© 2004 American Thoracic Society
Why Is Eosinophilic Bronchitis not Asthma?University of Glasgow Glasgow, United Kingdom Recently, doubts have arisen about the role of eosinophils in causing airway hyperresponsiveness in asthma. Treatment of patients with allergic asthma using anti–interleukin-5 monoclonal antibody does not prevent allergen-induced bronchoconstriction or airway hyperresponsiveness, despite markedly suppressing eosinophil numbers within the airways (1). Thus, eosinophils might not be directly involved in causing airway hyperresponsiveness, although this conclusion may need to be modified in the light of other data (2). Eosinophils are increased within the airways in eosinophilic bronchitis to levels similar to those found in asthma (3), and symptoms improve in association with the suppression of eosinophils by corticosteroids (4). Eosinophilic bronchitis, however, differs from asthma in several important ways. In comparison to asthmatic patients, those with eosinophilic bronchitis experience the symptom of cough alone and have both normal lung function and airway responsiveness (4). In the May 15 issue of the Journal, Kanazawa and colleagues (5) not only confirm these differences in airway function between asthma and eosinophilic bronchitis, but also provide new data to show that the production of vascular endothelial growth factor and airway permeability are increased in asthma but not in eosinophilic bronchitis. They go on to postulate that increased airway permeability induced by vascular endothelial growth factor in asthma may explain why airway hyperresponsiveness occurs in asthma and not in eosinophilic bronchitis. This and other recently published data comparing the pathology of asthma to eosinophilic bronchitis (6) raise important questions regarding the mechanisms of airway hyperresponsiveness in asthma. What evidence is there for the involvement of vascular endothelial growth factor in the pathogenesis of asthma? The expression of vascular endothelial growth factor is increased in asthmatic airways compared with those of normal control subjects, and this expression correlates inversely with airway hyperresponsiveness and directly with the degree of airway submucosal vascularity (7). Kanazawa and colleagues (5) found that induced sputum concentrations of vascular endothelial growth factor are elevated in corticosteroid-naive asthmatics compared with normal subjects. The levels of vascular endothelial growth factor are reduced in patients with corticosteroid-treated asthma, although the concentrations still remain higher than those found in normal individuals. These findings confirm previous reports from this group (8–10), although, in contrast to these results, bronchoalveolar lavage levels of vascular endothelial growth factor in asthma were reported to be similar to that of normal control subjects (11). The principal source of vascular endothelial growth factor within the airways is not established. Several types of airway cells, however, particularly macrophages, eosinophils, and CD34+ cells, as well as epithelial cells and smooth muscle cells, can produce this mediator (7). What could link vascular endothelial growth factor and altered airway function in asthma? The biological properties of vascular endothelial growth factor, including the induction of angiogenesis and increased permeability through activation of high-affinity receptors on endothelial cells, could increase airway responsiveness by causing edema and remodeling. In support of this hypothesis, Kanazawa and colleagues (5) found that an index of vascular permeability, derived from the ratio of albumin concentrations in induced sputum and serum, was increased in asthma. This index also correlated positively with vascular endothelial growth factor levels and inversely with airway hyperresponsiveness and lung function. The association of vascular endothelial growth factor, airway permeability, and airway hyperresponsiveness cannot be interpreted as inferring cause and effect. These findings, however, provide the basis for future studies into the mechanisms of airway hyperresponsiveness in asthma and in particular the role of airway vascular permeability and angiogenesis. How do alterations in airway vascular endothelial growth factor levels and permeability in asthma reported by Kanazawa and colleagues (5) relate to the findings from previous studies that have compared airway inflammation in asthma and eosinophilic bronchitis? In addition to airway eosinophilia, both conditions are associated with reticular basement membrane thickening and similar numbers of subepithelial T lymphocytes, mast cells, and macrophages (3). Infiltration of airway smooth muscle by mast cells that express interleukin-4 and interleukin-13 is a feature of asthma but not of eosinophilic bronchitis (6, 12). In asthma, therefore, is it possible that increased levels of vascular endothelial growth factor, airway permeability and airway smooth muscle mast cells are linked together to play a role in inducing airway hyperresponsiveness? Kanazawa and colleagues (5) have suggested that vascular endothelial growth factor–induced thickening of the bronchial wall might heighten the bronchoconstrictor response to mediators released from mast cells within airway smooth muscle. Interestingly, interleukin-4 and interleukin-13 increase the expression of vascular endothelial growth factor on airway smooth muscle (13). Possibly these cytokines cause both mast cell and vascular endothelial growth factor activation within airway smooth muscle, contributing to airway hyperresponsiveness and remodeling in asthma. What are the implications of Kanazawa and colleagues' (5) findings for future research in asthma? Sputum vascular endothelial growth factor could be investigated as a potential biomarker for monitoring asthma control, especially if it is found to provide indirect information on airway remodeling. We need to know whether vascular endothelial growth factor has a central role in causing airway hyperresponsiveness in asthma or if it is simply a marker for other more important pathological processes. If the former, then vascular endothelial growth factor inhibitors, which have been developed as angiogenesis inhibitors for treating cancer (14), could be of clinical benefit in asthma. Interestingly, in an animal model of toluene diisocyanate–induced hyperresponsiveness, a vascular endothelial growth factor blocker was found to reduce airway inflammation and hyperresponsiveness (15). In conclusion, studies such as those of Kanazawa and colleagues (5) comparing the clinical, physiological, and pathological features of asthma and eosinophilic bronchitis provide a useful guide to future research into the mechanisms of airway hyperresponsiveness and remodeling in asthma. FOOTNOTES Conflict of Interest Statement: N.C.T. and R.C. do not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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