Recent Advances in the Pathophysiology of        Asthma        Desmond M. Murphy and Paul M. OByrne        Chest 2010;137;...
CHEST                                Recent Advances in Chest Medicine                    Recent Advances in the Pathophys...
responses viewed traditionally as either innate or          and the host immune response. Airway inflammationacquired are i...
in small numbers to adjacent lymph nodes. Using a                            initiating immune response against airborne a...
the normal Th1/Th2 balance. Although elements ofthis hypothesis remain useful, the emerging roles forother T-cell subtypes...
described in COPD. A recently published study has           ticular in patients with steroid-resistant asthma.64described ...
IL-31 in promoting the influx of bone-marrow-derived                    kinase, with further experiments in rat models sug-...
proportion of both neutrophils and eosinophils in           manifestations of the disease, particularly in the devel-sputu...
14. Iikura M, Suto H, Kajiwara N, et al. IL-33 can promote sur-        35. Xiao S, Jin H, Korn T, et al. Retinoic acid inc...
marrow CD34+ cells from asthmatic subjects: significance           74. Hackett TL, Warner SM, Stefanowicz D, et al. Inducti...
92. Zanini A, Chetta A, Saetta M, et al. Chymase-positive mast         95. Lommatzsch M, Lindner Y, Edner A, Bratke K, Kue...
Recent Advances in the Pathophysiology of Asthma                  Desmond M. Murphy and Paul M. OByrne                    ...
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Asthma advances in pathophysiology

  1. 1. Recent Advances in the Pathophysiology of Asthma Desmond M. Murphy and Paul M. OByrne Chest 2010;137;1417-1426 DOI 10.1378/chest.09-1895 The online version of this article, along with updated information and services can be found online on the World Wide Web at: http://chestjournal.chestpubs.org/content/137/6/1417.full.html Chest is the official journal of the American College of Chest Physicians. It has been published monthly since 1935. Copyright2010by the American College of Chest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder. (http://chestjournal.chestpubs.org/site/misc/reprints.xhtml) ISSN:0012-3692Downloaded from chestjournal.chestpubs.org by guest on July 22, 2011 © 2010 American College of Chest Physicians
  2. 2. CHEST Recent Advances in Chest Medicine Recent Advances in the Pathophysiology of Asthma Desmond M. Murphy, MB, PhD; and Paul M. O’Byrne, MB, FCCP There has been an increased understanding, over the past 2 decades, that asthma is a chronic, immunologically mediated condition with a disturbance of the normal airway repair mechanism, which results in inflammatory changes and airway remodeling. The airway inflammation and remodeling together likely explain the clinical manifestations of asthma. The mechanisms by which the external environmental cues, together with the complex genetic actions, propagate the inflammatory process that characterize asthma are beginning to be understood. There is also an evolving awareness of the active participation of structural elements, such as the airway epithe- lium, airway smooth muscle, and endothelium, in this process. In tandem with this has come the realization that inflammatory cells respond in a coordinated, albeit dysfunctional manner, via an array of complex signaling pathways that facilitate communication between these cells; these structural elements within the lung and the bone marrow serve as reservoirs for and the source of inflammatory cells and their precursors. Although often viewed as separate mechanistic enti- ties, so-called innate and acquired immunity often overlap in the propagation of the asthmatic response. This review examines the newer information on the pathophysiologic characteristics of asthma and focuses on papers published over the past 3 years that have helped to improve current levels of understanding. CHEST 2010; 137(6):1417–1426 Abbreviations: CCR 5 chemokine receptor; IL 5 interleukin; NK 5 natural killer; TGF 5 transforming growth factor; Th 5 T-helper; TLR 5 toll-like receptor; TNF 5 tumor necrosis factor; Treg 5 T-regulatory; VEGF 5 vascular endothe- lial growth factorAsthmaclinically awith repeated, variable, episodic fests remains major health-care issue. It mani- cytokines such as interleukin (IL)-4, IL-5, and IL-13, the so-called Th2 cytokine milieu. These cytokinesattacks of breathlessness, cough, and wheeze occur- stimulate mast cells, cause eosinophilia, promote leu-ring secondary to bronchoconstriction in the setting kocytosis, and enhance B-cell IgE production, andof airway hyperresponsiveness and mucous hyperse- may also participate in the characteristic airwaycretion. Clinically, the disease may be divided into remodeling of asthma. However, for an individual toallergic and nonallergic asthma, distinguished by the develop an asthmatic phenotype appears to requirepresence or absence of IgE antibodies to common the combination of both exposure to appropriateenvironmental allergens. However, in both forms stimuli and a genetic predisposition.1,2of the disease, the airway is infiltrated by T-helper The last 3 decades have provided vast quantities(Th) cells, which predominantly secrete characteristic of research affording significant insights into the pathophysiologic characteristics of this complex entity.Manuscript received August 10, 2009; revision accepted November In this article, we review progress, over the past 3 years,16, 2009.Affiliations: From the Firestone Institute for Respiratory Health, that has augmented the level of understanding of theSt Joseph’s Healthcare; and the Department of Medicine, pathophysiologic characteristics of asthma.McMaster University, Hamilton, ON, Canada.Correspondence to: Paul O’Byrne, MB, FCCP, HSC 3W10,McMaster University, 1200 Main St W, Hamilton, ON, Canada, Innate and Acquired ImmuneL8N 3Z5; e-mail: obyrnep@mcmaster.ca Mechanisms in Asthma© 2010 American College of Chest Physicians. Reproductionof this article is prohibited without written permission from the The trigger factors precipitating acute asthmatic exa-American College of Chest Physicians (www.chestpubs.org/site/misc/reprints.xhtml). cerbations are, for the most part, either environmen-DOI: 10.1378/chest.09-1895 tal allergens or viruses, suggesting that immunologicwww.chestpubs.org CHEST / 137 / 6 / JUNE, 2010 1417 Downloaded from chestjournal.chestpubs.org by guest on July 22, 2011 © 2010 American College of Chest Physicians
  3. 3. responses viewed traditionally as either innate or and the host immune response. Airway inflammationacquired are in fact intertwined. The “hygiene in asthma reflects a distortion of this balance andhypothesis” for asthma pathogenesis contends that is orchestrated through complex interplay betweenmicrobiologic factors may also be inherently involved multiple effector and target components.in the suppression of the asthmatic phenotype, withchildhood exposure to microbiologic stimuli confer- Mast Cellsring a protective effect against the development of Mast cells are critical in mediating the acuteatopy.3 The proposed explanation for this effect is that response in asthma. While classically, mast cell acti-infection early in life stimulates a Th1 immunologic vation occurs following the binding of antigens toresponse (characterized by the release of cytokines FcεR1-bound, antigen-specific IgE, they may also besuch as interferon-g), rather than the Th2 response activated through other mechanisms, including stim-(characterized by cytokines such as IL-4, IL-5, IL-13, ulation of complement receptors, FcgR1, and viaand tumor necrosis factor [TNF]-a) associated with TLRs.10 Other novel mechanisms of mast cell activa-allergy and asthma. A person’s initial exposure to tion, independent of IgE, are via the protein S100A12microorganisms occurs in the birth canal during normal and the receptors CD200R3/CD200R, whereasvaginal delivery. A Dutch birth cohort study suggests IL-33, a member of the IL-1 cytokine family, hasan increased risk of asthma at 8 years of age in chil- demonstrated the ability to activate mast cells, evendren delivered by caesarean section and therefore in the absence of FcεR1 stimulation.11-15lends further credence to this hypothesis.4 Further TNF-a is preformed in mast cells and released asstudies suggest that a rural upbringing has a protective part of the asthmatic airway response. In animal andeffect on later development of allergy.3,5 It has been ex vivo models, mast-cell-derived TNF-a promotessuggested that the consumption of farm milk may be antigen- and Th17 cell-dependant neutrophilia afterprotective against subsequent atopy, with this protec- allergenic stimulation and induces dendritic celltive effect linked to CD14, thereby implicating toll- migration.16,17 