Search tips
Search criteria 


Logo of aairAllergy, Asthma & Immunology ResearchThis ArticleThis JournalAboutFor Contributorse-Submission
Allergy Asthma Immunol Res. 2010 July; 2(3): 165–171.
Published online 2010 May 6. doi:  10.4168/aair.2010.2.3.165
PMCID: PMC2892047

A Brief History of Asthma and Its Mechanisms to Modern Concepts of Disease Pathogenesis


The original concept of asthma being primarily a disease of airways smooth muscle drove the development of bronchodilator drugs. However when it was realised that airway inflammation underpinned the disordered airway function, this gave way to the development of controller therapies such as inhaled cromones and corticosteroids. More recently the discovery of complex interconnecting cytokine and chemokine networks has stimulated the development of biologics with varying success. With the recognition that airway wall "remodelling" is present early in asthma inception and is in part driven by aberrant epithelial-mesenchymal communication both genetic and environmental factors beyond allergen exposure such as virus infection and air pollution are being seen as being increasingly important not only in asthma exacerbations but in the origins of asthma and its evolution into different sub-phenotypes. This brings us round full circle to once again considering that the origins of asthma lie in defects in the formed elements of the airway; the epithelium, smooth muscle, and vasculature. Over the last 25 years Professor You Young Kim has engaged in the exciting discovery science of allergy and asthma and has made an enormous contribution in bringing Korea to the forefront of disease management and research, a position that both he and his colleagues can justly be proud of.

Keywords: Asthma, airway inflammation, airway remodeling, infection, epithelial-mesenchymal trophic unit, ADAM33


The word "asthma" originates from the Greek meaning short of breath, meaning that any patient with breathlessness was asthmatic. The term was refined in the latter part of the 19th Century with the publication of a treatise by Henry Hyde Salter entitled "On Asthma and its Treatment". In this scholarly work Salter defined asthma as "Paroxysmal dyspnoea of a peculiar character with intervals of healthy respiration between attacks", a description that captures his concept of a disease in which the airways narrow due to contraction of their smooth muscle.1 His book contains remarkably accurate illustrations of the airways in asthma and bronchitis as well as the cellular appearance of asthmatic sputum some 30 years before Paul Ehrlich described aniline stains for eosinophils (eosin) and mast cells (toluidine blue).2,3 He also described black coffee as a treatment for asthmatic spasms, a drink with a high content of theobromine, a derivative of theophylline and theophylline itself. This extraordinary insight into asthma stems from Dr Salter himself suffering from asthma himself. Thus, by the late nineteenth century, physicians adopted the view that asthma was a distinct disease which had a specific set of causes, clinical consequences, and requirements for treatment.

The father of modern medicine in the Western World, Sir William Osler (one of the three founders of the John Hopkins Medical School in Baltimore, US) described asthma in his first (1892) edition of the textbook Principles and Practice of Medicine4 in the following terms:

  1. Spasm of the bronchial muscles
  2. Swelling of the bronchial mucous membrane
  3. A special form of inflammation of the smaller bronchioles
  4. Having many resemblances to hay fever
  5. The affection running in families.
  6. Often beginning in childhood and sometimes lasting into old age.
  7. Bizarre and extraordinary variety of circumstances which at times induce a paroxysm:
    1. Climate and atmosphere e.g. hay, dust, cat
    2. Fright or violent emotion
    3. Diet (overloading of the stomach) or certain foods
    4. Cold infection
  8. Sputum is distinctive: rounded gelatinous masses ("perles") and Curschmann spirals & octahedral crystals of Leyden

These insights came as a consequence of Osler's drive to connect clinical observation with pathology and physiology. Asthma was treated largely a disease of "bronchospasm" since bronchodilators that included theophylline, ephedrine, adrenaline and by the first half of the 20th century, isoprenaline to be followed by the selective β2-adrenoceptor agonists, salbutamol, terbutaline, remiterol and fenoterol by inhalation and as oral medications. However, their very effectiveness in reversing bronchospasm and their initial apparent safety led to their unrestricted use as over-the-counter medications. Over-reliance on bronchodilators was thought to underlie the epidemic of asthma death reported in Australia, the US and the UK that peaked in the mid 1960s (isoprenaline-related) and a second peak in New Zealand in the mid 1980s (high dose fenoterol-related).5

These asthma death epidemics drew into sharp focus the shortfalls in asthma treatment and emphasised how little was understood about why the airways of asthmatics were so liable to bronchospasm. Although since the early 1920s asthma death was known to be associated with extensive inflammation and structural changes in the airways,6 very little was known about why this occurred and what relation it had to episodic bronchospasm. Indeed, asthma was largely managed as an acute disorder of episodic exacerbations. The discovery of reagin by Prausnitz and Kϋstner in 1921 as a serum substance that could passively transfer allergy to a specific agent (in this case cod allergen)7 subsequently led to the identification of IgE as the 5th immunoglobulin class IgE by Johansson and Ishizaka8 and provided the crucial link. It turned out that most asthmatics exhibited allergy to a wide range of indoor and outdoor agents including dust mites, pollens and animal proteins.


