560 Dolichyl Phosphate Dependent Mechanism of Exacerbations in Asthma: P-Glycoprotein Overexpression and E-Cadherin Loss

BACKGROUND: In asthma exacerbations there is a functional hyporesponsiveness of glucocorticoid (FHG) receptors (GR) on T cells, disbalance in activity of IL-2, IL-4, IL-10 and E-cadherin loss. Dolichyl phosphate (DolP) plays an essential role in cytokine synthesis, in constancy of glycoproteins of the GR and E-cadherin expression. The present study was carried out to estimate the role of DolP in mechanism of exacerbations. METHODS: The samples obtained from 82 patients with with frequent exacerbations (APFE group) (median duration > 14 day a year) and 83 patients without exacerbations over 12 months (APWE group). Dolichyl phosphate was defined in T-cells. Soluble E-cadherin was measured with ELISA in sputum and in bronchial epithelial cells (BEC). The intensity of glycoprotein synthesis in IL-2, IL-4, IL-10 and GR was estimated based on the number of starting glycosylation complexes (SGC) and radioimmunoassay. RESULTS: In APWE group Blood Dol concentration was 221.6 + 15.4 ng/mL and urinary Dol concentration was 16.2 + 4.5 mkg/mmol. In APFE group blood Dol was increased up to 4 times making up 455.2 + 31.7 ng/mL and urinary Dol concentration was increased up to 400%, making up to 32.2 + 4.7 mkg/mmol and 2 times in comparison with APWE group. APFE group had 3 to 4 times higher E-cadherin levels in sputum than APWE group. The synthesis of DolP was 7.5-fold decreased in T-lymphocytes in APFE group. APFE group T-cells membrans contain 5.6 to 6.4% of P-glycoprotein-170 as a marker of FHR receptors which differ from APWE ones in Pgp content by 9 to 11 times. DolP in the concentration 10 to 6 M aid 7 to 9-fold reducing P-glycoprotein-170 content in membranes of APFE T-cells to 0,4 to 0,6% and prevent loss of E-cadherin in BEC. T-cells from APFE group cultivated with corticosteroids and Polyprenol restore the possibility to induce IL-10 synthesis in vitro, enhanced the expression of alpha GP isoforms and made these cells more responsive to steroids. CONCLUSIONS: DolP level and N-glycosylation dirorders could correlate with P-glycoprotein overexpression in FHG in T-cells and E-cadherin loss in EC in asthma exacerbations. Dol detection in blood and urine opens up possibilities for exacerbations control and management.