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Modulation of Vasodilator-Stimulated Phosphoprotein In Vivo in Human Epithelial Cells by Segmental Allergen Challenge and β2-Agonist Therapy* FREE TO VIEW

Annette T. Hastie, PhD; Vikas Batra, MD; Sandhya Khurana, MD; Kathy A. Carpenter, BS; Rosemary Cirelli, MD; James G. Zangrilli, MD, FCCP; Stephen P. Peters, MD, PhD, FCCP
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*From the Thomas Jefferson University, Philadelphia, PA.

Correspondence to: Annette T. Hastie, PhD, Department of Medicine, Thomas Jefferson University, 1025 Walnut St, Room 805, Philadelphia, PA 19107; e-mail: annette.hastie@mail.tju.edu

Chest. 2003;123(3_suppl):377S. doi:10.1378/chest.123.3_suppl.377S
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The attachment and migration of airway epithelial cells is an important aspect of the repair of antigen-induced inflammatory injury in patients with asthma. Cytoskeletal reorganization is required for the altered attachment and migration of epithelial cells. Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion and actin filament binding in a variety of cells and acts as an inhibitor of cell movement. Phosphorylation of VASP via cyclic adenosine monophosphate-dependent and cyclic guanosine monophosphate-dependent protein kinases releases this “brake” on cell motility.

Segmental allergen (Ag) challenge increases phosphorylation of VASP in the airway epithelium. In addition, β2-agonist use increases epithelial VASP phosphorylation and, thereby, alters cell adhesion and motility.

Brush biopsy specimens from the human bronchial epithelium from asthmatic subjects were obtained in the following two separate protocols: (1) before (day 1) and after segmental allergen challenges (days 2, 9, and 16) in a recovery-from-injury protocol (nine patients); and (2) before (day 1) and 24 h after segmental allergen challenge (day 2) at baseline, after a 2-week period of regular therapy with an inhaled β2-agonist agent or placebo, and after 1 additional week of withdrawal from therapy with a β2-agonist agent or placebo (five patients [two patients receiving β2-agonist agent and three patients receiving placebo]). Cell lysates were assessed for VASP (46 kd) and phosphorylation of VASP (50 kd) by Western blot analyses.

The ratio of 50 kd/46 kd VASP in epithelial cells increased 1 to 2 weeks after Ag challenge but not significantly (p = 0.12). Asthmatic epithelial cells have a significantly lower ratio of 50 kd/46 kd VASP than do nonatopic, nonasthmatic epithelial cells (eight patients) [p < 0.001]. After inhaled β2-agonist use, the 50 kd/46 kd VASP ratio significantly increased in both control and challenged segment epithelium of asthmatic patients (p = 0.003), but not after placebo use (p = 0.79). Moreover, significantly increased numbers of Alcian blue-stained, mucin-secreting epithelial cells were observed in the BAL fluid of unchallenged segments of asthmatic patients receiving β2-agonist therapy, but not in that of patients receiving placebo (p < 0.001 for group; p = 0.014 for day; and p = 0.004 for group vs day interaction). Accordingly, significantly increased total numbers of epithelial cells in BAL fluid (ie, Alcian blue-stained, ciliated, and other columnar epithelial cells) were observed for β2-agonist agents but not placebo (p < 0.001 for group; and p = 0.014 for group vs day interaction).

Segmental Ag challenge does not significantly increase VASP phosphorylation, and asthmatic patients have significantly less VASP phosphorylation compared to healthy subjects, suggesting reduced epithelial cell motility in asthmatic patients. Inhaled β2-agonists increase VASP phosphorylation in vivo and alter epithelial cell adhesion, possibly affecting migration.

Abbreviation: VASP = vasodilator-stimulated phosphoprotein

This research was supported by National Institutes of Health grants HL67663 and AI24509.




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