In murine culture experiments, mast cellslike receptor (TLR) recognition and innate immune induce CD41 T-cell migration, but down-regulateinvolvement in the evolution of an atopic phenotype.6 FcεR1 expression only in Treg cells, while activated The main function of TLRs is in the recognition of Treg cells suppress mast cell FcεR1 expression. Thisinfectious agents to facilitate an appropriate host suggests bidirectional communication between mastimmunologic response. Advocates of the hygiene cells and Treg cells in modulating IgE-mediatedhypothesis originally believed that microbiologic responses.18 A role for mast cells in antigen presenta-stimulation of TLRs modified an individual’s suscep- tion is also suggested by the recent observation thattibility to asthma by promoting a Th1 rather than a mast cells stimulated by IgE-specific antigen undergoTh2 lymphocytic response to an allergen.3 However, FcεR1 cross-linking that enhances apoptosis. Thesewith the discovery of other T-cell subtypes and dead mast cells become ingested by dendritic cells,increasing evidence supporting pivotal roles for and this incorporated antigen helps propagate ongoingT-regulatory (Treg) and Th17 cells, the Th1/Th2 CD41 response.19paradigm of infection/atopy appears to oversimplify Whereas mast cells are generally considered proin-the complex mechanisms involved. flammatory and mediators of tissue destruction, Recent studies may help explain the similarity in they may conversely help limit airway damage.20response evoked by allergens and microbes in the Mast-cell-derived tryptase can cleave IgE, therebyasthmatic airway. The house mite allergen Der p 2 has preventing further mast cell activation and plau-been shown to have similar structural characteristics sibly helping to contain the allergic response.21,22to MD-2, an integral component of the TLR4/CD14/ Disappointingly, a recent human study examiningMD-2 transmembrane receptor and TLR signaling.7,8 a potential role for therapeutic intervention withAlso, Trompette et al9 have provided in vitro and the monoclonal antibody to TNF-a, golimumab, inin vivo evidence of functional similarity between Der severe, persistent asthma was abandoned because ofp 2 and MD-2. These results place TLRs in an ideal an unfavorable risk-benefit profile.23position to coordinate responses traditionally viewedseparately, as either innate or adaptive immunologic Basophilsreactions that typify the asthmatic response. Basophils have a crucial role in initiating allergic Effector Cells of Inflammation inflammation through the binding of antigen-specific and Remodeling in Asthma IgE antibodies at the FcεR1.24 Basophils also drive Th2 cell differentiation of activated naive CD41 T cells via In the healthy human airway there is normally a production of IL-4 and direct cell-cell contact.25 Murinefine balance between immune cells, the epithelium, studies show that following activation, basophils migrate1418 Recent Advances in Chest Medicine Downloaded from chestjournal.chestpubs.org by guest on July 22, 2011 © 2010 American College of Chest Physicians
  4. 4. in small numbers to adjacent lymph nodes. Using a initiating immune response against airborne antigen.basophil FcεR1-specific monoclonal antibody, it has Hence, dendritic cells may dictate the subsequentbeen demonstrated that the presence of basophils but T-cell response. Two major subsets of dendritic cellsnot mast cells is an absolute requirement for Th2 cell have been described, based on CD11c expression.differentiation.26 Basophils also increase humoral Myeloid (CD11c1) dendritic cells are proinflamma-immune responses on repeat antigenic exposure in the tory, critical to both Th2 sensitization and the second-presence of activated CD41 cells through the release of ary immune response, and typically produce IL-12.IL-4 and IL-6, which provide support for B-cell prolif- In contrast, plasmacytoid (CD11c2) dendritic cellseration and antibody generation.27 play a role in the induction of tolerance, preventing Mice lacking the Fc receptor for IgG FcgR res- inflammatory responses to harmless antigen, andpond to IL-3 in terms of normal development and mainly produce interferon-g (Table 1). Plasmacytoidproliferation but have defective IL-4 (and also IL-6) dendritic cells turn over peptide-major histocompat-production and impaired ability to stimulate Th2 ibility complex class 2 complexes when