This action might not be possible to undo. Are you sure you want to continue?
New insights into the relationship between airway inﬂammation and asthma
A. J. WARDLAW, C. E. BRIGHTLING, R. GREEN, G. WOLTMANN, P. BRADDING and I. D. PAVORD
Department of Respiratory Medicine, Institute for Lung Health, Leicester–Warwick Medical School, Glenfield Hospital, Groby Road, Leicester LE3 9QP, U.K.
Asthma is a condition characterized by variable airﬂow obstruction, airway hyper-responsiveness (AHR) and airway inﬂammation which is usually, but not invariably, eosinophilic. Current thoughts on the pathogenesis of asthma are focused on the idea that it is caused by an inappropriate response of the speciﬁc immune system to harmless antigens, particularly allergens such as cat dander and house dust mite, that result in Th2-mediated chronic inﬂammation. However, the relationship between inﬂammation and asthma is complex, with no good correlation between the severity of inﬂammation, at least as measured by the number of eosinophils, and the severity of asthma. In addition, there are a number of conditions, such as eosinophilic bronchitis and allergic rhinitis, in which there is a Th2-mediated inﬂammatory response, but no asthma, as measured by variable airﬂow obstruction or AHR. Bronchoconstriction can also occur without obvious airway inﬂammation, and neutrophilic inﬂammation can in some cases be associated with asthma. When we compared the immunopathology of eosinophilic bronchitis and asthma, the only diﬀerence we observed was that, in asthma, the airway smooth muscle (ASM) was inﬁltrated by mast cells, suggesting that airway obstruction and AHR are due to an ASM mast cell myositis. This observation emphasizes that the features that characterize asthma, as opposed to bronchitis, are due to abnormalities in smooth muscle responsiveness, which could be intrinsic or acquired, and that inﬂammation is only relevant in that it leads to these abnormalities. It also emphasizes the importance of micro-localization as an organizing principle in physiological responses to airway inﬂammation. Thus, if inﬂammation is localized to the epithelium and lamina propria, then the symptoms of bronchitis (cough and mucus hypersecretion) result, and it is only if the ASM is involved – for reasons that remain to be established – that asthma occurs.
Asthma is a condition that is characterized by variable airﬂow obstruction, airway hyper-responsiveness (AHR) and chronic airway inﬂammation that usually has an eosinophilic component. Pathophysiologically, as well
as accumulation of eosinophils and CD4 lymphocytes, there is activation of the epithelium and smooth muscle, mucus hypersecretion, thickening of the sub-epithelial collagen layer, mast cell degranulation, and smooth muscle hypertrophy and hyperplasia . A striking abnormality in patients that have died due to asthma is a
Key words : airway hyper-responsiveness, airway smooth muscle, asthma, eosinophils, inﬂammation. Abbreviations : ASM, airway smooth muscle ; AHR, airway hyper-responsiveness ; BAL, bronchoalveolar lavage ; BTS, British Thoracic Society ; COPD, chronic obstructive pulmonary disease ; EB, eosinophilic bronchitis ; FEV , forced expiratory volume in " 1 s ; GC, glucocorticoids ; IL, interleukin ; Pc , provocational concentration causing a 20 % fall in FEV ; VLA, very-late antigen. #! " Correspondence : Professor A. J. Wardlaw (e-mail aw24!le.ac.uk).
# 2002 The Biochemical Society and the Medical Research Society
but it is likely. Th2 cytokines such as IL-4 and IL-13 are also thought to have a direct effect. PGD2. J. and it is now is thought to affect up to 20 % of children and 5 % of adults in industrialized countries. and a careful analysis of the pathology of asthma deaths did not reveal any difference in epithelial loss between disease and control groups . considerable increase in the thickness of the airway wall throughout the bronchial tree. when ﬁbre-optic bronchoscopy studies demonstrated the presence of increased numbers of eosinophils. In this model the major effector cell is the eosinophil (Eos). and it was not # 2002 The Biochemical Society and the Medical Research Society until the mid 1980s. particularly on mucus hypersecretion. partly as a result of smooth muscle hypertrophy . This has included antagonists of interleukin-5 (IL-5) and very-late antigen-4 (VLA-4) to prevent airway eosinophilia. even in very mild disease. through the elaboration of specific granule proteins and leukotrienes. to relate to smooth muscle hypertrophy rather than the destructive obliterative bronchitis and emphysema that characterize the ﬁxed airﬂow obstruction of chronic obstructive pulmonary disease (COPD) [5. This model has been underpinned by the beneﬁcial effects of glucocorticoids (GC) on both airway inﬂammation and clinical manifestations of the disease. This is thought to cause eosinophilic inﬂammation of the airways. prostaglandin D2. the bronchospastic elements of the disease had been given greater prominence. There is no increase in the numbers of bronchial epithelial cells in induced sputum from asthmatics. The view of asthma as a disease of Th2-mediated inﬂammation has had a major impact on the direction of drug development. that asthma became viewed principally as a chronic inﬂammatory disease of the airways . which has focused on anti-inﬂammatory strategies targeted at the Th2 pathway. as modelled by the early response to antigen challenge. which in turn contributes to the abnormal physiology and pathology which characterizes the disease  (Figure 1). and therapies such as IL-12 that are directed at switching Th2 cells to Th1 cells [12–14]. while structural cells amplify the inflammatory process by the production of cytokines and cell-recruiting chemokines. This paradigm was reﬁned by the subsequent demonstration of increased numbers of cytokine-producing Th2 lymphocytes in the airways of atopic asthmatics. Patients with long-standing asthma often develop a degree of ﬁxed airﬂow obstruction. Although airway inﬂammation had long been recognized from post-mortem studies of asthma deaths as being a feature of asthma. Wardlaw and others Figure 1 Asthma as a disease of Th2-mediated chronic airway inflammation A currently widely accepted model of asthma is of a disease caused by chronic inflammation of the airways.6]. There has been a marked increase in the prevalence of asthma in the last quarter of the 20th century. Mast cells participate in acute bronchospasm. leukotriene . the studies that have reported this are weakened by the difﬁculty in assessing epithelial integrity in endobronchial biopsies. which in turn has led to the early use of inhaled GC becoming the mainstay of current guidelines on asthma management . causing considerable morbidity and a signiﬁcant degree of premature death . which has led to a widely supported model of asthma as a disease in which there is inappropriate activation of allergen-stimulated Th2 lymphocytes . IL-4 antagonists to reduce eosinophil inﬁltration and IgE production. which might be expected if epithelial fragility was present . directed largely by Th2 lymphocytes reacting to inhaled allergens and antigens. at least in part. The pathological basis of this is still uncertain.202 A. LT. Epithelial desquamation has long been considered to be a hallmark of asthma. However. The most .