Thus, by the 1980s a clearer understanding of how allergen exposure triggered chemical mediator release from airway mast cells (early reaction) and this resulted in turn led to the recruitment of eosinophils, basophils and mononuclear cells (late reaction),9,10 the latter response being associated with enhanced airway reactivity to irritant stimuli (bronchial hyperresponsiveness ??BHR). The allergic paradigm for asthma also explained why the mast cell stabilising agent, sodium cromoglicate, attenuated both the allergen-induced early and late bronchoconstrictor responses.11 Clinical trials in the 1970s had also established that inhaled corticosteroids, notably beclomethasone dipropionate ??BDP, was a highly effective controller drug for asthma when taken daily.12 The discovery that BDP reduced airway eosinophilic, mast cell and mononuclear cell inflammation13 and abrogated the late asthmatic reaction and accompanying BHR with allergen challenge14,15 created a mechanistic reason for their efficacy in controlling day-to-day asthma.

The mast cell had assumed centre stage as the principle triggering cell of asthma involving IgE-dependent activation with secretion of a wide array of autacoid, enzyme and proteoglycan mediators.16 However, little was known about how mast cell activation-secretion coupling occurred. Changes in Ca++ flux was considered important as confirmed by the inhibitory effects of Ca++ channel blockers such as nifedipine. You Young Kim, while on a Research Fellowship in my laboratory in 1983, showed that the lack of stimulus-related specificity and the high drug concentrations required suggested that classical calcium channel blockade was not responsible for the inhibition of mast cell mediator release observed.17 Although in the early 1980s histamine, prostaglandin D2, the cysteinyl leukotrienes [LTC4, LTD4 and LTE4 - previously known as slow reacting substance of anaphylaxis (SRS-A)], tryptase, chymase, heparin and exoglycosidases were all identified mast cell products with discrete proinflammatory effects, almost nothing was known about why mast cells were so sensitive to stimulation in asthma. At that time there was increasing interest in the role of T lymphocytes in underpinning the allergic response.18 A large number of poorly characterised factors had been traced back to lymphocytes such as neutrophil chemotactic factor, eosinophil chemotactic factor, macrophage inhibitory and activation factors, the underlying connection between these and the allergic phenotype remained a mystery.19


A breakthrough came with the identification of a special subset of T cells capable of secreting cytokines that selectively interacted with mast cells, basophils and eosinophils. These Th2-type T cells with their cytokine repertoire (IL-3, -4, -5, -9, -13 and GM-CSF) were responsible for the recruitment, priming and survival of the primary effecter cells of the allergic cascade.20 In genetically susceptible individuals (atopic) allergens prevalent in the indoor and outdoor environment were detected by and subsequently modified by a third set of cells, the antigen-presenting population, especially dendritic cells (DCs) that accumulated at epithelial surfaces such as the airways. The last decade has witnessed a huge increase in knowledge about how DCs recognise allergens and communicate the specific sensitising signal to naive T cells involving Class II MHC restricted allergen peptide presentation to the T cell receptor (CD3) and engagement of co-stimulatory molecules.21

Thus, a combination of genetic susceptibility and allergen exposure is crucial to initiating and then perpetuating the allergic cascade via DC-T-cell communication. Because of genetic background and environmental exposures, asthma associated with allergens is likely to vary greatly. One particular subgroup which is particularly vulnerable is those exposed to allergens in the work-place.22 Good example of this is the discovery by Kim et al that Citrus red mite (Panonychus citri) is the most common sensitizing allergen of asthma and rhinitis in citrus farmers in Korea.23 Allergy tests, questionnaire and BHR measured in 181 citrus fruit farmers revealed a prevalence of asthma of 12.1%, rhinitis 17.1% associated with a positive skin-prick test to allergens from the citrus red mite of 16.5%, cockroach 11.0% and Dermatophagoides farinae 9.3%. Importantly, in farmers with asthma or rhinitis, allergy to citrus red mite was associated with to 54.5% and 68.5% of subjects respectively thereby establishing a strong causal association in this exposed population.24 Citrus red mite allergy also proved to be a common sensitizing allergen in children living around citrus orchards.25 Another informative example of how local customs dictate allergic disease is the recognition of Korean ginseng-induced occupational asthma and the determination of IgE binding components.26

Beyond the recognition that allergen exposure in specific settings was a key step in the pathophysiology of asthma, the discovery that one could block the primary mast cell signalling cascade by directing a monoclonal antibody towards the IgE binding site to the high affinity receptor (FcεR1) without producing anaphylaxis was a great breakthrough27 since this was the first specific biologic to be used in the treatment of severe allergic asthma.28 Clinical trials of the monoclonal antibody, omalizumab, revealed efficacy as well as almost total inhibition of the early and late asthmatic responses to inhaled allergen.29 Airway biopsy, blood and sputum studies also established the anti-inflammatory activities of omalizumab.30 Cho et al had established that pathological changes in the airways progressively increased according to the severity of asthma.31 However, only one third to one half of patients with severe allergic asthma appeared to respond to omalizumab leading to the recommendation that treatment response at 16 weeks should be assessed using multiple endpoints. The reason why some patients with severe allergic asthma respond to omalizumab and others do not may relate to the extent that blockade of IgE binding to mast cells and dendritic cells produce down-regulation of FcER1.32


In addition to airway inflammation, there are extensive structural changes that occur in asthmatic airways that are especially prominent as the disease takes on a more severe and chronic phenotype.31 These include epithelial mucous metaplasia, deposition of matrix proteoglycans and collagens in the submucosa and between the bundles of smooth muscle, an increase in smooth muscle itself and proliferation of microvessels and nerves.6 These changes are referred to as remodelling. The increased thickness of the subepithelial lamina reticularis is diagnostic of asthma and also increases with disease severity but not disease duration.33 Indeed, this unique feature of asthma is present almost from the inception of the disease in early childhood34,35 and, as in adult asthma, is associated with atopy since it is also present in atopic subjects with asymptomatic BHR.36,37 It seems likely that such a response is the result of a dysfunctional airway epithelium which exhibits a breakdown in epithelial tight junction integrity compatible with impaired repair following injury.38 This impairment of barrier function is also accompanied by increased expression of epidermal growth factor receptors (EGFRs) and accompanying tyrosine kinase phosphorylation and yet impaired epithelial repair.39,40 This apparent conflict is explained by cell cycle inhibition resulting from increased nuclear translocation of the cell cycle inhibitor P21waf present at the inception of asthma.34,41 However, as the disease becomes more severe and chonic, epithelial thickening and squamous metaplasia may occur.33,42 EGFR activation is also a major pathway for epithelial mucous metaplasia and IL-8 production.43 InterIeukin 8 (CXCL 8) and related chemokines (CXCL 1-7) are powerful chemoattractants by interacting with CXCR2 on the surface of neutrophils. Their increased production by a dysfunctional epithelium44 may explain the increased neutrophil prominence observed in more severe and corticosteroid refractory asthma45 as well as in the airways of asthmatic patients who smoke.46

Impaired wound healing and failure to form adequate tight junction assemblies are phenotypes that persist when asthmatic epithelial cells are cultured in vitro and differentiated at an air liquid interface suggesting that the epithelium is primarily defective in asthma.38,47 In this respect, it is of interest that many of the newly identified genes that increase asthma susceptibility are preferentially expressed in the epithelium (e.g. DPP10, SPINK5, GPR 154, HLA-G, MUC8, chitinase 3-like-1 (YKL-40), PCDH-1, ORMDL3 and GSDLG).48 Altered barrier function has also recently been recognised as an important feature of atopic dermatitis (filaggrin mutations),49 food allergy50 and rhinosinusitis.51 In addition to innate defects in barrier function, environmental agents such as biologically active allergens (dust mites, pollens, fungi and occupational allergens e.g. proteases in washing powders) and virus infections are potent agents that can attack tight junctions.52,53

In addition to alterations in physical barrier function, the airway epithelium in asthma my also be functionally deficient. One example of this is the reduced ability of the airway epithelium to protect itself against oxidant injury both directly (tobacco smoke and outdoor air pollutants ??ozone, oxides of nitrogen and particles),54 all known to drive deterioration in asthma control. A further example is the ease with which common and usually innocuous respiratory viruses (e.g. those that cause common colds) can cause serious deterioration in asthma control (exacerbations) leading to the necessity to increase treatment, seek medical help or require hospital admission.55 Yearly monitoring of asthma in the Northern hemisphere reveals a cyclical nature to exacerbations both in the community and in hospital admissions.56 A large September-winter peak is followed by smaller spring and summer peaks. The former is driven by virus infection involving a wide variety of viruses but dominated by the subclasses of rhinovirus, while the latter smaller peaks relate more peaks of pollen exposure (e.g. tree followed by grass). The recent discovery of a new clade of rhinoviruses (Type C) seems to be especially linked to asthma exacerbations.57 In more tropical climates the seasonality of asthma exacerbations is no longer apparent, suggesting that climatic conditions are important for creating this periodicity.


