Epithelial Cell Proliferation Contributes to Airway Remodeling in Severe Asthma
- 15 July 2007
- journal article
- research article
- Published by American Thoracic Society in American Journal of Respiratory and Critical Care Medicine
- Vol. 176 (2), 138-145
- https://doi.org/10.1164/rccm.200607-1062oc
Abstract
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.Keywords
This publication has 70 references indexed in Scilit:
- Blocking airway mucous cell metaplasia by inhibiting EGFR antiapoptosis and IL-13 transdifferentiation signalsJCI Insight, 2006
- Differences in airway remodeling between subjects with severe and moderate asthmaJournal of Allergy and Clinical Immunology, 2005
- Regulation of Bcl-2 proteins during anoikis and amorphosisBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2004
- Proliferation and activation of bronchial epithelial cells in corticosteroid-dependent asthmaJournal of Allergy and Clinical Immunology, 2001
- The measurement of reticular basement membrane and submucosal collagen in the asthmatic airwayClinical and Experimental Allergy, 1997
- Fibroblast growth factor stimulates angiotensin converting enzyme expression in vascular smooth muscle cells. Possible mediator of the response to vascular injury.JCI Insight, 1995
- Airways Remodelling in Asthma: No Doubt, No More?International Archives of Allergy and Immunology, 1995
- Disruption of epithelial cell-matrix interactions induces apoptosisThe Journal of cell biology, 1994
- Spectroscopy of defects in germanium-doped silica glassJournal of Applied Physics, 1993
- Immunopathology of the bronchial mucosa in ‘late onset’ asthmaClinical and Experimental Allergy, 1977