Chest
Volume 122, Issue 6, Supplement, December 2002, Pages 278S-284S
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Corticosteroid-Induced Apoptosis of Airway Epithelium*: A Potential Mechanism for Chronic Airway Epithelial Damage in Asthma

https://doi.org/10.1378/chest.122.6_suppl.278SGet rights and content

Damage to the airway epithelium is one prominent feature of chronic asthma. Mucosal damage includes gap openings, partial denudation, and loss of ciliated cells. Apoptosis of the airway epithelium is increasingly recognized as a potential mechanism by which damage may occur. Corticosteroids (CSs) induce apoptosis in inflammatory cells, which in part explains their ability to suppress airway inflammation. However, CS therapy does not necessarily reverse epithelial damage. We examined whether CS therapy actually could induce airway epithelial apoptosis using culture models of primary airway epithelial cells and cell lines. The administration of CSs in low-micromolar concentrations induces apoptosis that involves the disruption of mitochondrial polarity, the activation of caspases, and the involvement of Bcl-2. Clear differences exist between CS-induced apoptosis in the cultured epithelium vs cultured hematopoietic cells in regard to time course and resistance to apoptosis. Our data suggest that the use of CSs, in concentrations that could be attained in vivo with the inhalation of potent preparations or with systemic administration, may be one factor in the airways remodeling and epithelial damage that is seen in many patients with chronic, persistent asthma.

Section snippets

The Airway Epithelium Undergoes Apoptosis When Stimulated To Do So

The airway epithelium has death receptors and can undergo apoptosis when these receptors are stimulated. We have demonstrated the expression of the death receptor Fas and its ligand, FasL, in 1HAEoāˆ’ cells, primary human bronchial epithelial cell in culture, and airway tissue sections from healthy human subjects.33 In additional experiments, we have demonstrated that airway epithelial cells in culture undergo apoptosis on the cross-ligation of Fas. This occurs in ā‰¤ 24 h, can approximate 30% of

CSs Elicit Apoptosis of the Airway Epithelium

With this in mind, we recently initiated a study36 to examine CS-induced apoptosis in the airway epithelium. We originally hypothesized that CSs would protect the airway epithelium from apoptotic stimuli. This hypothesis fit the available data, which suggested that CS therapy would aid in the restitution of a damaged airway epithelium37 without eliciting damage itself.35 To our surprise, CS treatment induced apoptosis in central airway epithelial cells. In both primary human airway epithelial

Conclusion

In summary, damage to the airway epithelium is an important pathologic event in patients with asthma, although demonstrating it by the currently available methods can be problematic. In addition to any derangements that may occur in the communication between the epithelium and underlying mesenchymal cells, and any damage that may be caused by inflammatory mediators and cells, we suggest that CSs may elicit apoptosis of the epithelium. Apoptosis is elicited in a concentration range similar to

ACKNOWLEDGMENT

I thank Kimm Hamann, PhD, Marcus Peter, PhD, and Charles Rudin, MD, at the University of Chicago for their advice. I thank Bertha Marroquin and Kimberly Wojcik for their many years of technical assistance.

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    This research was supported by grants HL-60531 and HL-63300 from the National Heart, Lung, and Blood Institute, and by grant CIHR 43898 from the Canadian Institute of Health Research.

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