An important question that requires answering is why the asthmatic airway is so vulnerable to respiratory virus infection. Using epithelial cells cultured in vitro, it has been shown that those from asthmatic subjects are more resistant to apoptosis induced by rhinoviruses leading to increased virus replication followed by cytotoxic death of the cell with enhanced virus shedding.58,59 Both for the major and minor rhinovirus subtypes, this defect in viral defence is a direct consequence of impaired production of the primary interferons (IFNs) IFN-β and λ. These cytokines represent the first line of defence against respiratory viruses through their double strand RNA interacting with endosomal toll like receptor (TLR) 3 to phosphorylate the transcription factor Interferon Regulatory Factor (IRF) 3 that on binding to the interferon sensitive response element in nuclear DNA leads to the induction of IFN α and β (the primary anti-viral response) that in turn activate the common interferon receptor to phosphorylate STAT1 that interacts with IRF and gamma-activated sequence (GAS) to induce the production of a wide range of antiviral proteins such as Mx1, IFI1, IFI204, IRF7 and IP10 (secondary anti-viral response).60 This abnormality in innate immunity provides a unique opportunity for treating severe acute exacerbations with inhaled human IFN-β which is now in clinical trial.

The discovery that both barrier function and innate immunity in asthma are abnormal reinforces the pivotal position that the airway epithelium is in to orchestrate cellular events of asthma. A recent important development is the observation that rhino-virus infection in the first 2 years of life is a much more powerful risk factor than allergen exposure at this age.61,62 Indeed it is now looking increasingly likely that impaired epithelial functions predispose the genetically at risk child to developing asthma involving a wide array of environmental insults such as common respiratory virus infections, air pollution, exposure to irritant chemicals (e.g. tobacco smoke) with these factors enhancing the ability of airway dendritic cells (DCs) to overrespond or respond differently to environmental allergens.22 Since Rate and colleagues have recently shown that epithelial production of IFN-β is the principle factor in driving airway DCs down a Th1 pathway, reduced production of this primary interferon may account as occurs in asthma may account for the biased Th2 response that occurs in this disease.63 A deficiency in recruitment of plasmacytoid DCs may further exacerbate virus-induced wheezing in those destined to develop asthma in childhood.64 Additional factors include the enhanced production of Th2 polarising cytokines such as thymic stromal lymphopoietin (TSLP),65 IL-35 (a newly identified member of the IL-1 family),66 CCL5, CCL17 and CCL22.67


Susceptibility to asthma may also reside in the matrix and smooth muscle components of the airways. In 2000 we suggested that in asthma reactivation of the epithelial-mesenchymal trophic unit (EMTU) that is normally involved in foetal branching morphogenesis, leads to exuberant release of a range of growth factors that drive the increase in smooth muscle, angiogenesis and deposition of matrix68 that drive the initial modelling and then remodelling of the entire airway wall in proportion to the disease subphenotype. Such a model embraces the wide number of environmental insults such as associated with asthma at its onset, during exacerbations and in its progression.69 One susceptibility gene associated with the EMTU is ADAM33, the first novel asthma gene to be positionally cloned. ADAM33 is encoded on chromosome 20p13 and is tightly regulated in its expression, being limited to mesenchymal cells such as smooth muscle and fibroblasts.70 Although consisting as 21 exons encoding multiple functions, the metalloprotease activity has aroused most interest as it is potentially "druggable". Polymorphic variation of ADAM33 has been associated with childhood onset asthma and BHR, impaired lung function in infancy, accelerated decline in lung function that occurs in severe asthma and most recently, COPD.71 In a landmark publication, Lee and colleagues discovered that rather than existing solely as a membrane-associated protein of 120kD, ADAM33 can be cleaved into a soluble fragment of 55kD.72 sADAM 33 expressing the catalytic subunit immune-localises to the asthmatic epithelium and to the lamina reticularis beneath the basement membrane as well as to mesenchymal cells. In asthma airway levels of sADAM33 increase in proportion to disease severity and inversely with lung function. Using the soluble catalytic subunit, we have recently shown that ADAM33 is a powerful angiogenesis factor73 as well as increasing smooth muscle in developing foetal lung. Thus, although being identified as an asthma gene, it is looking increasingly as if ADAM33 is a gene involved in multiple aspects of airway modelling and remodelling.


In concluding this brief review, I wanted to say a few words about Professor You Young Kim. Professor Kim first joined my research group in Southampton, UK in 1983 when, as mentioned earlier, he studied activation-secretion coupling in human mast cells and basophils with Martin Church and me. Professor Kim was my first overseas Research Fellow (Fig. 1) and blazed a trail that others were to follow. On his return to Seoul in 1984, he set about building Allergy as a clinical and scientific speciality in Korea. His achievements are little short of outstanding. His enthusiasm to embrace the full spectrum of clinical and scientific aspects of allergy from the most basic to the most applied, his championship of encouraging only the very best level of clinical service and scientific endeavour and his strong belief in encouraging the younger generation to strive towards excellence is truly admirable. Over a span of 25 years he has propelled Korea into the forefront of the field of allergy that is truly in the top league internationally. This has been recognised by the high quality congresses that he and his colleagues have organised in and brought to Korea. It is therefore a fitting tribute of his esteem that the 2015 World Allergy Congress will be held in Seoul Korea. I and my colleagues in the UK wish Professor You Young Kim a very happy and well deserved retirement from his University post. He leaves with the clear knowledge that all his labours have translated into outstanding success. I am sure Sir William Osler, if he was still alive, would be as proud as I am to have been associated with this extraordinary man and his achievements.

Fig. 1
Prof. You Young Kim (right) and the author. This photograph was taken during Prof. Kim's overseas Research Fellowship at Southampton University, UK in 1983.


The author acknowledges the support of the UK Medical Research Council. Professor Holgate is an MRC Clinical Research Professor.


There are no financial or other issues that might lead to conflict of interest.


