title: Epithelial cell proliferation contributes to airway remodeling in severe asthma.
abstract: BACKGROUND
  Despite long-term therapy with corticosteroids, patients with severe asthma develop irreversible airway obstruction.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110-1093, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Cohen
authors.forename: Xueping
authors.initials: X
authors.lastname: E
authors.forename: Jaime
authors.initials: J
authors.lastname: Tarsi
authors.forename: Thiruvamoor
authors.initials: T
authors.lastname: Ramkumar
authors.forename: Todd K
authors.initials: TK
authors.lastname: Horiuchi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Cochran
authors.forename: Steve
authors.initials: S
authors.lastname: DeMartino
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Schechtman
authors.forename: Iftikhar
authors.initials: I
authors.lastname: Hussain
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
mesh_terms: D000328:Adult; D000368:Aged; D001249:Asthma / Q000378:metabolism / Q000473:pathology*; D001980:Bronchi / Q000378:metabolism / Q000473:pathology*; D016022:Case-Control Studies; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000502:physiology*; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D012720:Severity of Illness Index
chemical_list: D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein