© 2002 American Thoracic Society
Corticosteroid-induced epithelial shedding in asthmaTo the Editor:We read with interest the study from Dorscheid and colleagues (1) who suggested that corticosteroids might contribute to and not prevent the epithelial cell shedding in chronic asthma. This conclusion is based on their results showing that corticosteroids elicit apoptosis in primary airway epithelial cell and in the cell line 1HAEo-. The authors claimed that studies performed on the distribution of corticosteroids in humans suggested that airway tissue concentrations are at least within the nanomolar range (2, 3). The data reported by the authors showed that less than 15% of apoptotic cells were found after incubation with micromolar concentrations of dexamethasone for 24 hours. Moreover, no effect was shown for concentrations lower than 3 µM budesonide, beclomethasone, and triamcinolone. Using the 1HAEo- cell line, the authors did not show a significant decrease in proliferation using micromolar concentration of dexamethasone. There are two points we would like to address in this letter. First, we need to be cautious about these results regarding either the small percentage of apoptosis found and the high concentrations of steroids used. Second, we think that it is somewhat difficult to interpret data obtained from SV40 transformed cell line. When we study apoptosis, it is to some extent inappropriate to use immortalized cells. The scientific observations found in the article by Dorscheid and colleagues are not supported by clinical observations. In a previous study (4), we evaluated epithelium morphology and patterns of cell apoptosis, proliferation, and activation in bronchial biopsy specimens obtained from 16 control subjects, 9 untreated, 9 inhaled corticosteroid-treated, and 19 corticosteroid-dependent asthmatic subjects. This study showed that in bronchial epithelial cells from corticosteroid-dependent asthmatics, markers of cell survival and proliferation were coexpressed with markers of cell activation, suggesting that in this disease, epithelium repair was associated with a persistent activation state of epithelial cells. This study suggested that epithelial cells from corticosteroid-dependent asthmatics showed an enhanced proliferative response with a very low number of apoptotic cells. In conclusion, despite the important question raised by Dorscheid and colleagues, we are not convinced that the data presented in their article sustained the authors' assumption that corticosteroids participate in epithelial turnover in asthma.
a Hopital Arnaud de Villeneuve Montpellier, France REFERENCES
From the Authors:We appreciate the letter from Dr. Carayol and colleagues regarding our article in the November 2001 issue of AJRCCM (1), and would like to address their concerns.Concentrations that can be attained by inhaled corticosteroids in the periciliary fluid are calculated to be in the micromolar range (1). Other studies (2, 3) using tissue analysis suggest in vivo concentrations are in the nanomolar range. Corticosteroid concentrations determined in whole lung tissue are unlikely to reflect the conditions at the apical surface of the airway epithelium. Exposing both an SV40 transformed cell line and primary airway epithelial cells, our data demonstrated that dexamethasone, in a concentration range similar to that which can be attained in vivo by inhaled corticosteroids, reduces proliferation and induces significant apoptosis. Another concern was the "small percentage" of apoptosis and questions about its relevance. The authors' own work (4) demonstrates that asthmatics regularly using inhaled corticosteroids manifest a shorter epithelium (spreading of epithelial cells to heal injuries) and reduced proliferation. Interpretation of endobronchial biopsies is prone to error from the small size as a proportion of total airway surface. Even so, there is evidence that corticosteroids are associated with in vivo apoptosis. Benayoun and colleagues (5) found increased activated caspase-3 in endobronchial biopsies of asthmatic subjects when compared with normal subjects. This finding was further exaggerated in those treated with corticosteroids. Chagani and colleagues (6) suggest that excessive epithelial apoptosis corresponds to asthma severity. Trautmann and colleagues (7) have also shown significant apotosis in airway epithelium of asthmatics (see Figure 5 of their article) in response to inflammatory cell stimuli. The area that remains unexplored is the effect that "low" rates of apoptosis may have on chronic remodeling of the asthmatic airway. If 15% of the epithelium needs replacement on a regular basis due to apoptosis (approximately 1% is normal), and proliferation is reduced or limited, a long-term consequence would not require a greater rate of cell death than what we have demonstrated in our paper. We agree with the authors that often clinical practice and basic scientific observations do not support each other, but rarely does this make either incorrect. However, our data raise the possibility that corticosteroids may participate in the epithelial cell turnover seen in asthma. What role this may play in the development of chronic airway remodeling remains to be identified.
a University of British Columbia Vancouver, BC, Canada REFERENCES
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