1. Sakula A. Henry hyde salter (1823-71): A biographical sketch. Thorax. 1985;40:887–888. [PMC free article] [PubMed]
2. Vyas H, Krishnaswamy G. Paul ehrlich's "Mastzellen"--from aniline dyes to DNA chip arrays: A historical review of developments in mast cell research. Methods Mol Biol. 2006;315:3–11. [PubMed]
3. McEwen BJ. Eosinophils: A review. Vet Res Commun. 1992;16:11–44. [PubMed]
4. Osler W. The Principles and Practice of Medicine. 1st ed. NY: D. Appleton and Company; 1892. pp. 497–501.
5. Pearce N. The use of beta agonists and the risk of death and near death from asthma. J Clin Epidemiol. 2009;62:582–587. [PubMed]
6. Holgate ST. Pathogenesis of asthma. Clin Exp Allergy. 2008;38:872–897. [PubMed]
7. Ovary Z. From prausnitz-kustner to passive cutaneous anaphylaxis and beyond. Chem Immunol. 1990;49:90–120. [PubMed]
8. Ishizaka K, Ishizaka T. Mechanisms of reaginic hypersensitivity and IgE antibody response. Immunol Rev. 1978;41:109–148. [PubMed]
9. Austen KF. Reaction mechanisms in the release of mediators of immediate hypersensitivity from human lung tissue. Fed Proc. 1974;33:2256–2262. [PubMed]
10. Durham SR, Carroll M, Walsh GM, Kay AB. Leukocyte activation in allergen-induced late-phase asthmatic reactions. N Engl J Med. 1984;311:1398–1402. [PubMed]
11. Holgate ST. Reflections on the mechanism(s) of action of sodium cromoglycate (intal) and the role of mast cells in asthma. Respir Med. 1989;83(Suppl A):25–31. [PubMed]
12. Turner-Warwick M. Corticosteroid aerosols: The future? Postgrad Med J. 1974;50(suppl 4):80–84. [PubMed]
13. Djukanovic R, Wilson JW, Britten KM, Wilson SJ, Walls AF, Roche WR, Howarth PH, Holgate ST. Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma. Am Rev Respir Dis. 1992;145:669–674. [PubMed]
14. Burge PS, Efthimiou J, Turner-Warwick M, Nelmes PT. Double-blind trials of inhaled beclomethasone diproprionate and fluocortin butyl ester in allergen-induced immediate and late asthmatic reactions. Clin Allergy. 1982;12:523–531. [PubMed]
15. Cockcroft DW. The bronchial late response in the pathogenesis of asthma and its modulation by therapy. Ann Allergy. 1985;55:857–862. [PubMed]
16. Soter NA, Austen KF. The diversity of mast cell-derived mediators: Implications for acute, subacute, and chronic cutaneous inflammatory disorders. J Invest Dermatol. 1976;67:313–319. [PubMed]
17. Kim YY, Holgate ST, Church MK. Inhibition of histamine release from dispersed human lung and tonsillar mast cells by nicardipine and nifedipine. Br J Clin Pharmacol. 1985;19:631–638. [PMC free article] [PubMed]
18. Kay AB. Cell-mediated immune response in asthma. Agents Actions Suppl. 1989;28:365–373. [PubMed]
19. Wasserman SI. Mediators of immediate hypersensitivity. J Allergy Clin Immunol. 1983;72:101–119. [PubMed]
20. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992;326:298–304. [PubMed]
21. Lambrecht BN, Hammad H. Biology of lung dendritic cells at the origin of asthma. Immunity. 2009;31:412–424. [PubMed]
22. Maestrelli P, Boschetto P, Fabbri LM, Mapp CE. Mechanisms of occupational asthma. J Allergy Clin Immunol. 2009;123:531–542. [PubMed]
23. Kim YK, Son JW, Kim HY, Park HS, Lee MH, Cho SH, Min KU, Kim YY. New occupational allergen in citrus farmers: Citrus red mite (panonychus citri) Ann Allergy Asthma Immunol. 1999;82:223–228. [PubMed]
24. Kim YK, Son JW, Kim HY, Park HS, Lee MH, Cho SH, Min KU, Kim YY. Citrus red mite (Panonychus citri) is the most common sensitizing allergen of asthma and rhinitis in citrus farmers. Clin Exp Allergy. 1999;29:1102–1109. [PubMed]
25. Lee MH, Cho SH, Park HS, Bahn JW, Lee BJ, Son JW, Kim YK, Koh YY, Min KU, Kim YY. Citrus red mite (panonychus citri) is a common sensitizing allergen among children living around citrus orchards. Ann Allergy Asthma Immunol. 2000;85:200–204. [PubMed]
26. Kim KM, Kwon HS, Jeon SG, Park CH, Sohn SW, Kim DI, Kim SS, Chang YS, Kim YK, Cho SH, Min KU, Kim YY. Korean ginseng-induced occupational asthma and determination of IgE binding components. J Korean Med Sci. 2008;23:232–235. [PMC free article] [PubMed]
27. Corne J, Djukanovic R, Thomas L, Warner J, Botta L, Grandordy B, Gygax D, Heusser C, Patalano F, Richardson W, Kilchherr E, Staehelin T, Davis F, Gordon W, Sun L, Liou R, Wang G, Chang TW, Holgate S. The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: Efficacy, safety, and pharmacokinetics. J Clin Invest. 1997;99:879–887. [PMC free article] [PubMed]
28. Holgate ST, Chuchalin AG, Hebert J, Lotvall J, Persson GB, Chung KF, Bousquet J, Kerstjens HA, Fox H, Thirlwell J, Cioppa GD. Efficacy and safety of a recombinant anti-immunoglobulin E antibody (omalizumab) in severe allergic asthma. Clin Exp Allergy. 2004;34:632–638. [PubMed]
29. Fahy JV, Fleming HE, Wong HH, Liu JT, Su JQ, Reimann J, Fick RB, Jr, Boushey HA. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med. 1997;155:1828–1834. [PubMed]