activated, withdifferentiation.28 In culture, basophils themselves the result that they are inefficient at presenting exog-possess the ability to release IL-3 following FcεR1 enous antigen but useful at presenting self-antigenactivation, and this IL-3 promotes IL-13 release, sug- and viral antigen in a continuous manner followinggesting an autocrine function of IL-3 in upregulating activation.30 Therefore, in the regulation of allergythe basophilic response.29 and asthma, plasmacytoid and myeloid dendritic cells would appear to have opposing/balancing roles.Dendritic Cells T Lymphocytes Pulmonary dendritic cells are potent antigen-presenting cells with the capability to rapidly migrate A paradigm emerged whereby the fundamentalto draining lymph nodes, suggesting an innate role in problem in asthma was believed to be disturbance of Table 1—Summary of the Key Mediators of Asthmatic Inflammatory ResponseMediator Potential Sources Potential Key ActionsIL-4 Mast cells, basophils Immunoglobulin class switching of B cells from IgG to IgE; differentiation of Th2 cells; maturation of dendritic cellsIL-5 Mast cells Differentiation and enhanced survival of eosinophilsIL-13 Mast cells, basophils Immunoglobulin class switching of B cells from IgG to IgE; induction of inflammatory cytokine release from epithelial and other structural cellsTNF-a Mast cells, alveolar macrophages, T cells, Induction of proinflammatory cytokine release from structural cells; epithelial cells, airway smooth muscle promotion of Th17-induced neutrophilia; enhancement of dendritic cell migration; induction of CD4 T-cell migration; antigen presentation; modulation of Treg cellsIL-6 “Structural” cells, dendritic cells, basophils Aids Th17 expansion and developmentIL-17A Th17 cells Promote neutrophilia via induction of proinflammatory cytokine and chemokine release from structural cellsIL-33 Structural cells such as epithelial cells Promote differentiation to Th2 cells; chemoattractant for Th2 cells; enhance survival of, and cytokine production by, mast cellsSCF Structural cells, mast cells, and eosinophils Growth factor and chemoattractant for mast cellsTGF-b Eosinophils, mast cells, and macrophages Proliferation of fibroblasts; possibly induction of EMT; development of immune tolerance via promotion of a Treg response; in combination with IL-6, may promote a Th17 responseVEGF Structural cells, eosinophils Angiogenic promotion of vascular remodelingTSLP Epithelial cells Promotion of a Th2 response; activation of dendritic cells and mast cellsNeurotrophin Epithelial cells, fibroblasts, airway smooth Enhanced airway eosinophilia; mast cell recruitment and activation; (NGF and BDNF) muscle cells, macrophages, mast cells, increased airway hyperresponsiveness; promotion of airway eosinophils, and lymphocytes inflammatory responseLipoxins Derived at mucosal surface from interaction Attenuate bronchial hyperresponsiveness and promote resolution between neutrophils and primarily epithelial of inflammation cells, but also platelets, endothelial cells, leukocytes, and fibroblastsResolvins Interaction between neutrophils and Enhance resolution of airway inflammation and attenuate bronchial structural cells hyperresponsivenessProtectins Interaction between neutrophils and Decrease allergic airway inflammation and airway hyperresponsiveness structural cellsBDNF 5 brain derived neurotrophic factor; EMT 5 epithelial mysenchymal transition; IL 5 interleukin; NGF 5 nerve growth factor; SCF 5 stemcell factor; TGF 5 transforming growth factor; Th 5 T-helper; TNF 5 tumor necrosis factor; Treg 5 T-regulatory; TSLP 5 thymic stromal lymphopoietin;VEGF 5 vascular endothelial growth factor.www.chestpubs.org CHEST / 137 / 6 / JUNE, 2010 1419 Downloaded from chestjournal.chestpubs.org by guest on July 22, 2011 © 2010 American College of Chest Physicians