with a sensitivity and speciﬁcity greater than 90 %. wheeze. Indeed. In some. these hallmarks of the disease are not routinely measured in making the diagnosis . The diagnosis of asthma. However. " and\or a Pc (provocational concentration causing a #! 20 % fall in FEV ) of less than 4 mg\ml. On current evidence their similarities in both patho# 2002 The Biochemical Society and the Medical Research Society . within this diagnostic framework. followed by the sputum eosinophilia . AHR is perhaps the most distinctive physiological abnormality in asthma . a common cause of cough which is discussed in more detail below . and suggest that the intrinsic lung factor involves modulation of smooth muscle physiology. In this review we have re-examined the relationship between airway inﬂammation and asthma. It seems clear.21]. remarkably in our opinion. particularly as measured by AHR and FEV (forced expiratory volume in 1 s). cases these individuals will give a history of asthma in childhood or early adult life. Our prejudice is the latter. it is not sufﬁcient to explain all the features of the disease. From the outset it was clear from bronchoscopic studies that there was no close relationship between the severity of airway inﬂammation and the severity of asthma. There is. possibly intrinsic to the airway. or the pattern of inﬂammation (see Table 1). although there are virtually no studies examining this important issue . In addition. is often based largely on symptoms and home peak-ﬂow readings. home peak-ﬂow readings are unreliable as a diagnostic tool because of poor technique and compliance [20. including patients with rhinitis without evidence of AHR or bronchoconstriction. Other factors. and eosinophilic bronchitis (EB). sputum eosinophilia and measurement #! of variable airﬂow obstruction (either by home peakﬂow monitoring or direct reversibility). There is an unresolved debate about whether this overlap syndrome simply represents co-existence of two common diseases or whether there are common pathogenic mechanisms. We believe that this is incorrect. severe) Acute severe asthma Brittle asthma Nocturnal Exercise-induced Extrinsic (atopic) Intrinsic (non-atopic) Virally induced Occupational High-performance athletics Eosinophilic Neutrophilic Fixed airflow obstruction (airway remodelling) Aetiological Pathological WHAT IS ASTHMA ? There is general agreement that asthma is a disease characterized by symptoms of episodic cough. and is therefore likely to be inaccurate in many cases. there is a tendency to be nihilistic about establishing an accurate diagnosis of asthma. a less than 10-pack-year smoking history. and either directly demonstrable reversibility in FEV or peak ﬂow of greater than 20 %. the presence of sputum eosinophilia ( 3 %) is helpful in conﬁrming the diagnosis. Pc was the #! most useful test. with some authorities viewing asthma as an illdeﬁned syndrome that is difﬁcult to diagnose objectively . breathlessness and chest tightness. for example where the Pc is between 4 and #! 8 mg\ml without obvious reversibility. In addition. although. A signiﬁcant smoking history ( 15 pack years) in the context of airﬂow obstruction makes a diagnosis of smoking-related airﬂow obstruction (COPD) more likely than asthma. Th2mediated inﬂammation can explain at best only part of the pathophysiology of asthma. as discussed below. is uncertain. It is clear that. or a single disease with a variable aetiology and presentation. must be involved. Unless serial measurements are undertaken. signiﬁcant increases in FEV after bronchodilators can only be " demonstrated in a minority of patients with mild to moderate asthma . therefore. The extent to which these phenotypes represent different diseases with a similar physiological outcome. presumed aetiology. which is usually relieved by bronchodilators and is associated with variable airﬂow obstruction . where the key pathological feature is airway eosinophilia. This " dissociation has become even more obvious with the use of induced sputum to measure airway inﬂammation in larger groups of subjects with a broader range of disease severity and clinical phenotype than the mild extrinsic asthma that has been the staple of bronchoscopic studies . Table 1 Asthma phenotypes Classification Symptom-based Types Chronic (mild. there are a number of phenotypes. In borderline " cases. however. but more information on this potentially informative group of patients is needed. While there is currently no ‘ gold standard ’ for the diagnosis of asthma. In a recent analysis of the sensitivity and speciﬁcity of Pc .Relationship between airway inflammation and asthma 203 frequently used animal model of asthma involves allergen challenge of Th2-sensitized mice. particularly in a primary-care setting. that while inﬂammation almost invariably accompanies asthma. but far from all. Most deﬁnitions also include AHR and eosinophilic airway inﬂammation. moderate. an overlap syndrome in which older adults with a signiﬁcant smoking history have asthmatic features to their disease. These can be classiﬁed according to clinical features. there are a number of examples where eosinophilic airway inﬂammation is not accompanied by asthma. our approach is to accept the diagnosis where a person has consistent symptoms.
