.Am J Respir Crit Care Med. 1999; 160: 406-410Crossref PubMed Scopus (375) Google Scholar However, despite differing functional effects on the airways, the immunopathology of asthma and EB is virtually identical.6Brightling C.E. Symon F.A. Birring S.S. Bradding P. Pavord I.D. Wardlaw A.J. TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis.J Allergy Clin Immunol. 2002; 110: 899-905Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar, 7Brightling C.E. Symon F.A. Birring S.S. Bradding P. Wardlaw A.J. Pavord I.D. Comparison of airway immunopathology of eosinophilic bronchitis and asthma.Thorax. 2003; 58: 528-532Crossref PubMed Scopus (202) Google Scholar Thus, in bronchoalveolar lavage, induced sputum, and airway biopsies, the extent of T-cell and eosinophil infiltration and activation, mucosal mast cell numbers, IL-4 and IL-5 cytokine expression, epithelial integrity, subbasement membrane collagen deposition, and mediator concentrations including histamine and PGD2 are almost identical. This leads us to the conclusion that many of the immunopathological features previously attributed to causing asthma may not, in fact, be fundamental to the development of airflow obstruction and BHR. After a series of in-depth studies we have found only 2 key differences between the pathology of asthma and eosinophilic bronchitis. The first is that the concentration of IL-13 is elevated in the induced sputum of subjects with asthma but not subjects with EB.8Berry M.A. Parker D. Neale N. Woodman L. Morgan A. Monk P. et al.Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis.J Allergy Clin Immunol. 2004; 114: 1106-1109Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar The numbers of IL-13+ cells in the airway mucosa in asthma is relatively low but increased when compared with EB, with most of the IL-13+ cells identified as eosinophils. However, the most striking difference between the pathology of asthma and EB is in the ASM. Abnormal ASM function is fundamentally important to the pathophysiology of asthma and yet, surprisingly, this compartment has not been the focus of detailed immunopathological assessments. In subjects with asthma, we have observed that there are many mast cells between the ASM bundles, but virtually none in the ASM from patients with EB or normal subjects (Fig 2).9Brightling C.E. Bradding P. Symon F.A. Holgate S.T. Wardlaw A.J. Pavord I.D. Mast cell infiltration of airway smooth muscle in asthma.N Engl J Med. 2002; 346: 1699-1705Crossref PubMed Scopus (1020) Google Scholar This has been confirmed in a further independent study.10El-Shazly A. Berger P. Girodet P.O. Ousova O. Fayon M. Vernejoux J.M. et al.Fraktalkine produced by airway smooth muscle cells contributes to mast cell recruitment in asthma.J Immunol. 2006; 176: 1860-1868PubMed Google Scholar The majority of mast cells in the ASM were of the MCTC phenotype—that is, containing both tryptase and chymase—and also expressed IL-4 and IL-13, but interestingly, not IL-5 (Fig 2).11Brightling C.E. Symon F.A. Holgate S.T. Wardlaw A.J. Pavord I.D. Bradding P. IL-4 and IL-13 are co-localised to mast cells within airway smooth muscle in asthma.Clin Exp Allergy. 2003; 33: 1711-1716Crossref PubMed Scopus (123) Google Scholar In contrast, in asthmatic biopsies there were almost no T cells or eosinophils in the ASM of any of the study groups. This indicates that ASM infiltration by mast cells may be one of the critical determinants of the asthmatic phenotype, and could explain the observed correlation between ASM mast cell numbers and BHR within the asthmatic group. These observations have further implications. For example, not only might it clarify why many atopic patients do not have asthma but also it could explain why the presence of asthma is such a strong risk factor for death from anaphylaxis and allergen desensitization.12Bock S.A. Munoz-Furlong A. Sampson H.A. Fatalities due to anaphylactic reactions to foods.J Allergy Clin Immunol. 