Sabah F Iqbal, MD 1,2, Angela S Benton, BAS 1, Alan M Watson, PhD, 1,2 Mary C Rose, PhD 1,2, Robert J Freishtat, MD, MPH 1,2 1 Children’s National Medical Center, Washington, DC 2 George Washington University, Washington, DC

 The authors have documented that they have nothing to disclose.

 Increasing prevalence and severity  14.7 million annual lost school days*  196,000 hospital admissions**  730,000 ED visits** *National Health Interview Survey, 2002 **National Hospital Medical Care Survey, /100083/1,000*

InflammationRemodeling ?

Injured asthmatic respiratory epithelium is characterized by asynchronous regeneration and will resynchronize in the presence of glucocorticoids

 Primary differentiated HBE cells at an air-liquid interface (ALI) were used (Mattek, Ashland, MA)  ‘Gold standard’ model in airway epithelial research as it mimics the human airway  Heterogeneous mixture of ciliated, goblet and basal cells Mucus layer Stimuli Goblet cell Ciliated cell Collagen

/- DEX Mechanical Wound Photo +/- DEX

Asthma - DEX Normal - DEX Normal + DEX Asthma + DEX 048 hours Bright –field microscopy (16X) 1mm

 Flow cytometry  BrdU (bromodeoxyuridine)  Cellular proliferation/mitosis  7-AAD (7-amino-actinomycin-D)  DNA label/cell cycle phase

G2 G1

 Proliferating normal cells were more likely to be found in G1 of the cell cycle  Normal cell cycling  Proliferating asthmatic cells were more evenly distributed among G1 and S  Consistent with asynchronous cell cycling  DEX, given at doses analogous to endogenous steroids, re-synchronized the cell cycle

 Chronotherapeutic trials (Pincus et al, 1997)  Single late-afternoon dose of GC improves lung function, symptoms, and inflammation

InflammationRemodeling ?

 DEX at pharmacologic doses may correct for the asynchronous processes and allow normal rapid healing  Use nasal epithelium cells from pediatric patients with asthma and in controls

 K12 Mentoring Committee:  Mary Rose Ph.D.  Robert Freishtat M.D.  Eric Hoffman Ph.D.  Anamaris Colberg-Poley Ph.D.  Stephen Teach M.D.  Angela Benton  Alan Watson Ph.D.  Teresa Hawley Ph.D.  Funded by the National Institutes of Health - National Heart, Lung, and Blood Institute grant number K12HL090020