Published ahead of print on April 26, 2007, doi:10.1164/rccm.200607-1062OC Am. J. Respir. Crit. Care Med., Volume 176, Number 2, July 2007, 138-145 A more recent version of this article appeared on July 15, 2007
Submitted on July 31, 2006 Epithelial Cell Proliferation Contributes to Airway Remodeling in Severe AsthmaLance Cohen1,1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA, 2 Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA, 3 Division of Allergy and Immunology, Washington University School of Medicine, St. Louis, MO, USA, 4 Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA; Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA * To whom correspondence should be addressed. E-mail: castrom{at}im.wustl.edu.
Rationale: Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction. We hypothesized that there would be structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling. Methods: In bronchial biopsies from 21 normal, 11 chronic bronchitis, 9 mild and 31 severe asthma subjects, 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 deoxynucleotidylmediated dUTP nick end labeling (TUNEL) was used to study cellular apoptosis. Results: Airway epithelial and LR thickness was greater in severe asthma subjects compared to mild asthma, normal and diseased controls (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 severe asthma subjects as compared to normals 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 severe asthma as compared to the normals per TUNEL assay (P=0.002) suggesting increased cell death. Conclusion: In severe asthma, as compared to mild asthma, normal and diseased controls, we have 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
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