2001; 107: 191-193Abstract Full Text PDF PubMed Scopus (1354) Google Scholar In many instances, it is likely that cellular communication within the airways works across a distance of 1 to 2 μm and that cell-cell contact is critical to influence function. The localization of mast cells within the ASM in asthma will facilitate specific interactions between these cells and ASM in terms of both localized mediator release and direct cell-cell contact. Therefore, it is entirely plausible that the presence of mast cells within the ASM could contribute to the development of ASM hypertrophy and hyperplasia, smooth muscle dysfunction expressed as BHR, and variable airflow obstruction. It is reasonable to hypothesize that the primary stimulus for mast cell recruitment lies within the ASM involving the release of chemoattractants for mast cells or their progenitors. The ASM secretes many chemokines and growth factors that exhibit mast cell chemotactic activity. These include CCL11, CXCL8, and CXCL12. We have demonstrated that human lung mast cells (HLMCs) express CXCR3,13Brightling C.E. Kaur D. Berger P. Morgan A.J. Wardlaw A.J. Bradding P. Differential expression of CCR3 and CXCR3 by human lung and bone marrow-derived mast cells: implications for tissue mast cell migration.J Leuk Biol. 2005; 77: 759-766Crossref PubMed Scopus (82) Google Scholar and ASM secretes the 3 CXCR3 ligands CXCL9, CXCL10, and CXCL11.14Brightling C.E. Ammit A.J. Kaur D. Black J.L. Wardlaw A.J. Hughes J.M. et al.The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle.Am J Respir Crit Care Med. 2005; 171: 1103-1108Crossref PubMed Scopus (233) Google Scholar Of importance, cultured human ASM from subjects with asthma preferentially secrete CXCL10 after cytokine activation, and this accounts in large part for the greatly enhanced HLMC chemotaxis mediated by conditioned medium from asthmatic compared with normal ASM.14Brightling C.E. Ammit A.J. Kaur D. Black J.L. Wardlaw A.J. Hughes J.M. et al.The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle.Am J Respir Crit Care Med. 2005; 171: 1103-1108Crossref PubMed Scopus (233) Google Scholar The relevance of this to mast cell recruitment by the asthmatic ASM in vivo is further demonstrated by the increased expression of CXCL10 by the ASM in bronchial biopsies from subjects with asthma compared with normal subjects, and by the enrichment of CXCR3+ mast cells within the ASM bundles compared with the surrounding airway mucosa.14Brightling C.E. Ammit A.J. Kaur D. Black J.L. Wardlaw A.J. Hughes J.M. et al.The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle.Am J Respir Crit Care Med. 2005; 171: 1103-1108Crossref PubMed Scopus (233) Google Scholar Other chemoattractants may also contribute to the ASM mast cell myositis. Stem cell factor (SCF; c-kit ligand) is produced by both ASM and mast cells and is both a chemoattractant and an essential survival factor for mast cells. In addition, TGF-β is another mast cell chemoattractant released by ASM after exposure to tryptase, providing a mechanism through which mast cells might contribute to further mast cell recruitment15Berger P. Girodet P.O. Begueret H. Ousova O. Perng D.W. Marthan R. et al.Tryptase-stimulated human airway smooth muscle cells induce cytokine synthesis and mast cell chemotaxis.FASEB J. 2003; 17: 2139-2141Crossref PubMed Scopus (139) Google Scholar via autocrine pathways. Once present in the ASM bundle, adhesion of mast cells to ASM cells is likely to be important for the retention of mast cells and the functional interaction between the 2 cell types. This hypothesis is supported by the observation that unlike T cells and eosinophils, which adhere poorly to ASM, HLMCs adhere readily.16Yang W. Kaur D. Okayama Y. Ito A. Wardlaw A.J. Brightling C.E. et al.Human lung mast cells adhere to human airway smooth muscle, in part, via tumor suppressor in lung cancer-1.J Immunol. 2006; 176: 1238-1243PubMed Google Scholar Interestingly, this is mediated in part via a molecule known as tumor suppressor in lung cancer 1 (TSLC-1; also known as SgIGSF, IGSF4, RA175, Necl2, and SynCAM). Tumor suppressor in lung cancer 1 is highly expressed by HLMC and mediates HLMC adhesion to ASM through a heterophilic Ca2+-independent mechanism. The classic mast cell autacoid mediators histamine, PGD2, and LTC4 are all potent agonists for ASM contraction. Exogenously administered tryp tase induces bronchoconstriction and BHR in dogs and sheep,17Sekizawa K. Caughey G.H. Lazarus S.C. Gold W.M. Nadel J.A. Mast cell tryptase causes airway smooth muscle hyperresponsiveness in dogs.J Clin Invest. 