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Experimental Biology 2010: Asthmatic Bronchial Epithelium Is Intrinsically Inflammogenic, Mitotically Dyssynchronous, And Is Rescued By Glucocorticoids
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Asthmatic Bronchial Epithelium Is Intrinsically Inflammogenic, Mitotically Dyssynchronous, And Is Rescued By Glucocorticoids
R.J. Freishtat1, 2, A.M. Watson1, A.S. Benton1, S.F. Iqbal1, 2, D.K. Pillai1, M.C. Rose1, E.P. Hoffman1; 1. Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC 2. Division of Emergency Medicine, Children's National Medical Center, Washington, DC
Purpose of Study: Asthma is a chronic inflammatory condition characterized by pathological airway regeneration/remodeling. Anti-inflammatory glucocorticoids (GC) reduce asthma symptoms but do not abrogate long-term lung function decline. This suggests that pathological remodeling of asthmatic airways may not be mediated by inflammation as previously thought but rather intrinsic to the airway epithelium. The goal of the current study was to define the intrinsic inflammogenic and regenerative properties of asthmatic and normal bronchial epithelium. Methods Used: Human primary differentiated bronchial epithelia were mechanically scrape-wounded in GC-free bromodeoxyuridine (BrdU)-containing medium. Epithelia were pulsed with dexamethasone (DEX) (0 or 20nM) for 2 hours prior to wounding and daily over the ensuing 48 hours. Wound healing, inflammation, and regeneration were analyzed by microscopy and/or flow cytometry. Summary of Results: Normal (n=3) and asthmatic (n=3) epithelia were indistinguishably quiescent at baseline. Following wounding, marked differences became apparent. Wounded asthmatic epithelia secreted more basolateral IL-1ß, IL-10, and TGF-ß1 (<0.001 < P < 0.024) than normals and showed 50% fewer mitotically-active (BrdU+) cells (mean±SEM: 0.27±0.03% vs. 0.56±0.07% of total cells; P=0.02). Asthmatic cells were dyssynchronously distributed among the cell cycle phases (G1/G0:52±10, S:25±4, G2/M:23±7% vs. 71±1, 12±2, 17±2%). Accordingly asthmatic epithelia regenerated less efficiently than normals (wound area reduction=51.3±5.6% vs. 78.6±7.7%; P=0.013). DEX-treatment of wounded asthmatic epithelia normalized inflammation, mitotic activity, and wound healing. Conclusions: These data, generated in an airway model lacking bone marrow-derived inflammatory cells, support the concept that asthmatic epithelium is intrinsically inflammogenic. Whether this is a consequence of, or a contributor to, poorly synchronized asthmatic epithelial mitosis is unclear. However, GC treatment apparently both inhibits inflammation and restores asthmatic epithelial regeneration/mitotic synchrony.
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