The key question in asthma. A large number of studies have now examined this relationship in endobronchial biopsies. in particular the almost invariable association of these two conditions. although it is likely that this is due to a number of different pathological processes. such as variable airﬂow obstruction. In some cases the disease patterns represent easily understood differences in severity. measured either by cell counts or NO in exhaled air. we have measured sputum eosinophilia in over 200 patients attending our . In other conditions. whereas the airway diseases that do not overlap. are characterized by airway inflammation but without variable airflow obstruction. Our view is that asthma is a single disease with a number of aetiologies linked by AHR. where. ASTHMA AND AIRWAY INFLAMMATION The relationship between airway inﬂammation and asthma is complex. As well as there being a number of different phenotypes within a diagnosis of asthma. In particular there is no close relationship between the severity of airway inﬂammation. this is far from absolute. or hypertension has a number of aetiologies linked by abnormalities in vascular smooth muscle physiology. This is most obvious in COPD. particularly during exacerbations.204 A. pathology or physiology. in the same way that bronchiectasis is a single disease with different causes linked around defective lung defences. there are several other airway diseases in which airway inﬂammation is associated with clinical and pathophysiological features that are seen in asthma. argues strongly against this. and the literature is generally very consistent in showing at best a weak correlation. and either the severity of AHR or abnormalities in FEV " [15. In this Figure the diseases that overlap with asthma include variable airflow obstruction as part of their pathophysiology. is why do only some individuals develop AHR and bronchoconstriction in response to airway inﬂammation ? Is this because of the nature of the inﬂammation. or cough and sputum production (bronchitis) (Figure 3). physiology and clinical features outweigh their differences. reversible airﬂow obstruction is sometimes a prominent feature. sputum and bronchoalveolar lavage (BAL) and bronchial wash. as discussed above. variable airﬂow obstruction and chronic mucosal inﬂammation. airway inﬂammation occurs without AHR or variable airﬂow obstruction. cystic fibrosis. For example. or extrinsic compared with intrinsic asthma. In other cases. for example EB and most cases of COPD. or a combination of the two ? It is also possible that AHR is entirely independent of inﬂammation. an intrinsic difference in the response of the airways to inﬂammation. the differences may be more fundamental. for example where neutrophils predominate over eosinophils (‘ neutrophilic asthma ’). Variable airﬂow obstruction is also a common feature of bronchiectasis . such as EB. there are a number of other diseases and syndromes that overlap in terms of symptoms. as well as some adults. virally induced wheeze overlaps with asthma in a still poorly understood manner . Wardlaw and others Figure 2 Asthma is one of a number of overlapping obstructive airway diseases While we envisage asthma as a single discrete disease. For example. cough and wheeze (Figure 2). A unifying hypothesis of asthma needs to explain the relationship with these other conditions. J. nocturnal asthma is usually simply a feature of poor disease control. While there is a bias for eosinophilic inﬂammation to be associated with asthma and neutrophilic inﬂammation with bronchitis.28]. One can therefore conclude that bronchial inﬂammation can lead to two different outcomes : either episodic bronchoconstriction # 2002 The Biochemical Society and the Medical Research Society and AHR (asthma-like). CF. but the available evidence. therefore. In children. Both asthma and bronchitis can lead to ﬁxed airﬂow obstruction (airway remodelling).
as deﬁned by appropriate symptoms and either demonstrable variable airﬂow obstruction or AHR. . molecular weight .. although for eosinophils cell counts usually correlate well with concentrations of eosinophilspeciﬁc mediators in the BAL. The reason why in some cases inflammation leads to bronchoconstriction and AHR (an asthma-like phenotype with wheeze and bronchodilator-responsive shortness of breath). despite almost complete ablation of the BAL and blood eosinophilia [32a]. PV. Many conditions are characterized by airway inflammation in which either Th2/eosinophilic or Th1/neutrophilic responses predominate. Although the relevance of allergen challenge to clinical disease is debatable. as well as in a study of treatment with inhaled steroids [30. when given by aerosol to mice . even if there was a better correlation between eosinophilic inﬂammation and severity of asthma within an individual. an anti-VLA-4 monoclonal antibody was able to block ovalbumin-induced AHR. this is far from absolute. it should be remembered that patients with asthma usually also have symptoms of bronchitis.Relationship between airway inflammation and asthma 205 Figure 3 Asthma and airway inflammation Shown is a schematic representation of the complex and indirect relationship between airway inflammation and asthma. post viral . is at the crux of what causes asthma. whereas in others it leads only to symptoms of bronchitis (cough and sputum production). EB . A caveat is that virtually all the studies that have investigated this relationship are cross-sectional. as we believe these are the most specific hallmarks of the disease. it would still mean that there was considerable variability in sensitivity to airway inﬂammation between individuals. occupational asthma . Occ. Bronch. There was a reasonable correlation between changes in sputum eosinophil numbers and AHR after allergen challenge. that the interpretation of that study and others using the anti-IL-5 antibody is complicated by the observation that.31]. For example. Although we are using the term ‘ asthma-like ’ to describe variable airflow obstruction and AHR. Eos. bronchial hyper-responsiveness. and have found only a very weak correlation between sputum eosinophils or NO and AHR in atopic subjects. BHR. and no correlation at all in patients with non-atopic disease . however. Mwt. Although there is a bias towards eosinophilic inflammation being associated with asthma. Further support for the apparent dissociation between asthma and eosinophilic inﬂammation is provided by the study by Leckie et al. in which an anti-IL-5 monoclonal antibody markedly reduced eosinophil numbers in the blood and sputum. outpatient clinics with a diagnosis of asthma [ranging in severity from step 1 to step 4 according to British Thoracic Society (BTS) guidelines]. there was still a signiﬁcant tissue eosinophilia after 3 months of treatment with anti-IL-5. Another caveat is that the level of activation of leucocytes such as T cells and eosinophils may be more important than cell numbers. and what is lacking are longitudinal studies in clinical disease. these studies further illustrate the # 2002 The Biochemical Society and the Medical Research Society . but had no effect either on AHR in patients with mild asthma or on the late response to allergen challenge. It should be noted. but not airway eosinophilia. However. in a group of mild asthmatics. Asthma. relating changes in inﬂammation to changes in lung function and symptoms. A dissociation between AHR and the eosinophilia has also been seen in animal models of allergen challenge.