  5. 5. the normal Th1/Th2 balance. Although elements ofthis hypothesis remain useful, the emerging roles forother T-cell subtypes in asthma suggest that it is toosimplistic. Th17 cells are a distinct population ofCD41 cells that produce IL-17A, IL-17F, IL-22,TNF-a, and IL-21, and express the transcription fac-tor RORgt.31 Recently, Th17 cells were isolated frombiopsy samples obtained from patients with asthma.32 IL-17 induces the release of a range of proinflam-matory cytokines and chemokines from a variety ofcell types.31 It is linked to the development of airwayneutrophilia, and its presence in the asthmatic airwaycorrelates with increased disease severity. In murinemodels of asthma, IL-23 and Th17 cells enhanceantigen-induced airway recruitment of both eosino-phils and neutrophils, while mast-cell-derived TNF Figure 1. Kaplan-Meier analysis of patients without an asthmahas been shown to illicit a Th17-mediated airway neu- exacerbation during a study by Nair et al47 examining the effect of the monoclonal antibody to interleukin-5, mepolizumab, introphilic response following antigen challenge.16,33 patients with steroid-dependant asthma The median time to first Treg cells play roles in the determination of self- exacerbation was 20 weeks in the mepolizumab group vs 12 weekstolerance and the regulation of immune responses. in the placebo group (P 5 .003).Th17 and Treg cells have opposing actions, being inthe main proinflammatory and antiinflammatory, phenotype or the clinical manifestations of asthma.respectively. Experimental data suggest that retinoic Despite this, therapies that reduce sputum eosino-acid suppresses Th17 cell differentiation while pro- philia are effective in both forms of asthma.42moting Treg expansion.34,35 Further studies have IL-5 has a key role in the modulation of eosinophilbrought this a step further and demonstrated recip- differentiation and the promotion of eosinophil sur-rocal generation of Treg and Th17 cells, with the vival. Hence, targeting IL-5 would seem a logicalpresence of transforming growth factor (TGF)-b in therapeutic strategy for allergic asthma. Indeed, anti-isolation favoring a Treg response, while TGF-b in IL-5 therapy has demonstrated clinical efficacy incombination with IL-6 favored a Th17 response.35,36 hypereosinophilic syndromes.43 In patients with asthma,A similar reciprocal relationship between Th17 and a monoclonal IL-5 antibody, while markedly reduc-Treg cells, dependant on the relative levels of RORgt ing blood eosinophils, only partially abrogated theand Foxp3, with Foxp3 attenuating the function of pulmonary eosinophilic response and, subsequently,RORgt, has also been shown.37 had minimal impact on clinical outcomes.44,45 More Invariant natural killer (NK) T cells produce both recent studies in patients with refractory, eosinophilicTh1 and Th2 cytokines in large quantities and therefore asthma have demonstrated the ability of an anti-IL-5enhance the function of dendritic cells, NK-T cells, monoclonal antibody (mepolizumab) to reduce bothB cells, and conventional T-cell subsets. Initial studies blood and sputum eosinophil levels, reduce exacer-suggested a potential role for invariant NK-T cells in bations, and facilitate a reduction in oral corticosteroidthe pathophysiologic development of asthma.38 Later dose (Fig 1).46,47 These results indicate that, at least instudies have, however, disputed this.39,40 Furthermore, a subset of patients with asthma, eosinophils areit has also been reported that NK-T cells alone or in critical effector cells in persistent asthma and severecombination with memory CD81 T cells are insuffi- exacerbations.cient to induce allergic airway inflammation in miceand their presence is not a prerequisite for its develop- Neutrophilsment.41 The nature of the part played by invariant NK-Tcells has therefore yet to be conclusively illustrated. In acute, severe exacerbations of asthma, there are increased eosinophils and neutrophils within the air-Eosinophils way, with the increase in neutrophils proportionately higher than that of eosinophils.48 Inhaled corticoster- The precise role eosinophils play in the pathophys- oids reduce airway eosinophils, but increase airwayiologic causes of asthma remains controversial. Asthma neutrophils and increase the expression of the neu-can be divided into eosinophilic and noneosinophilic trophil chemoattractant IL-8, which is associatedasthma depending on the presence or absence of air- with loss of asthma control.49 There has been long-way eosinophils. The inference from this is that standing interest in the observed differences andeosinophils are not a prerequisite for the asthmatic similarities between the asthmatic airway and that1420 Recent Advances in Chest Medicine Downloaded from chestjournal.chestpubs.org by guest on July 22, 2011 © 2010 American College of Chest Physicians
