Epithelial Cell Proliferation Contributes to Airway Remodeling in Severe Asthma

• Published in: American journal of respiratory and critical care medicine Vol. 176; no. 2; pp. 138 - 145
• Main Authors: Cohen, Lance, E, Xueping, Tarsi, Jaime, Ramkumar, Thiruvamoor, Horiuchi, Todd K, Cochran, Rebecca, DeMartino, Steve, Schechtman, Kenneth B, Hussain, Iftikhar, Holtzman, Michael J, Castro, Mario, and NHLBI Severe Asthma Research Program (SARP)
• Format: Journal Article
• Language: English
• Published: New York, NY Am Thoracic Soc 15.07.2007; American Lung Association; American Thoracic Society
• Subjects: Adult; Aged; Airway management; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Asthma; Asthma - metabolism; Asthma - pathology; B. Asthma and Allergy; Biological and medical sciences; Biopsy; Blood. Blood and plasma substitutes. Blood products. Blood cells. Blood typing. Plasmapheresis. Apheresis; Bronchi - metabolism; Bronchi - pathology; Bronchitis; Case-Control Studies; Cell cycle; Cell death; Cell growth; Cell Proliferation; Emergency and intensive respiratory care; Epithelial Cells - physiology; Female; Humans; Intensive care medicine; Ki-67 Antigen - metabolism; Male; Medical sciences; Middle Aged; Proto-Oncogene Proteins c-bcl-2 - metabolism; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Retinoblastoma; Retinoblastoma Protein - metabolism; Severity of Illness Index; Steroids; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Viral infections; Cell proliferation; Lung disease; Intensive care; Respiratory disease; Epithelium; Obstruction; Asthma; desquamation; Bronchus disease; Epithelial cell; Obstructive pulmonary disease; airflow obstruction; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200607-1062OC

Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction. To evaluate if there are structural and functional differences in the airway epithelium in severe asthma associated with airway remodeling. 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. 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. 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.