Strikingly. so that obvious explanations. We have found that in 10–20 % of asthmatics there is no increase in sputum eosinophils. While EB is interesting in its own right. but without wheeze. This was despite #! the observation that the overall numbers of mast cells in the airway lamina propria in the three groups was the same. We have investigated the immunopathology of EB in comparison with that of mild (atopic and non-atopic) # 2002 The Biochemical Society and the Medical Research Society asthma. and have conﬁrmed that EB is characterized by a submucosal eosinophilic inﬂammation which looks very similar to that in asthma. minimally productive cough and are found to have an airway eosinophilia ( 3 % in sputum). The clinical features of ‘ eosinophilic ’ and ‘ neutrophilic ’ asthma are the same. This suggests that characterizing the type and pattern of airway inﬂammation in asthma should be an integral part of management. to a mast cell myositis. suggesting the presence of # activated mast cells in the epithelium . it has particular signiﬁcance in offering clues as to why eosinophilic airway inﬂammation in some. we would suggest that the patient will only suffer from symptoms of bronchitis (i. then it has profound implications for our understanding of asthma. and many of these patients have a sputum neutrophilia. although it can only be diagnosed if measurement of airway eosinophils is undertaken . Mast cell mediators are also of obvious relevance to ASM function [42. There was also a signiﬁcant correlation between the number of mast cells in the ASM and the Pc . cough and sputum production). there was no inﬁltration of the ASM by eosinophils or T cells in asthma or EB. although in most cases it is steroid responsive. we propose that the asthmatic phenotype is caused fundamentally by an abnormality in disease ASM physiology. which has been relatively ignored because of the difﬁculty in co-localizing structures within the airway using endobronchial biopsies. As eosinophilic inﬂammation is closely tied to a Th2 pattern of cytokine production.206 A. in which the neutrophilic phenotype remained stable in terms of both cell counts and response to steroids . If the inﬂammatory response is restricted to the epithelium and submucosa. in a pilot study we found that our patients with neutrophilic asthma did less well on inhaled GC than eosinophilic asthmatics. Thus ASM hypertrophy . individuals leads to asthma. including the presence of subepithelial thickening of the collagen layer . are unlikely. J. at least in part. such as occult bronchiectasis and smoking. It was not possible to link this to the clinical status of the patients . The expression of T-cell activation and of chemokine receptors and T-cell cytokines was also similar to those in asthma. It is not obviously related to atopy.e. variable airﬂow obstruction or airway hyper-responsiveness . it is therefore the localization of mast cells within the ASM that is implicated in causing bronchoconstriction and AHR. Indeed.43]. The idea that direct mast cell interactions with ASM cause asthma is plausible. discussed below. but not all. It has been found in 13 % of patients who present with cough (which is one of the commonest respiratory causes of presentation to both primary and secondary care). because it would suggest that while Th2\eosinophilic inﬂammation commonly leads to asthma. Any unifying hypothesis of asthma therefore has to encompass all types of airway inﬂammation. the only difference we observed between the two conditions was inﬁltration of the airway smooth muscle (ASM) by mast cells in asthmatics. and our previous demonstration that EB is characterized by increased amounts of histamine and prostaglandin D in the sputum. suggesting a fundamentally different aetiological pathway. On this evidence. EB AND ASTHMA EB is a condition of unknown aetiology in which patients present with a chronic. A similar group has also been identiﬁed among patients with severe asthma by bronchial biopsy  and induced sputum . we speculate that in ‘ neutrophilic ’ asthma there is a Th1 pattern. Indeed. but not in patients with EB or in normal subjects . other types of inﬂammation can equally well do so. Wardlaw and others complex relationship between inﬂammation and lung physiology. An important aspect of neutrophilic asthma is the possibility that these patients will be less responsive to treatment with GC. even in those patients not taking inhaled steroids. If this interpretation of the data is correct. Not all asthma is associated with eosinophilic inﬂammation. as it is likely that cellular communication works across a distance of 1–2 µm rather than the thousands of µm involved in the depth of the lamina propria. shortness of breath. as response to steroids in both asthma and COPD correlates with the degree of airway eosinophilia . with both showing a Th2 pattern of T-cell activation . and this has been conﬁrmed by a 1-year longitudinal study. in that it implies that the key aspect of the inﬂammatory response is the way in which it alters ASM physiology. Indeed micro-localization is likely to be a fundamental organizing principle of the inﬂammatory response. This would be important to demonstrate. due. Further support for our data is offered by a study of resected lung tissue in which those samples that contracted to allergen had increased numbers of mast cells within the ASM compared with samples where no contraction was observed. ASTHMA AS A DISEASE OF ASM Stimulated by our study of EB. The natural history of the disease is unclear.