  6. 6. described in COPD. A recently published study has ticular in patients with steroid-resistant asthma.64described elevated levels of granulocyte-macrophage Particulate matter has also been shown to induce thecolony-stimulating factor in the sputum of patients release of proinflammatory mediators and inducewith moderate to severe asthma and also in patients cycloxygenase-2 expression in human airway epithe-with COPD, regardless of its severity.50 Therefore, it lial cells.65 In addition to acting as a potent source ofappears likely that an increase in airway neutrophils proinflammatory cytokines, epithelial cells possesshas important clinical implications in asthma.51 the ability to present self-antigen, with resultant effects on the regulation of CD41 T-cell function, including the induction of Foxp3 Treg cells, thus pro- The Regulation of Inflammatory moting immune tolerance.66 Cell Production in Asthma The process of airway remodeling involves altera- tions to the various components of airway structure, The bone marrow represents a vast source of with fibroproliferation, influx of myofibroblasts, col-potential effector cells with the ability to affect lagen deposition, hypertrophy of airway smooth mus-inflammation.52 While the bone marrow may act as a cle, and reticular basement membrane thickeningreservoir for mature granulocytes, it is increasingly typical. Remodeling occurs in asthma, and indeed,recognized that hemopoietic progenitor stem cells parameters associated with remodeling are increasedmay be released from the bone marrow and recruited in severe disease, with the airway mucosa of patientsto sites of injury, including the lung, and participate with severe asthma displaying evidence of increasedin the inflammatory and the reparative processes.53 proliferation of epithelium and increased thickening Allergen inhalation challenge experiments impli- of the epithelium and lamina reticularis.60 The para-cate upregulation of the chemokine receptor (CCR) 3 digm of remodeling as a chronic, dysfunctional, repairin facilitating the egress of these progenitors from the response to ongoing inflammation has, however,bone marrow. Eotaxin-1 up-regulates CCR3 on recently been challenged. While studies demonstrateCD341 cells, with the resultant increased release of a progressive loss of lung function associated withthese cells into the circulation, while pharmacologic severe asthma exacerbations,67,68 it has been recognizeddown-regulation of CCR3 attenuates sputum eosino- that remodeling may occur very early in asthma andphilia in response to allergen inhalation in patients may in some cases even predate clinical symptoms.with mild to moderate asthma.54,55 Down-regulation Airway biopsy studies in children suggest that patho-of CXCR4 on bone marrow CD341 cells and reduced logic changes such as epithelial loss, basement mem-stromal-cell-derived factor 1a may further promote brane thickening, and angiogenesis occur early in theprogenitor cell efflux from the bone marrow following asthmatic airway.59,69 Although there exist progenitorallergen challenge, while attenuation of expression of cell types within the bronchial epithelium with thethe adhesion molecule b1-integrin on progenitor cells capacity for renewal following injury, repair pathwaysmay aid their release into the circulation.56,57 are likely dysfunctional in asthma.70 In the asthmatic airway, there are increased num- Airway Structural Cells in Asthma bers of subepithelial myofibroblasts, and allergen challenge in people with asthma leads to increased Traditionally viewed as a passive defensive barrier accumulation of myofibroblasts in the airwayto pathogenic insult, the airway epithelium is now mucosa.58,71 The precise source of these fibroblasts inaccorded a pivotal position in orchestrating the host airway disease remains a topical source of debate.inflammatory response in airway remodeling and Fibroblastic infiltration of the lung may plausibly befibroproliferation.58 Multiple asthma biopsy studies secondary to the recruitment of circulating bone-have demonstrated airway epithelial abnormality, marrow-derived progenitors termed fibrocytes to theand the epithelium, placed at the interface between airway and to the proliferation and expansion of resi-the external environment and the host, appears to be dent fibroblasts, or possibly, epithelial cells mayboth a site of action and of reaction within the asth- undergo phenotypic change to effector fibroblastsmatic inflammatory cascade.58-60 through a process termed