Epithelial cell proliferation contributes to airway remodeling in severe asthma

Lance Cohen, E. Xueping, Jaime Tarsi, Thiruvamoor Ramkumar, Todd K. Horiuchi, Rebecca Cochran, Steve DeMartino, Kenneth B. Schechtman, Iftikhar Hussain, Michael J. Holtzman, Mario Castro, Elliot Israel, Bruce D. Levy, Gautham Marigowda, Serpil C. Erzurum, Raed A. Dweik, Suzy A.A. Comhair, Abigail R. Lara, Marcelle Baaklini, Daniel LaskowskiJacqueline Pyle, W. Gerald Teague, Anne M. Fitzpatrick, Eric Hunter, Kian F. Chung, Mark Hew, Alfonso Torrego, Sally Meah, Mun Lim, Sally E. Wenzel, Diane Rhodes, William J. Calhoun, Melissa P. Clark, Renee Folger, Rebecca Z. Wade, Bill T. Ameredes, Dori Smith, Benjamin Gaston, Peter Urban, William W. Busse, Nizar Jarjour, Erin Billmeyer, Cheri Swenson, Gina Crisafi, Eugene R. Bleecker, Deborah Meyers, Wendy Moore, Stephen Peters, Annette Hastie, Gregory Hawkins, Jeffrey Krings, Regina Smith, Leonard Bacharier, James R. Murphy, Douglas Curran-Everett, Patricia Noel

Research output: Contribution to journalArticle

157 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)138-145
Number of pages8
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume176
Issue number2
DOIs
StatePublished - Jul 15 2007

Keywords

  • Airflow obstruction
  • Desquamation
  • Epithelium

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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    Cohen, L., Xueping, E., Tarsi, J., Ramkumar, T., Horiuchi, T. K., Cochran, R., DeMartino, S., Schechtman, K. B., Hussain, I., Holtzman, M. J., Castro, M., Israel, E., Levy, B. D., Marigowda, G., Erzurum, S. C., Dweik, R. A., Comhair, S. A. A., Lara, A. R., Baaklini, M., ... Noel, P. (2007). Epithelial cell proliferation contributes to airway remodeling in severe asthma. American Journal of Respiratory and Critical Care Medicine, 176(2), 138-145. https://doi.org/10.1164/rccm.200607-1062OC