Abnormal stretch responses could also lead to AHR. BHR. In a sense this is revisiting the ideas of the 1970s. chronic administration of β -adreno# ceptor agonists. which may well occur through a mechanism with distinct intracellular signalling pathways that are simply not susceptible to current therapies. as mast cell recruitment to the ASM is likely to be due to a speciﬁc mast cell chemoattractant or growth factor.46] and other mast cellderived growth factors and AHR by a priming effect of mast cell mediators on ASM . Eos. There is evidence for a genetic component to AHR in both animals and humans. Localization of inflammation to the epithelium will lead to symptoms of bronchitis (cough and mucus production). although the picture is currently complex. which is known to be produced by the ASM . Our model envisages AHR as being due to an exaggerated stimulus–response relationship between the ASM and bronchoconstrictor stimuli. This hypothesis was undermined by the relative lack of efﬁcacy of antihistamines and mast cell stabilizers. Furthermore. could be caused by tryptase [45.49]. These could be due to a direct effect on ASM or indirectly via a mast-cell-dependent pathway. with no single gene pattern emerging [55. and in recent years attention has focused on the role of ASM as an ampliﬁer of the inﬂammatory response through the generation of pro-inﬂammatory cytokines [52. while it is probable that there is some connection between generalized airway inﬂammation and the development of an ASM mast cell myositis. such as stem cell factor. when asthma was seen principally as a type 1 hypersensitivity reaction leading to smooth muscle bronchospasm. with eosinophil or neutrophil counts in # 2002 The Biochemical Society and the Medical Research Society .56]. This function of ASM is consistent with our hypothesis. In mild asthma this abnormality is caused by a mast cell myositis (although T cells and eosinophils could be involved in more severe disease). or the toxic effects of low-molecular-mass chemicals in certain types of occupational asthma. and both cromoglycate and nedocromil sodium have weak effects on mediator release from lung mast cells and exhibit tachyphylaxis [48. can lead to enhanced release of mediators . eosinophils . but on the background of a genetic predisposition. In addition.53]. because. in asthma the predominant mechanism of mast cell degranulation appears to be piecemeal . this is likely to be complex. This exaggerated response is likely to be partly acquired. but it may also occur as a result of respiratory viral and bacterial infections. histamine is only one of a number of mast cell mediators.Relationship between airway inflammation and asthma 207 Figure 4 Asthma as a disease primarily of abnormal ASM physiology A new model for asthma is presented in which an abnormality in ASM physiology is the fundamental cause of the disease. bronchial hyper-responsiveness. but not asthma. However. It is striking that many patients with atopic rhinitis have eosinophilic inﬂammation of the lower airways. Is this because their ASM does not become inﬁltrated with mast cells or because they are genetically resistant to bronchoconstrictor stimuli ? Does the failure of inhaled GC to return AHR to normal in many asthmatics reﬂect a failure to treat the underlying mast cell myositis or because an abnormality in the ASM remains even after the mast cells have gone  ? Our model also explains the weak relationship between the various measures of airway inﬂammation and asthma. such as cromoglycate. although relatively few investigators currently view asthma fundamentally as a disease of ASM. Interest in the role of the ASM in asthma has continued. HVS. hyperventilation syndrome . in contrast with attenuating mast cell secretion. but no AHR even after allergen challenge . for example as a result of mast cell inﬁltration. in treating asthma.
especially as eosinophil inﬁltration of the ASM has been demonstrated in a guineapig model of asthma .208 A. Non-inﬂammatory mechanisms could also lead to abnormal ASM physiology. including respiratory viruses and bacterial infections. recruitment of these cells to the ASM may occur in more severe disease. It is this. that causes the airﬂow obstruction. This was achieved without a difference in the amounts of treatment. the T-cell-dependent. As an estate agent might say. including corticosteroids. Wheeze associated with bacterial infections of the airways in COPD and bronchiectasis could be due to a direct effect of bacterial products on ASM. ‘ location. which is not related to severity of asthma. Although a mast cell myositis may well be the ﬁnal common pathway in all asthma phenotypes. as this phrase is also used to describe changes in the matrix composition of the airways. it is possible that alternative mechanisms leading to abnormal ASM physiology are involved. and encompasses marked eosinophilic inﬂammation and impaction of the airway with mucus and cell debris. whereas in the BTS group there were 108 severe exacerbations and six admissions for asthma. Severe exacerbations leading to # 2002 The Biochemical Society and the Medical Research Society . inﬂammation-independent. or at least associated with. although the terminology is somewhat confusing. Respiratory viruses have been shown in vitro to modulate ASM function. the severity of asthma could be related to the intensity of the ASM myositis. in the sputum group there were only 35 exacerbations and one admission. particularly when sensitized with atopic serum . wheeze and AHR caused by respiratory viruses could be due to a direct effect on ASM . This strongly implies a close association between eosinophils and severe exacerbations. but neutrophilic asthma also occurs. we have undertaken a blinded. location. acute severe asthma are the major cause of signiﬁcant morbidity and mortality in asthma. AHR or variable airﬂow obstruction. and long-standing asthma can lead to a degree of ﬁxed airﬂow obstruction. A minority of asthmatics develop severe exacerbations leading to acute severe asthma. J. While we have not observed eosinophil or T-cell inﬁltration of the ASM in our group of mild asthmatics. mediated by Th2-derived cytokines. although it is generally a feature of long-standing asthma and is presumed to be due to unopposed chronic inﬂammation. there are a number of other causes. and bronchitis leading to cough. One key message of our observation is the importance of leucocyte micro-localization in the physiological response to airway inﬂammation. Over the course of 1 year we found that. Although the inﬂammatory response is usually caused by. suggesting the presence of permanent structural changes to the airway. Indeed. However. location ’ ! This principle has also been emphasized by investigators proposing a primary neural mechanisms for asthma . used by the two groups. We hypothesize that AHR and variable airﬂow obstruction are caused principally by mast cellmediated abnormalities in ASM responsiveness. late-phase bronchoconstriction seen in some patients undergoing immunotherapy using Fel D1 peptides could be associated with migration of activated T cells into the ASM . SUMMARY AND CONCLUSIONS Airway inﬂammation is closely associated with asthma. For example. Asthma is characterized by AHR and variable airﬂow obstruction which leads to wheeze and breathlessness. This is often referred to as ‘ airway remodelling ’. there is increasing evidence that eosinophils are important in causing severe exacerbations of asthma. in terms of both the number and range of inﬂammatory cells involved. allergens. including the thickened sub-epithelial collagen layer. In support of the idea that eosinophils are important in this aspect of asthma. Wardlaw and others sputum and biopsies acting as a very indirect measure of the relevant abnormality. On the EOSINOPHILS AND SEVERE EXACERBATIONS OF ASTHMA Does this model imply that there is no role for eosinophils and Th2 cells in mediating the pathogenesis of asthma ? It certainly implies that they are neither necessary nor sufﬁcient for the development of AHR and variable airﬂow obstruction. but the relationship is complex and indirect. The pathology of severe exacerbations can be assumed from that of asthma deaths. Similarly.66]. randomized study in which we have managed one group of moderately severe asthmatics according to standard BTS guidelines and the other group according to a protocol based on maintaining a normal sputum eosinophil count by appropriate use of corticosteroids. and one explanation for the high prevalence of asthma in hyperventilation syndrome and high-performance athletes could be the response of the ASM to exaggerated stretch associated with frequent periods of hyperventilation (Figure 4) . Stretch has a profound effect on smooth muscle cells . although whether it is causal remains to be seen . The commonest pattern of inﬂammation in asthma is eosinophilic. as much as spasm of the ASM. The pathophysiological basis for ﬁxed airﬂow obstruction in asthma is largely unknown. and remain difﬁcult to prevent and treat. The interesting observations that inhibition of deep inspiration renders normal subjects hyper-responsive and that the bronchoprotective effect of deep inspiration is lost in asthma also implicate differential responses of the ASM as being central to AHR [65. Another key feature of asthma is the development of a degree of ﬁxed airﬂow obstruction. especially as T-cellderived cytokines have been shown to modulate ASM contraction .