epithelial-mesenchymal The airway epithelium is known to be a major transition. Airway biopsies have demonstrated thesource of proinflammatory mediators. Recent examples increased presence of fibrocytes in the airway smoothinclude thymic stromal lymphopoietin, an epithelial- muscle bundle of patients with asthma of varyingderived cytokine expressed in the asthmatic airway, severity compared with control subjects. Further-which has been shown to activate dendritic cells, more, in an ex vivo model, airway smooth musclepromote Th2 responses, and activate mast cells.61-63 cells promoted fibrocyte migration.72 A murine modelEndothelin-1 is also increased in airway epithelial of chronic allergenic-stimulated airway remodelingbiopsies in patients with severe asthma and in par- has revealed a crucial role for stem cell factor andwww.chestpubs.org CHEST / 137 / 6 / JUNE, 2010 1421 Downloaded from chestjournal.chestpubs.org by guest on July 22, 2011 © 2010 American College of Chest Physicians
  7. 7. IL-31 in promoting the influx of bone-marrow-derived kinase, with further experiments in rat models sug-fibroblast progenitors to the lung.73 Recently, primary gesting that this may be associated with the potentialairway epithelial cells derived from subjects with to increase maximal flow and thereby contribute to theasthma demonstrated increased susceptibility to TGF- airway hyperresponsiveness seen in asthma.82 Airwayb-induced epithelial mesenchymal transition than smooth muscle cells can also be induced to secretethose derived from normal subjects.74 mediators that may promote mast cell chemotaxis, Fibroblast culture, animal, and human studies sup- proliferation, and survival, while cell-cell interactionport the ability of leukotrienes to promote airway between airway smooth muscle cells and mast cellsremodeling.75-77 Bronchial epithelial cell experiments enhances activated complement-induced mast cellhave demonstrated a role for TLR signaling in the degranulation.83-85 Interestingly, human lung mast cellsactivation of epidermal growth factor receptor, sug- will migrate toward Th2 cytokine-stimulated airwaygesting a role for TLRs in potentiating remodeling.78 smooth muscle cells from subjects with asthma,Histamine is capable of inducing the transition from but not subjects without asthma, while supernatantsfibroblasts to myofibroblasts, as measured by a-smooth obtained from airway smooth muscle cell cultures ofmuscle actin expression, and can, in addition, induce subjects without asthma inhibit the chemotacticconnective-tissue-growth-factor expression in fibro- action of asthmatic airway smooth muscle cells.86blasts, suggesting the ability to participate in the pro- In a recent study examining differences betweencess of remodeling.79,80 chronic persistent and intermittent persistent Airway smooth muscle mass is increased in the asthma, endobronchial biopsy specimens showedasthmatic airway.81 Asthmatic airway smooth muscle increased a-smooth muscle actin immunoperoxidaseshows increased expression of the fast myosin heavy staining in samples obtained from subjects withchain isoform transgelin, as well as myosin light chain chronic persistent asthma. There was also an increased Figure 2. The pathophysiologic mechanism of asthma involves a coordinated, albeit dysfunctional, multisystem response to airway stimulation, involving the airway epithelium, airway smooth muscle, circulatory system, regional lymph nodes, and the bone marrow, with these elements in tandem with effector inflammatory cells such as dendritic cells, mast cells, T cells, and eosinophils, as well as cytok- ines and chemokines propagating the host inflammatory response. The airway epithelium appears to be inherently abnormal. Over time, the epithelium, smooth muscle, and vasculature undergo structural changes termed remodeling. The regional lymph nodes serve as stations to facilitate a specific immune response, while the bone marrow serves as a source of both effector inflammatory cells and fibrocytes, which contribute to airway inflammation and remodeling, respectively. DC 5 dendritic cell; MC 5 mast cell; Th 5 T helper; TLR 5 toll-like receptor.1422 Recent Advances in Chest Medicine Downloaded from chestjournal.chestpubs.org by guest on July 22, 2011 © 2010 American College of Chest Physicians
