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Am J Respir Crit Care Med. 2007 Jul 15;176(2):138-45. Epub 2007 Apr 26.

Epithelial cell proliferation contributes to airway remodeling in severe asthma.

Author information

1
Department of Medicine, Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110-1093, USA.

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.

PMID:
17463414
PMCID:
PMC1994213
DOI:
10.1164/rccm.200607-1062OC
[Indexed for MEDLINE]
Free PMC Article

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