1989; 83: 175-179Crossref PubMed Scopus (140) Google Scholar and in vitro, tryptase can potentiate the contractile response of sensitized bronchi to histamine.18Berger P. Compton S.J. Molimard M. Walls A.F. N'Guyen C. Marthan R. et al.Mast cell tryptase as a mediator of hyperresponsiveness in human isolated bronchi.Clin Exp Allergy. 1999; 29: 804-812Crossref PubMed Scopus (66) Google Scholar Tryptase-induced bronchoconstriction in animal models is likely to be mediated by mast cell activation because it may be blocked by pretreatment with antihistamines. Human tryptase can act as a stimulus for histamine release from mast cells from several tissues including those of the lung,19He S. Aslam A. Gaca M.D. He Y. Buckley M.G. Hollenberg M.D. et al.Inhibitors of tryptase as mast cell-stabilizing agents in the human airways: effects of tryptase and other agonists of proteinase-activated receptor 2 on histamine release.J Pharmacol Exp Ther. 2004; 309: 119-126Crossref PubMed Scopus (52) Google Scholar and consistent with this, inhibitors of this protease can be effective as mast cell stabilizing agents. In addition to its ability to stimulate cytokine release from ASM, tryptase can act as a potent mitogen in vitro.20Berger P. Perng D.W. Thabrew H. Compton S.J. Cairns J.A. McEuen A.R. et al.Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells.J Appl Physiol. 2001; 91: 1372-1379Crossref PubMed Scopus (152) Google Scholar, 21Brown J.K. Jones C.A. Rooney L.A. Caughey G.H. Hall I.P. Tryptase's potent mitogenic effects in human airway smooth muscle cells are via nonproteolytic actions.Am J Physiol Lung Cell Mol Physiol. 2002; 282: L197-L206PubMed Google Scholar The precise mechanism whereby tryptase may interact with these cells is unclear. Several studies have suggested the need for an intact catalytic site,20Berger P. Perng D.W. Thabrew H. Compton S.J. Cairns J.A. McEuen A.R. et al.Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells.J Appl Physiol. 2001; 91: 1372-1379Crossref PubMed Scopus (152) Google Scholar although there is a report that nonproteolytic actions may be involved in mitogenesis.21Brown J.K. Jones C.A. Rooney L.A. Caughey G.H. Hall I.P. Tryptase's potent mitogenic effects in human airway smooth muscle cells are via nonproteolytic actions.Am J Physiol Lung Cell Mol Physiol. 2002; 282: L197-L206PubMed Google Scholar ASMs abundantly express the G-protein–coupled receptor PAR2, peptide agonists of which can stimulate mitogenesis and cytokine release similar to that seen with tryptase.20Berger P. Perng D.W. Thabrew H. Compton S.J. Cairns J.A. McEuen A.R. et al.Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells.J Appl Physiol. 2001; 91: 1372-1379Crossref PubMed Scopus (152) Google Scholar IL-4 and IL-13 are also believed to be key in the development of BHR. This is supported by an in vivo study in mice in which instillation of TH2 cell conditioned medium to the airways of naive mice induced BHR within 6 hours. This required expression of the IL-4 receptor α subunit and signal transducer and activator of transcription 6, suggesting a critical role for IL-4 and/or IL-13, and both of these cytokines produced similar effects when administered individually.22Venkayya R. Lam M. Willkom M. Grunig G. Corry D.B. Erle D.J. The Th2 lymphocyte products IL-4 and IL-13 rapidly induce airway hyperresponsiveness through direct effects on resident airway cells.Am J Respir Cell Mol Biol. 2002; 26: 202-208Crossref PubMed Scopus (198) Google Scholar IL-4 and IL-13 and also enhance the magnitude of agonist-induced intracellular Ca2+ responses in cultured human ASM. In asthma, there are few T cells within the ASM, but mast cells at this site do express both IL-4 (Fig 2) and IL-13,11Brightling C.E. Symon F.A. Holgate S.T. Wardlaw A.J. Pavord I.D. Bradding P. IL-4 and IL-13 are co-localised to mast cells within airway smooth muscle in asthma.Clin Exp Allergy. 