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, But Not Fas, Mediates Reduction of Allergen-Induced Mucous Cell Metaplasia by Inducing Apoptosis
* Lovelace Respiratory Research Institute, and
Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87108; and
Aventis Pharmaceutical, Inc., Bridgewater, NJ 08870.
Inflammatory responses induced by allergen exposure cause mucous
cell metaplasia (MCM) by differentiation of existing and proliferating
epithelial cells into mucus-storing cells. Airway epithelia have
various mechanisms that resolve these changes to form normal airway
epithelia. In this report, we first investigated the state of mucous
cell metaplasia and the mechanisms by which MCM is reduced despite
continued exposures to allergen. After 5 days of allergen exposure,
extensive MCM had developed but was reduced when allergen challenge was
continued for 15 days. During this exposure period, IL-13 levels
decreased and IFN-
levels increased in the bronchoalveolar lavage
fluid. In contrast, IL-13 levels decreased but IFN- was not detected
at any time point during the resolution of MCM following cessation of
allergen exposure. Instillation of IFN- but not anti-Fas caused
accelerated resolution of MCM and MCM was not resolved in
Stat1-deficient mice exposed to allergen for 15 days, confirming that
IFN- is crucial for reducing MCM during prolonged exposures to
allergen. IFN- but not anti-Fas induced apoptotic cell death in
proliferating normal human bronchial epithelial cells and in human
bronchial epithelial cells from subjects with asthma. The apoptotic
effect of IFN- was caspase dependent and was inhibited by IL-13,
indicating that the Th2 milieu in asthmatics may maintain MCM by
preventing cell death in metaplastic mucous cells. These studies could
be useful in the understanding of deficiencies leading to chronicity in
airway changes and designing novel therapies to reverse MCM and airway
obstruction in asthmatics.
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