Proliferation and activation of bronchial epithelial cells in corticosteroid-dependent asthma

doi:10.1067/mai.2001.119160

Journal of Allergy and Clinical Immunology

Volume 108, Issue 5, November 2001, Pages 738-746

https://doi.org/10.1067/mai.2001.119160 Get rights and content

Abstract

Background: Structural and functional characteristics of bronchial epithelial cells in corticosteroid-dependent asthma are unknown. Objective: In bronchial biopsy specimens from 16 control, 9 untreated asthmatic, 9 inhaled corticosteroid–treated asthmatic, and 19 corticosteroid-dependent asthmatic subjects, we evaluated epithelium morphology and patterns of cell apoptosis, proliferation, and activation. Methods: We used the terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) technique to study apoptosis. Immunohistochemistry was used to evaluate the expression of molecules related to apoptosis (such as Bcl-2 and P53), cell proliferation (PCNA), and cell activation (NFκB and CD40/CD40-L). Results: Epithelium thickness was higher in corticosteroid-dependent asthmatic and control subjects than in inhaled corticosteroid–treated and untreated asthmatic subjects (P < .0001 and P < .0003). Very few TUNEL-positive epithelial cells were found in the 4 groups. Bcl-2 expression was higher in all groups of asthmatic subjects than in controls (P < .001). In corticosteroid-dependent asthmatic subjects, PCNA, NFκB, and CD40-L expression was higher than in inhaled corticosteroid–treated asthmatic (P < .001), untreated asthmatic (P < .001 and P < .04), and control (P < .01) subjects. CD40 expression was greater in corticosteroid-dependent asthmatic and untreated asthmatic subjects than in inhaled corticosteroid–treated asthmatic subjects (P < .0001 and P < .0006) and controls (P < .02 and P < .03). In corticosteroid-dependent asthma, PCNA expression was correlated with the epithelium thickness (P < .007). Conclusion: This study shows that in bronchial epithelial cells of corticosteroid-dependent asthma, markers of cell survival and proliferation are coexpressed with markers of cell activation, suggesting that in this disease epithelium repair is associated with a persistent activation state of epithelial cells. (J Allergy Clin Immunol 2001;108:738-46.)

Section snippets

Subjects

Thirty-seven asthmatic subjects were selected according to the American Thoracic Society's criteria, as previously described.¹³ The clinical severity of asthma was assessed according to the Global Initiative for Asthma guidelines.¹ Subjects were distributed into 3 groups according to treatment.

The first group consisted of 9 subjects (age [years]: range, 22-55; median, 29; 25th-75th percentiles, 24.7-34.7) with mild persistent asthma who received intermittent inhaled short-acting β₂-agonists as

Characteristics of the subjects

The demographic characteristics of the 4 study groups are presented in Table I.

. Demographic characteristics of the subjects

Characteristic	Subject group
	Normal	Asthmatic
	Normal	Untreated	ICS–treated	OCS-dependent
No. of subjects	16	9	9	19
Age (y)	29.5 (25-39)	29 (24.7-34.7)	43 (32.7-45.7)	44 (31-56)
Sex (% male)	58	59	60	43
FEV₁ (% predicted)	100 (100-105)	62 (59.5-75.7)	80.5 (79.5-82.5)	58 (48.5-63.2)
Oral prednisone dose (mg/day)	0	0	0	52 (10-60)

Results are expressed in medians; 25th-75th percentile values are shown in parentheses.

Discussion

The results of this study show that epithelial thickness is greater in OCS-dependent asthma than in untreated asthma even though the severity of the disease is increased. In ICS-treated asthma, the epithelium appears to present with a structural aspect intermediate between that seen in untreated asthma and that seen in OCS-dependent asthma. We also found that epithelial cells of all asthmatic subjects expressed higher levels of the antiapoptotic marker Bcl-2 than did epithelial cells of

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^☆: Supported by a CNR-INSERM grant.

^☆☆: Reprint requests: A. Maurizio Vignola, MD, PhD, Istituto di Fisiopatologia, Respiratoria C.N.R., Via Trabucco 180 - 90146 Palermo, Italy.

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Asthma, Rhinitis, Other Respiratory DiseasesProliferation and activation of bronchial epithelial cells in corticosteroid-dependent asthma☆,☆☆

Abstract

Section snippets

Subjects

Characteristics of the subjects

Discussion

J Allergy Clin Immunol

Immunol Today

Immunol Today

FEBS Lett

Global strategy for asthma management and prevention

Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids

Am J Respir Crit Care Med

Glucocorticoid receptors in bronchial epithelial cells in asthma

Am J Respir Crit Care Med

Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity

Am Rev Respir Dis

Transforming growth factor-β expression in muco-sal biopsies in asthma and chronic bronchitis

Am J Respir Crit Care Med

Functional characteristics of bronchial epithelium obtained by brushing from asthmatic and normal subjects

Am Rev Respir Dis

Detection of GM-CSF in asthmatic bronchial epithelium and decrease by inhaled corticosteroids

Am Rev Respir Dis

The proto-oncogene Bcl-2 and its role in regulating apoptosis

Nat Med

Transcription factors and asthma

Eur Respir J

Eosinophilic inflammation in asthma

N Engl J Med

Asthma, Rhinitis, Other Respiratory Diseases
Proliferation and activation of bronchial epithelial cells in corticosteroid-dependent asthma☆,☆☆