30. Holgate S, Smith N, Massanari M, Jimenez P. Effects of omalizumab on markers of inflammation in patients with allergic asthma. Allergy. 2009;64:1728–1736. [PubMed]
31. Eckman JA, Sterba PM, Kelly D, Alexander V, Liu MC, Bochner BS, Macglashan DW, Jr, Saini SS. Effects of omalizumab on basophil and mast cell responses using an intranasal cat allergen challenge. J Allergy Clin Immunol. 2009;125:889–895. [PMC free article] [PubMed]
32. Cho SH, Seo JY, Choi DC, Yoon HJ, Cho YJ, Min KU, Lee GK, Seo JW, Kim YY. Pathological changes according to the severity of asthma. Clin Exp Allergy. 1996;26:1210–1219. [PubMed]
33. Kaminska M, Foley S, Maghni K, Storness-Bliss C, Coxson H, Ghezzo H, Lemiere C, Olivenstein R, Ernst P, Hamid Q, Martin J. Airway remodeling in subjects with severe asthma with or without chronic persistent airflow obstruction. J Allergy Clin Immunol. 2009;124:45–51. [PubMed]
34. Fedorov IA, Wilson SJ, Davies DE, Holgate ST. Epithelial stress and structural remodelling in childhood asthma. Thorax. 2005;60:389–394. [PMC free article] [PubMed]
35. Saglani S, Payne DN, Zhu J, Wang Z, Nicholson AG, Bush A, Jeffery PK. Early detection of airway wall remodeling and eosinophilic inflammation in preschool wheezers. Am J Respir Crit Care Med. 2007;176:858–864. [PubMed]
36. Djukanovic R, Lai CK, Wilson JW, Britten KM, Wilson SJ, Roche WR, Howarth PH, Holgate ST. Bronchial mucosal manifestations of atopy: A comparison of markers of inflammation between atopic asthmatics, atopic nonasthmatics and healthy controls. Eur Respir J. 1992;5:538–544. [PubMed]
37. Sohn SW, Chang YS, Lee HS, Chung DH, Lee CT, Kim YH, Kim YK, Min KU, Kim YY, Cho SH. Atopy may be an important determinant of subepithelial fibrosis in subjects with asymptomatic airway hyperresponsiveness. J Korean Med Sci. 2008;23:390–396. [PMC free article] [PubMed]
38. Holgate ST. Epithelium dysfunction in asthma. J Allergy Clin Immunol. 2007;120:1233–1244. [PubMed]
39. Polosa R, Puddicombe SM, Krishna MT, Tuck AB, Howarth PH, Holgate ST, Davies DE. Expression of c-erbB receptors and ligands in the bronchial epithelium of asthmatic subjects. J Allergy Clin Immunol. 2002;109:75–81. [PubMed]
40. Hamilton LM, Puddicombe SM, Dearman RJ, Kimber I, Sandstrom T, Wallin A, Howarth PH, Holgate ST, Wilson SJ, Davies DE. Altered protein tyrosine phosphorylation in asthmatic bronchial epithelium. Eur Respir J. 2005;25:978–985. [PubMed]
41. Puddicombe SM, Torres-Lozano C, Richter A, Bucchieri F, Lordan JL, Howarth PH, Vrugt B, Albers R, Djukanovic R, Holgate ST, Wilson SJ, Davies DE. Increased expression of p21(waf) cyclin-dependent kinase inhibitor in asthmatic bronchial epithelium. Am J Respir Cell Mol Biol. 2003;28:61–68. [PubMed]
42. Cohen L, E X, Tarsi J, Ramkumar T, Horiuchi TK, Cochran R, DeMartino S, Schechtman KB, Hussain I, Holtzman MJ, Castro M. Epithelial cell proliferation contributes to airway remodeling in severe asthma. Am J Respir Crit Care Med. 2007;176:138–145. [PMC free article] [PubMed]
43. Burgel PR, Nadel JA. Epidermal growth factor receptor-mediated innate immune responses and their roles in airway diseases. Eur Respir J. 2008;32:1068–1081. [PubMed]
44. Hamilton LM, Torres-Lozano C, Puddicombe SM, Richter A, Kimber I, Dearman RJ, Vrugt B, Aalbers R, Holgate ST, Djukanovic R, Wilson SJ, Davies DE. The role of the epidermal growth factor receptor in sustaining neutrophil inflammation in severe asthma. Clin Exp Allergy. 2003;33:233–240. [PubMed]
45. Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: Insights from clinical studies. Proc Am Thorac Soc. 2009;6:256–259. [PubMed]
46. Chalmers GW, MacLeod KJ, Thomson L, Little SA, McSharry C, Thomson NC. Smoking and airway inflammation in patients with mild asthma. Chest. 2001;120:1917–1922. [PubMed]
47. de Boer WI, Sharma HS, Baelemans SM, Hoogsteden HC, Lambrecht BN, Braunstahl GJ. Altered expression of epithelial junctional proteins in atopic asthma: Possible role in inflammation. Can J Physiol Pharmacol. 2008;86:105–112. [PubMed]
48. Cookson W. The immunogenetics of asthma and eczema: A new focus on the epithelium. Nat Rev Immunol. 2004;4:978–988. [PubMed]
49. O'Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2008;122:689–693. [PubMed]
50. Groschwitz KR, Hogan SP. Intestinal barrier function: molecular regulation and disease pathogenesis. J Allergy Clin Immunol. 2009;124:3–20. [PubMed]
51. Tieu DD, Kern RC, Schleimer RP. Alterations in epithelial barrier function and host defense responses in chronic rhinosinusitis. J Allergy Clin Immunol. 2009;124:37–42. [PMC free article] [PubMed]
52. Runswick S, Mitchell T, Davies P, Robinson C, Garrod DR. Pollen proteolytic enzymes degrade tight junctions. Respirology. 2007;12:834–842. [PubMed]
53. Gershwin LJ. Effects of allergenic extracts on airway epithelium. Curr Allergy Asthma Rep. 2007;7:357–362. [PubMed]