  8. 8. proportion of both neutrophils and eosinophils in manifestations of the disease, particularly in the devel-sputum obtained from this group.87 opment of severe exacerbations. The epithelium, The angiogenic changes associated with asthma smooth muscle, and vascular and neuronal elements ofmay also occur early in the pathophysiologic develop- the asthmatic lung also show evidence of dysfunction.ment of the disease (Fig 2).59 Airway smooth muscle While these structural components undergo consider-cells from subjects with asthma but not healthy sub- able architectural disturbance through remodeling,jects can promote in vitro angiogenesis.88 BAL fluid they additionally act as a potent source of critical effec-obtained from patients with asthma has been shown tor cells within the asthmatic airway.to possess a proangiogenic effect, which appears tobe mediated through the actions of vascular endothe-lial growth factor (VEGF), while further studies of Acknowledgmentsthe asthmatic airway demonstrate increased vascular- Financial/nonfinancial disclosures: The authors have reportedity and higher levels of VEGF, and potentially impli- to CHEST the following conflicts of interest: Dr Murphy is a past recipient of an European Respiratory Society fellowship. Dr O’Byrnecate mast cells as a significant source of VEGF.89-92 is on advisory boards for AstraZeneca, GlaxoSmithKline, Topigen,However, increased vascularity and higher VEGF Wyeth, and Schering-Plough. He has received speakers honorialevels exist both in patients with asthma and patients from AstraZeneca and GlaxoSmithKline, and has received research support from AstraZeneca, GlaxoSmithKline, Merck,with eosinophilic bronchitis but without asthma, Wyeth, Schering-Plough, and Alexion.implying that vascular remodeling may not directlyinfluence airway hyperresponsiveness.93 Studies point to an interactive process between the Referencesimmunologic and neuronal systems in the propaga- 1. Kabesch M, Schedel M, Carr D, et al. IL-4/IL-13 pathwaytion of asthmatic response. Murine models of asthma genetics strongly influence serum IgE levels and childhoodhave shown that the communicative process between asthma. J Allergy Clin Immunol. 2006;117(2):269-274. 2. Loza MJ, Chang BL. Association between Q551R IL4Rthe two systems may be linked via the ion channel genetic variants and atopic asthma risk demonstrated byTRPA1.94 In human studies, increased levels of brain- meta-analysis. J Allergy Clin Immunol. 2007;120(3):578-585.derived neurotrophic factor have been associated with 3. von Hertzen L, Haahtela T. Disconnection of man and theloss of control in patients with mild allergic asthma.95 soil: reason for the asthma and atopy epidemic? J Allergy Clin Immunol. 2006;117(2):334-344. 4. Roduit C, Scholtens S, de Jongste JC, et al. Asthma at 8 years of age in children born by caesarean section. Thorax. 2009; Endogenous Antiinflammatory Mediators 64(2):107-113. 5. Debarry J, Garn H, Hanuszkiewicz A, et al. Acinetobacter Much of this article and indeed research to date has lwoffii and Lactococcus lactis strains isolated from farmfocused on proinflammation, fibroproliferation, and cowsheds possess strong allergy-protective properties. 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  12. 12. Recent Advances in the Pathophysiology of Asthma Desmond M. Murphy and Paul M. OByrne Chest 2010;137; 1417-1426 DOI 10.1378/chest.09-1895 This information is current as of July 22, 2011Updated Information & ServicesUpdated Information and services can be found at:http://chestjournal.chestpubs.org/content/137/6/1417.full.htmlReferencesThis article cites 98 articles, 56 of which can be accessed free at:http://chestjournal.chestpubs.org/content/137/6/1417.full.html#ref-list-1Permissions & LicensingInformation about reproducing this article in parts (figures, tables) or in its entirety can befound online at:http://www.chestpubs.org/site/misc/reprints.xhtmlReprintsInformation about ordering reprints can be found online:http://www.chestpubs.org/site/misc/reprints.xhtmlCitation AlertsReceive free e-mail alerts when new articles cite this article. To sign up, select the"Services" link to the right of the online article.Images in PowerPoint formatFigures that appear in CHEST articles can be downloaded for teaching purposes inPowerPoint slide format. See any online figure for directions. Downloaded from chestjournal.chestpubs.org by guest on July 22, 2011 © 2010 American College of Chest Physicians

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