One can only speculate on the cause of ﬁxed airﬂow obstruction (Figure 5). Allergy 54 (Suppl. (1993) The structure of large and small airways in nonfatal and fatal asthma. J. Respir. J. Care Med. (1996) Pathology of mild. and Bochner. 56. J. Clin. 62–69 Robinson. Br. I. Dis. A.Relationship between airway inflammation and asthma 209 Figure 5 Relationship between patterns of airway inflammation and clinical and physiological outcomes in asthma Asthma is a disease with a number of different clinical and physiological outcomes. other hand. 782–789 3 Carroll. 25–42 Bryan. J. R. and James. and fatal asthma. P. J. Treatment of asthma should therefore be targeted at reversing the inﬁltration of ASM by mast cells. (1997) The use of induced sputum to investigate airway inﬂammation. D. A. Chest Med. and Elias. Invest. Hansel. S. F. D. 206. 1) Bryan. 21. Dunnette. (1999) The epidemiology of childhood asthma. N. A. Leckie. Am. Goh. M. and Carroll. J.. (2000) Consequences of long-term inﬂammation. A. 405–410 4 Pavord. Dis. 137. J. Respir. et al. S.. 154. Respir. Allergy 29 (Suppl. A. Med. V. E. 331–343 1 12 13 14 15 16 # 2002 The Biochemical Society and the Medical Research Society . Relationship to bronchial hyperreactivity. P. 160. (1992) Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. T.. 147. R. 326. Med. Am. Clin. T. (1998) The role of adhesion molecules in allergic inﬂammation and their suitability as targets of antiallergic therapy. Airway remodeling. J. 406–410 9 10 11 REFERENCES Kay. J. C. P. and the late asthmatic response. B. A. symptoms associated with variable airflow obstruction and AHR being due to a mast cell myositis. Ward.. E. Engl. 2149–2153 Schleimer. 985–1003 Brightling. J.. L. A. Eur. 6 7 8 Jeffery. Bull. Respir. N. Am. I. Wardlaw. (2000) Novel therapy for asthma. and Pavord. A. Expert Opin.. Crit. as well as the treatment of the airway eosinophilia with corticosteroids. 14–26 Strachan. Respir. G. J. Q. Drugs 9. S. Exp. While some of these outcomes are likely to be influenced by the severity and longevity of the disease. and Barnes. A. and Hargreave. 298–304 Kay.. D. Thorax 52.. Lancet 356. Morton. 15. with bronchitic symptoms being due to inflammation localized to the epithelium. Rev. M. (1997) T cells as orchestrators of the asthmatic response.. (1988) Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. methods of measurement and relation to function. Collins. Elliot. 2). S. I. Thorax 52 (Suppl. C. Hamid. B. K. and severe exacerbations being due to eosinophil-mediated effects.. Clin. Green. R. et al. Rev. Pizzichini. P. Exp.. 49).. 56–67 NAC\BTS\RCP (1997) The British Guidelines on Asthma Managment. severe. (1999) Eosinophilic bronchitis is an important cause of chronic cough. Care Med... S. A. N. 7–11 Wardlaw. Ying. A. which vary in prominence between different individuals and within the same individual over time. J. 498–501 5 Homer. Crit. Gleich. G. B.. O’Connor.. S66–S69 2 James. E. (2000) Airway smooth muscle in health and disease . R. 15–23 Wardlaw. A. The relationship between airway inflammation and the fixed airflow obstruction that occurs in some patients with asthma is not at all clear. severe exacerbations of asthma may be more closely associated with eosinophil-mediated damage. Pizzichini. J. (1999) Differences and similarities between chronic obstructive pulmonary disease and asthma. M. S.. D. B. Matti. (2000) Effects of recombinant human interleukin-12 on eosinophils. Symp. Ciba Found. Am. B. we believe that they are underpinned by differences in the pattern of the inflammatory response. Allergy 28 (Suppl. Woltmann... J. airway hyper-responsiveness. J. 3). (2000) Eosinophils in asthma and other allergic diseases. and Pavord. K. For this to be done effectively will require a much more detailed understanding of how mast cells accumulate in the ASM and how this leads to AHR and bronchoconstriction. and Kay. S. Brightling.
