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Epithelial Cell Proliferation Contributes to Airway Remodeling in Severe Asthma

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, ² Division of Biostatistics, ³ Division of Allergy and Immunology, and ⁴ Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri

Correspondence and requests for reprints should be addressed to Mario Castro, M.D., M.P.H., Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110-1093. E-mail: castrom{at}wustl.edu

Rationale: Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction.

Objectives: To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling.

Methods: In bronchial biopsies from 21 normal subjects, 11 subjects with chronic bronchitis, 9 subjects with mild asthma, and 31 subjects with severe asthma, we evaluated epithelial cell morphology: epithelial thickness, lamina reticularis (LR) thickness, and epithelial desquamation. Levels of retinoblastoma protein (Rb), Ki67, and Bcl-2 were measured, reflecting cellular proliferation and death. Terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis.

Measurements and Main Results: Airway epithelial and LR thickness was greater in subjects with severe asthma compared with those with mild asthma, normal subjects, and diseased control subjects (p = 0.009 and 0.033, respectively). There was no significant difference in epithelial desquamation between groups. Active, hypophosphorylated Rb expression was decreased (p = 0.002) and Ki67 was increased (p < 0.01) in the epithelium of subjects with severe asthma as compared with normal subjects, indicating increased cellular proliferation. Bcl-2 expression was decreased (p < 0.001), indicating decreased cell death suppression. There was a greater level of apoptotic activity in the airway biopsy in subjects with severe asthma as compared with the normal subjects using the TUNEL assay (p = 0.002), suggesting increased cell death.

Conclusions: In subjects with severe asthma, as compared with subjects with mild asthma, normal subjects, and diseased control subjects, we found novel evidence of increased cellular proliferation in the airway contributing to a thickened epithelium and LR. These changes may contribute to the progressive decline in lung function and airway remodeling in patients with severe asthma.

Key Words: epithelium • desquamation • airflow obstruction

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Airway remodeling in asthma refers to structural changes in the airway, including subepithelial fibrosis, smooth muscle hypertrophy, and blood vessel hyperplasia. Limited knowledge exists on airway remodeling in severe asthma. What This Study Adds to the Field In severe asthma, there is increased cellular proliferation in the airway contributing to a thickened epithelium and lamina reticularis.

 

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