2003; 33: 1711-1716Crossref PubMed Scopus (123) Google Scholar revealing a further pathway through which mast cells could contribute to the development of BHR. Chymase is a chymotryptic protease of mast cells whose roles in asthma have been less extensively studied than tryptase, but it is expressed by those mast cells infiltrating the ASM in asthma.9Brightling C.E. Bradding P. Symon F.A. Holgate S.T. Wardlaw A.J. Pavord I.D. Mast cell infiltration of airway smooth muscle in asthma.N Engl J Med. 2002; 346: 1699-1705Crossref PubMed Scopus (1020) Google Scholar Interestingly, chymase degrades human ASM pericellular matrix and inhibits T-cell adhesion to ASM, which might explain the paucity of T cells within this structure in asthma.23Lazaar A.L. Plotnick M.I. Kucich U. Crichton I. Lotfi S. Das S.K.P. et al.Mast cell chymase modifies cell-matrix interactions and inhibits mitogen-induced proliferation of human airway smooth muscle cells.J Immunol. 2002; 169: 1014-1020PubMed Google Scholar Consistent with roles in tissue remodeling are the ability of chymase to process type 1 procollagen to initiate the formation of collagen fibrils, to activate matrix metalloprotease 1, and to stimulate the release of extracellular TGF-β1 (see review24Walls A.F. The roles of neutral proteases in asthma and rhinitis.in: Busse W.W. Holgate S.T. Asthma and rhinitis. Blackwell, Boston2000: 968-997Google Scholar). Further roles in controlling the bioavailability of cytokines and growth factors are suggested by the findings that chymase can convert IL-1β into the active form, degrade IL-4, and induce the release of membrane-bound SCF. Although characterized as a potent stimulus for mucus secretion, relatively little is known of the direct actions of chymase on cells, and apart from being able to inactivate PAR1, it does not seem to act on any of the PARs. The effects of combined secretion of chymase, tryptase, and other mast cell mediators in vivo remains unclear and will perhaps be best delineated in coculture experiments using intact human lung mast cells and primary cultures of asthmatic ASM cells. Mast cells infiltrate the bronchial epithelium in asthma.3Bradding P. Mast cells in asthma.in: Busse W.W. Holgate S.T. Asthma & rhinitis. Blackwell Scientific Publications, Inc, Boston2000: 319-338Google Scholar This is likely to be of importance in disease pathogenesis for 2 reasons. First, mast cells are placed at the portal of entry of noxious stimuli such as aeroallergens, which would facilitate an effector role in the ongoing immunologic response (antigen presentation, TH2 cell differentiation, IgE synthesis). Second, there are likely to be important consequences of mast cell degranulation on epithelial function. For example, mast cells adhere avidly to bronchial epithelial cells,25Sanmugalingam D. Wardlaw A.J. Bradding P. Adhesion of human lung mast cells to bronchial epithelium: evidence for a novel carbohydrate-mediated mechanism.J Leukoc Biol. 2000; 68: 38-46PubMed Google Scholar and tryptase stimulates airway epithelial IL-8 release and can upregulate intercellular adhesion molecule 1 expression.26Cairns J.A. Walls A.F. Mast cell tryptase is a mitogen for epithelial cells: stimulation of IL-8 production and intercellular adhesion molecule-1 expression.J Immunol. 1996; 156: 275-283PubMed Google Scholar At this site, mast cells could also more readily respond to other stimuli, such as hyperosmolar or inhaled adenosine. Severe mucus plugging is a well known feature of severe fatal asthma but is also recognized as a feature of milder disease, and results from mucus hypersecretion by hyperplastic submucosal glands and epithelial goblet cells. Carroll et al27Carroll N.G. Mutavdzic S. James A.L. Increased mast cells and neutrophils in submucosal mucous glands and mucus plugging in patients with asthma.Thorax. 