401–409 Moqbel.. W. Med. Walsh. (1989) Roles of mast cell tryptase and chymase in airway function. Y. J. A. H.. S. Hartmann. in the press Pin. (1995) Asthma and wheezing in young children. Mostgaard. J. H. Br. Jones. (2001) Regulation of the inﬂammatory response in asthma by mast cell products. Hillier. mechanisms. C.. and respiratory function in bronchiectasis.. 149–153 Ammit. S. L. 534 Brightling. A.. Y.. Allergy 30 (Suppl. H.. Respir. 109. Zhang. (1997) National and international guidelines for the diagnosis and treatment of asthma. Dis. Am. D. Hughes. Symon. P.. Thorax 39. Wardlaw and others 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 32a 33 34 35 Nicklas. Am. S. D. Woltmann. P. M. Crit. R. The Odense Schoolchild Study. E. Schwartz. J. B. and Church. R. W. 1480–1485 Green. 145... Respir. X. 743 Henderson. B. (2000) Airway smooth muscle as a target in asthma. E. 24. Opin. Dis. A. I. A. Rev. D. G. and interactions with other mast cell mediators. Med. P. Wardlaw. 878–882 Holgate. G. J. S. (1984) Atopy. G. Lowman. M. Dolovich. L39–L46 Okayama. Lancet i. N. C. A. 1618 Siersted. E. A. D. C.. K.. J. R. C.. J. E.. G. H. C. et al. Thorax. N. G. W. S. 146–154 Caughey. and role in mediating mitogenesis.. 598–603 Marklund. A.. J. McKenna. Rooney. Invest. W. K. (2000) Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease : a randomised controlled trial. Potency. Clin. G. J. J. G. (1999) Non-eosinophilic corticosteroid unresponsive asthma. 332. P. J. Chinn. Immunol. C. C. D. et al.. Ward. 145. J. Ward.. J. M. J. E.. P. Menzies-Gow. (1992) Bronchial mucosal manifestations of atopy : a comparison of markers of inﬂammation between atopic asthmatics. C. J.. S.. C. Bradding. (1992) Inhibition proﬁles of sodium cromoglycate and nedocromil sodium on mediator release from mast cells of human skin. 168–171 Green. Chi.. and Pavord. et al. B. (1993) The relationship between inﬂammation and hyperreactivity of the airways in asthma. Care Med. Tyler. et al. and Pavord. and Morley. 79. M. C. et al. M. Allergy Clin. A. J. R. 257. S.. Woltmann. Denburg. Chest 121. 1699–1705 Brightling.. J. Exp. E. Clin. 1841–1847 Hirst. Allergy 23. S.210 A. 268–276 Swystun. Kurlak. 1001–1008 Gibson. et al. (2000) Induced sputum inﬂammatory mediator concentrations in eosinophilic bronchitis and asthma. Bradding. R. Brightling. and Lewis. and Caughey. J.. S. R.. Physiol. F. and Fitzgerald. 51–55 Wardlaw. Chest 107 (Suppl. C. and Kay. D. et al. J. Tunsater. (2002) Cytokine expression in bronchoalveolar lavage T-lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis. A.. Cooper. Armour. Clin. Hansen. Curr. (1999) How often is the diagnosis bronchial asthma correct ? Fam. Dis. J. J. I. Chest 119. E. I. Brightling. Hyldebrandt. (1997) Human airway smooth muscle cells express and release RANTES in response to T helper 1 cytokines : regulation by T helper 2 cytokines and corticosteroids. (1992) Changes in the cellular proﬁle of induced sputum after allergen-induced asthmatic responses... M. Hirst. 2144–2148 Flood-Page. I. R. 258–259 Lorber. P. (1988) Effects of nedocromil sodium (Tilade) on the activation of human eosinophils and neutrophils and the release of histamine from mast cells. and Hargreave.. Exp. (2000) Mast cell tryptase release and asthmatic responses to allergen increase with regular use of salbutamol. H... 1).. J. G. H. J. A. Am. Crit. G. (1997) Mast cell numbers are increased in the smooth muscle of human sensitized isolated bronchi.. A.. Biol. Jose.. E. G. V. R. Exp. T. Simpson. P. K. Rees. A320 Gibson. 309. (1999) Clinicians should be proactive in testing for asthma. Wardlaw.. J.. 318. J. G. G. and Black. Lancet 356. Crit. 16. 106. Hansen. H. S. Respir. T. J. and Caughey. D. Bekir. R. N.. 1051–1057 Higgins. 158. and the late asthmatic response. C. D. Am. Brightling. 588–593 Murphy.. (1994) Evaluation of peak expiratory ﬂow variability in an adolescent population sample. Ruoss. A.. 109. D. Respir. Robinson. 3083–3092 Wenzel. 162. (2002) Reduced asthma exacerbations with a management strategy directed at normalising the sputum eosinophil count. Care Med. (1995) Tryptaseinduced mitogenesis in airway smooth muscle cells. A. Cromwell. Monteiro.. B. Immunol. 155. Albert. (1998) Objective measures and the diagnosis of asthma. and Pavord. M. Respir. Ramsdale. I. Lancet 353. F. C. (2001) Mast cell tryptase activates extracellularregulated kinases (p44\p42) in airway smooth-muscle cells : importance of proteolytic events. E. Benyon. 1265–1269 Pavord. 57–64 Djukanovic. Allergy 43. Clin. Holgate. J. Immunol. S. R... J. B. 1). A. Am. lung. J. P. H. tonsil. J. (2001) Heterogeneity of airway inﬂammation in persistent asthma : evidence of neutrophilic inﬂammation and increased sputum interleukin-8. P. S. 28–32 Hart. S. J. 538–544 John. Lancet 356. Gordon. C. 95S–96S Brown. B. Lai. Br... C. 54–59 # 2002 The Biochemical Society and the Medical Research Society . Exp. N. and Saltos. I. 317. and Tattersﬁeld. A. and Cochrane.. M. H. N.. Wardlaw. B.. Care Med. T.. Immunol. Respir. Parker. I. J. I. Symon. Khan. and Burrows. Parkin. J. Pavord. O’Byrne. 160. E. J. C. (2002) Analysis of sputum in adults with asthma : Identiﬁcation of a subgroup with neutrophilic. L. Med. Johnson. A. J. Birring. 1346–1348 Brightling. 1329–1336 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 Brightling. P. J. A. 1123–1129 Brown. 118. (1994) Do asthmatic patients correctly record home spirometry measurements ? Br. Walls. Langmack. B... (1992) Comparison of bronchial reactivity and peak expiratory ﬂow variability measurements for epidemiologic studies. D. Am. H. Respir. E. Respir.). Crit. Immunol. Engl. R. Am. (1999) Evidence that severe asthma can be divided pathologically into two inﬂammatory subtypes with distinct physiologic and clinical characteristics.... G. L. (2002) Mast-cell inﬁltration of airway smooth muscle in asthma. 149. Med. 165. X. A. J. Engl. M. J. and Kay. 179–184 Silverman. Britton.. R. O. H. Wilson. Cell Biol. E.. A. J. Rev. Clin. H. (2002) Does anti-IL-5 deplete bronchial mucosal eosinophils in mild atopic asthma ? J. atopic nonasthmatics and healthy controls. Brightling. and Oxhoj. and Wardlaw. S. time course. L.. Respir. M. (2000) Effects of an interleukin-5 blocking monoclonal antibody on eosinophils. (2000) The role of mast cells and basophils in inﬂammation.. P. Cell Mol. L.... L. Woltmann. Burney. airway hyper-responsiveness.. S. C. Allergy 30 (Suppl. 100. F. A. J. E. (1989) Chronic cough : eosinophilic bronchitis without asthma.... 855–861 Chowienczyk. 181–182 Chapman. Jr. D. M.. and Bengtsson. A. 5. N. ten Brinke. L. Am. 3. Woltmann. Freitag. A. L. C. and Wardlaw. K. Barnes. W. R. J... Am. Crit.. Davis... (2002) A comparison of the validity of different diagnostic tests in adults with asthma. Pract. Foster. J. E. P. Respir. (1997) Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inﬂammation and hyperresponsiveness in a mouse model of asthma. A randomised comparison with traditional management. E. Med. P. D. A. C.. Care Med. G.. 2213–2214 Leckie. Jones. 112–116 Britton. J. Lawson. K. D. Allergy Clin. P. Rev. Kaltenborn. Reen. Pulm. inhaled corticosteroid resistant disease. and Cockcroft. C. B. Care Med. immunological changes. and Pavord. et al.. Allergy Clin... We need a simple diagnostic test – but don’t yet have one. A. 346. J. (1978) Responses to isoproterenol in a general population sample. Eur. Wardlaw... C. et al. J. adenoid and intestine. Compton. Allergy 22. E. Med.. K. Am. J. 227–228 Hunter. J.
