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Abstract
BackgroundVasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP via cAMP and cGMP dependent protein kinases releases this "brake" on cell motility. Thus, phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Two hypotheses were examined: (1) injury from segmental allergen challenge increases VASP phosphorylation in airway epithelium in asthmatic but not nonasthmatic normal subjects, (2) regular in vivo β2-agonist use increases VASP phosphorylation in asthmatic epithelium, altering cell adhesion.MethodsBronchial epithelium was obtained from asthmatic and non-asthmatic normal subjects before and after segmental allergen challenge, and after regularly inhaled albuterol, in three separate protocols. VASP phosphorylation was examined in Western blots of epithelial samples. DNA was obtained for β2-adrenergic receptor haplotype determination.ResultsAlthough VASP phosphorylation increased, it was not significantly greater after allergen challenge in asthmatics or normals. However, VASP phosphorylation in epithelium of nonasthmatic normal subjects was double that observed in asthmatic subjects, both at baseline and after challenge. Regularly inhaled albuterol significantly increased VASP phosphorylation in asthmatic subjects in both unchallenged and antigen challenged lung segment epithelium. There was also a significant increase in epithelial cells in the bronchoalveolar lavage of the unchallenged lung segment after regular inhalation of albuterol but not of placebo. The haplotypes of the β2-adrenergic receptor did not appear to associate with increased or decreased phosphorylation of VASP.ConclusionDecreased VASP phosphorylation was observed in epithelial cells of asthmatics compared to nonasthmatic normals, despite response to β-agonist. The decreased phosphorylation does not appear to be associated with a particular β2-adrenergic receptor haplotype. The observed decrease in VASP phosphorylation suggests greater inhibition of actin reorganization which is necessary for altering attachment and migration required during epithelial repair.
Highlights
Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement
Allergen-induced inflammation effect on vasodilator-stimulated phosphoprotein (VASP) phosphorylation To test the hypothesis that allergen-induced inflammation would increase phosphorylation of VASP, we examined the ratio of phosphorylated 50 KD to 46 KD VASP in epithelium from allergic asthmatic and nonallergic nonasthmatic normal subjects before and after segmental allergen challenge in the recovery from injury protocol (Table 2)
The ratio of 50/46 KD VASP in epithelial cells of both asthmatic and normal subjects increased after Ag challenge (p = 0.08 for the effect of day on 50/46 KD VASP ratio), but did not reach significance in either group (Figure 2)
Summary
Vasodilator-stimulated phosphoprotein (VASP) mediates focal adhesion, actin filament binding and polymerization in a variety of cells, thereby inhibiting cell movement. Phosphorylation of VASP may be necessary for epithelial cell repair of damage from allergen-induced inflammation. Attachment and migration of airway epithelial cells is an important aspect of repair of injury induced by allergens and other agents in asthma. Cytoskeletal reorganization, mediated through actin filament remodeling, is required to facilitate attachment and migration of epithelial cells into damaged areas. VASP and two other members of the ENA/VASP family in mammalian cells, MENA (mammalian ENAbled) and EVL (ENA/VASP-like) slow or inhibit fibroblast motility by altering the dynamics of actin filament structure [3,4]. The ratio of the 50 KD to the 46 KD molecular form of VASP within a cell sample provides a measure of VASP phosphorylation and indicates active remodeling of the actin cytoskeleton during cell attachment and migration
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