2002; 57: 677-682Crossref PubMed Scopus (145) Google Scholar performed a detailed analysis of cartilaginous airways in postmortem lung specimens from patients with fatal asthma, patients with asthma who died from other causes (nonfatal asthma), and subjects without asthma who died of nonpulmonary causes. Immunohistochemistry for mast cell tryptase revealed a significant increase in the number of mast cells within the mucosal gland stroma in nonfatal asthma (Fig 3) and a marked increase in the number of degranulated mast cells in both fatal asthma and nonfatal asthma compared with normal controls. They established significant correlations between the density of both intact and degranulated mast cells in the within mucous glands with the degree of mucus obstruction in the airways. Taken together, these data provide some support for a role of mast cells in the development of mucous gland hyperplasia and the mucus gland secretion characteristic of asthma. Numerous mast cell products are likely to contribute to these features of asthma including histamine, PGD2, LTC4, IL-6, IL-13, TNF-α, tryptase, and chymase. A further molecule of interest and of relevance to the epithelium and mucosal glands is amphiregullin, a member of the epidermal growth factor family. Amphiregullin expression is induced in human progenitor–derived mast cells after activation through FcεRI,28Wang S.W. Oh C.K. Cho S.H. Hu G. Martin R. Demissie-Sanders S. et al.Amphiregulin expression in human mast cells and its effect on the primary human lung fibroblasts.J Allergy Clin Immunol. 2005; 115: 287-294Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 29Okumura S. Sagara H. Fukuda T. Saito H. Okayama Y. FcepsilonRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells.J Allergy Clin Immunol. 2005; 115: 272-279Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar an effect that is not suppressed by dexamethasone. Amphiregullin is expressed at increased levels by mast cells in the asthmatic bronchial mucosa, and in vitro, mast cell–derived amphiregullin increases mucin gene expression in the NCI-H292 epithelial cell line. These observations focus attention on mast cell–derived amphiregullin as contributing to epithelial goblet cell metaplasia and mucus hypersecretion in asthma, which is refractory to corticosteroids. In addition, recombinant amphiregullin induces the proliferation of human airway fibroblasts but not ASM cells, suggesting a further mechanism whereby mast cells can contribute to subepithelial fibrosis (Fig 4). TNF-α is a proinflammatory cytokine strongly implicated in the pathogenesis of asthma.30Bradding P. Roberts J.A. Britten K.M. Montefort S. Djukanovic R. Mueller R. et al.Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines.Am J Respir Cell Mol Biol. 1994; 10: 471-480Crossref PubMed Scopus (759) Google Scholar When administered by inhalation to animals and human beings, it induces both BHR and sputum neutrophilia and exacerbates BHR in patients with asthma.31Thomas P.S. Yates D.H. Barnes P.J. Tumor necrosis factor-alpha increases airway responsiveness and sputum neutrophilia in normal human subjects.Am J Respir Crit Care Med. 1995; 152: 76-80Crossref PubMed Scopus (333) Google Scholar, 32Thomas P.S. Heywood G. Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma.Thorax. 2002; 57: 774-778Crossref PubMed Scopus (128) Google Scholar TNF-α immunoreactivity is increased in the airways of patients with mild asthma, largely because of increased expression by mucosal mast cells.30Bradding P. Roberts J.A. Britten K.M. Montefort S. Djukanovic R. Mueller R. et al.Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines.Am J Respir Cell Mol Biol. 1994; 10: 471-480Crossref PubMed Scopus (759) Google Scholar Two studies have recently shown that TNF-α expression is increased markedly in severe asthma, as shown by increased protein in bronchoalveolar lavage, increased protein expression on PBMCs, and both increased protein and a 30-fold increase in mRNA in the bronchial mucosa,33Berry M.A. Hargadon B. Shelley M. Parker D. Shaw D.E. Green R.H. et al.Evidence of a role of TNFα in refractory asthma.N Engl J Med. 2006; 354: 697-708Crossref PubMed Scopus (715) Google Scholar, 34Howarth P.H. Babu K.S. Arshad H.S. Lau L.C. Buckley M.G. McConnell W. et al.Tumour necrosis factor (TNF{alpha}) as a novel therapeutic target in symptomatic corticosteroid-dependent asthma.Thorax. 2005; 60: 1012-1018Crossref PubMed Scopus (466) Google Scholar despite patients receiving high-dose inhaled and oral corticosteroid therapy. Interestingly, the increased protein expression in endobronchial biopsies was accounted for by increased numbers of TNF-α+ mast cells.34Howarth P.H. Babu K.S. Arshad H.S. Lau L.C. Buckley M.G. McConnell W. et al.Tumour necrosis factor (TNF{alpha
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