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Goblet Cell Rebound and Airway Dysfunction with Corticosteroid Withdrawal in a Mouse Model of Asthma

¹ Firestone Institute for Respiratory Health, Department of Medicine, McMaster University, Hamilton, Ontario, Canada; ² Centecor R&D, Radnor, Pennsylvania

Correspondence and requests for reprints should be addressed to Mark D. Inman, M.D., Ph.D., Firestone Institute for Respiratory Health, St. Joseph's Healthcare, 50 Charlton Avenue, East Hamilton, Ontario, L8N 4A6 Canada. E-mail: inmanma{at}mcmaster.ca

Rationale: Although corticosteroids are highly effective at preventing allergen-induced increases in goblet cell numbers, we observed in unpublished experiments a rebound increase in goblet cell numbers in mice after the simultaneous withdrawal of corticosteroid and cessation of exposure to allergen that reached levels greater than those observed in mice exposed to allergen alone, without corticosteroid treatment.

Objectives: To formally explore the goblet cell hyperplasia rebound observed after corticosteroid withdrawal in allergen-exposed mice to determine the mechanism responsible for this previously undescribed pathology.

Methods: Mice airways were assessed for mucin-containing goblet cells after exposure to varying durations of allergen and corticosteroid.

Measurements and Main Results: We confirmed that the simultaneous withdrawal of corticosteroid and cessation of exposure to allergen resulted in a goblet cell hyperplasia rebound that reached levels greater than those observed in allergen-exposed corticosteroid naive mice. Importantly, the goblet cell rebound was associated with a significant airway dysfunction greater than that observed in allergen-exposed corticosteroid naive mice. The goblet cell hyperplasia rebound is independent of the type of corticosteroid or allergen and was associated with an increased level of bronchoalveolar lavage IL-13. Inhibition of IL-13, but not CD4⁺ T cells, completely inhibited the goblet cell hyperplasia rebound and, critically, the associated airway dysfunction.

Conclusions: These findings suggest that certain corticosteroid treatment regimes may actually potentiate airway remodeling and dysfunction in patients with asthma and lead to increased exacerbations and worsening of asthma symptoms.

Key Words: asthma • goblet cells • airway resistance • pathophysiology • glucocorticoids

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Corticosteroid therapy is generally highly effective in human and experimental asthma, but treatment-related complications are incompletely understood. What This Study Adds to the Field We observed a goblet cell hyperplasia rebound pathology associated with airway dysfunction after the simultaneous withdrawal of prolonged corticosteroid therapy and chronic exposure to allergen in mice. Our findings suggest that certain corticosteroid treatment regimes may actually potentiate airway remodeling and dysfunction in patients with asthma and lead to increased exacerbations and worsening of asthma symptoms.