54. Hole AM, Draper A, Jolliffe G, Cullinan P, Jones M, Taylor AJ. Occupational asthma caused by bacillary amylase used in the detergent industry. Occup Environ Med. 2000;57:840–842. [PMC free article] [PubMed]
55. Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, Symington P, O'Toole S, Myint SH, Tyrrell DA, Holgate ST. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ. 1995;310:1225–1229. [PMC free article] [PubMed]
56. Sears MR, Johnston NW. Understanding the september asthma epidemic. J Allergy Clin Immunol. 2007;120:526–529. [PubMed]
57. Miller EK, Edwards KM, Weinberg GA, Iwane MK, Griffin MR, Hall CB, Zhu Y, Szilagyi PG, Morin LL, Heil LH, Lu X, Williams JV. A novel group of rhinoviruses is associated with asthma hospitalizations. J Allergy Clin Immunol. 2009;123:98–104. [PubMed]
58. Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, Holgate ST, Davies DE. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J Exp Med. 2005;201:937–947. [PMC free article] [PubMed]
59. Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett NW, Kebadze T, Mallia P, Stanciu LA, Parker HL, Slater L, Lewis-Antes A, Kon OM, Holgate ST, Davies DE, Kotenko SV, Papi A, Johnston SL. Role of deficient type III interferon-lambda production in asthma exacerbations. Nat Med. 2006;12:1023–1026. [PubMed]
60. Lee HR, Kim MH, Lee JS, Liang C, Jung JU. Viral interferon regulatory factors. J Interferon Cytokine Res. 2009;29:621–627. [PubMed]
61. Jackson DJ, Gangnon RE, Evans MD, Roberg KA, Anderson EL, Pappas TE, Printz MC, Lee WM, Shult PA, Reisdorf E, Carlson-Dakes KT, Salazar LP, DaSilva DF, Tisler CJ, Gern JE, Lemanske RF., Jr Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children. Am J Respir Crit Care Med. 2008;178:667–672. [PMC free article] [PubMed]
62. Kotaniemi-Syrjanen A, Reijonen TM, Korhonen K, Waris M, Vainionpaa R, Korppi M. Wheezing due to rhinovirus infection in infancy: Bronchial hyperresponsiveness at school age. Pediatr Int. 2008;50:506–510. [PubMed]
63. Rate A, Upham JW, Bosco A, McKenna KL, Holt PG. Airway epithelial cells regulate the functional phenotype of locally differentiating dendritic cells: implications for the pathogenesis of infectious and allergic airway disease. J Immunol. 2009;182:72–83. [PubMed]
64. Upham JW, Zhang G, Rate A, Yerkovich ST, Kusel M, Sly PD, Holt PG. Plasmacytoid dendritic cells during infancy are inversely associated with childhood respiratory tract infections and wheezing. J Allergy Clin Immunol. 2009;124:707–713. [PubMed]
65. Esnault S, Rosenthal LA, Wang DS, Malter JS. Thymic stromal lymphopoietin (TSLP) as a bridge between infection and atopy. Int J Clin Exp Pathol. 2008;1:325–330. [PMC free article] [PubMed]
66. Collison LW, Vignali DA. Interleukin-35: odd one out or part of the family? Immunol Rev. 2008;226:248–262. [PMC free article] [PubMed]
67. Bisset LR, Schmid-Grendelmeier P. Chemokines and their receptors in the pathogenesis of allergic asthma: Progress and perspective. Curr Opin Pulm Med. 2005;11:35–42. [PubMed]
68. Holgate ST, Davies DE, Lackie PM, Wilson SJ, Puddicombe SM, Lordan JL. Epithelial-mesenchymal interactions in the pathogenesis of asthma. J Allergy Clin Immunol. 2000;105:193–204. [PubMed]
69. Holgate ST, Davies DE. Rethinking the pathogenesis of asthma. Immunity. 2009;31:362–367. [PubMed]
70. Van Eerdewegh P, Little RD, Dupuis J, Del Mastro RG, Falls K, Simon J, Torrey D, Pandit S, McKenny J, Braunschweiger K, Walsh A, Liu Z, Hayward B, Folz C, Manning SP, Bawa A, Saracino L, Thackston M, Benchekroun Y, Capparell N, Wang M, Adair R, Feng Y, Dubois J, FitzGerald MG, Huang H, Gibson R, Allen KM, Pedan A, Danzig MR, Umland SP, Egan RW, Cuss FM, Rorke S, Clough JB, Holloway JW, Holgate ST, Keith TP. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature. 2002;418:426–430. [PubMed]
71. Holgate ST, Yang Y, Haitchi HM, Powell RM, Holloway JW, Yoshisue H, Pang YY, Cakebread J, Davies DE. The genetics of asthma: ADAM33 as an example of a susceptibility gene. Proc Am Thorac Soc. 2006;3:440–443. [PubMed]
72. Lee JY, Park SW, Chang HK, Kim HY, Rhim T, Lee JH, Jang AS, Koh ES, Park CS. A disintegrin and metalloproteinase 33 protein in patients with asthma: Relevance to airflow limitation. Am J Respir Crit Care Med. 2006;173:729–735. [PubMed]
73. Puxeddu I, Pang YY, Harvey A, Haitchi HM, Nicholas B, Yoshisue H, Ribatti D, Clough G, Powell RM, Murphy G, Hanley NA, Wilson DI, Howarth PH, Holgate ST, Davies DE. The soluble form of a disintegrin and metalloprotease 33 promotes angiogenesis: implications for airway remodeling in asthma. J Allergy Clin Immunol. 2008;121:1400–1406. [PubMed]

Articles from Allergy, Asthma & Immunology Research are provided here courtesy of Korean Academy of Asthma, Allergy and Clinical Immunology and Korean Academy of Pediatric Allergy and Respiratory Disease