. D. (2000) Allergy and asthma in elite summer sport athletes. M. N. J. W. N. Permutt. 711–720 Smith. T. A. Respir. Cell Mol.. and Costello. G. M. Lung Cell. and Fryer. 163. E. R. C. Biol. W. Hum. 102. Cell Mol. Rev.. (2001) The lack of the bronchoprotective and not the bronchodilatory ability of deep inspiration is associated with airway hyperresponsiveness. Respir. Am. H. G. 444–452 # 2002 The Biochemical Society and the Medical Research Society . Invest. N. and Grunstein. B. J. M.. J. G. J. (1988) Dosage and time effects of inhaled budesonide on bronchial hyperreactivity. Kay. Maskeri. Clin. Tabar. Physiol. D. Carter. 89. Kephart. Eur. and Togias. 951–954 Ewart. 10. (2001) Genomewide screen and identiﬁcation of gene–gene interactions for asthma-susceptibility loci in three U. M.. (1999) Regulation of TH1. Hakonarson. M. 273.. C. B. R.and TH2-type cytokine expression and action in atopic asthmatic sensitized airway smooth muscle.. Clin. 1077–1087 Costello. S.. M. P. Jacoby. M. and Frossard. C. H. Permutt. I. Clin. S. R. B. Carter. Physiol. J. 106. N. J. Koeter. N. C. J. Am. (2001) Mechanism of cooperative effects of rhinovirus and atopic sensitization on airway responsiveness. Allergy 55. Med. Mitzner. et al. M. D. K. 1732–1741 Grunstein. Mol. 137. Hodinka. Campbell.. I. J. (2000) Potent bronchoprotective effect of deep inspiration and its absence in asthma. B.. and Chuang. Schmidlin. Am. (2000) Comparison of allergen-induced changes in bronchial hyperresponsiveness and airway inﬂammation between mildly allergic asthma patients and allergic rhinitis patients.. (1997) Pretreatment with antibody to eosinophil major basic protein prevents hyperresponsiveness by protecting neuronal M2 muscarinic receptors in antigen-challenged guinea pigs. 68. T. Maskeri. L229–L238 Scichilone. S..Relationship between airway inflammation and asthma 211 54 55 56 57 58 59 60 Kassel. 2254–2262 Haselden. L. and Urbiola.. van der Mark. Janiga. Fryer. D. D. A. Gleich. Exp. Am. C. H. A. G. O.. Schoﬁeld. A. 13. and Bruce.. Massard. Meyers. M. C. L.. M. and Larche. (1999) Immunoglobulin E-independent major histocompatibility complex-restricted T cell peptide epitope-induced late asthmatic reactions... Meyers. D. W. Scichilone. 531–539 Kraan. Gleich. 103. G. D.. 1885–1894 61 62 63 64 65 66 67 68 Hakonarson. 85–90 Helenius. A. Respir. J. E.. 413–419 Kapsali. Garcia. Immunol. and Togias. J. 44–48 Evans.. Invest. Laube. 189.. T. J. (1999) Human bronchial smooth muscle cells in culture produce stem cell factor. Jacoby. Physiol. G.. Am. Ober. J. M.. B.. A. (1994) Strain increases airway smooth muscle cell proliferation. and Haahtela... Respir. Care Med. B. Am. J. and Grunstein. Dis.. M. Physiol. Kim. J.. J. L.. A.. J. D. R.. et al. Hodinka. Gasser. Biol. Genet. 280.. F. H. C.. 487–495 Xu.. Olaguibel. J. R. (1996) Airway hyperresponsiveness to acetylcholine : segregation analysis and evidence for linkage to murine chromosome 6. and Levitt. E. Appl. Invest. Duvernelle. N.. Allergy Clin. Respir. 14. DiSilvestre. W. J. populations : collaborative study on the genetics of asthma.. S. B. 100. Maskeri. Am. 1437–1446 Alvarez. A. B. L93–L103 Hakonarson.S. C. A. (1998) Mechanism of rhinovirus-induced changes in airway smooth muscle responsiveness. M. J. (1997) Localization of eosinophils to airway nerves and effect on neuronal M2 muscarinic receptor function. Crit. H.
This action might not be possible to undo. Are you sure you want to continue?
We've moved you to where you read on your other device.
Get the full title to continue listening from where you left off, or restart the preview.