4140 Dolichyl Phosphate Dependent Mechanism of Exacerbations In Asthma: P-Glycoprotein Overexpression and E-Cadherin Loss

Wednesday, 7 December 2011
Poster Hall (Cancún Center)

Galina Kuznecova, MSc , Epidemiology, Preventive Medicine Institute, Riga, Latvia

Ivans S Kuznecovs, MD , Allergy and Immunology, Preventive Medicine Institute, Riga, Latvia

Inese Joksta, MD , Allergy and Immunology, Preventive Medicine Institute, Riga, Latvia

Sergejs Kuznecovs, MD , Preventive Medicine Institute, Riga, Latvia

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 + 31.7ng/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 3-4 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 - 6,4% of P-glycoprotein-170  as a marker of FHR receptors which  differ from APWE ones  in Pgp content by 9-11 times.  DolP in the concentration 10-6 M aid 7-9-fold reducing P-glycoprotein-170 content in membranes of APFE   T-cells to 0,4-0,6% 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.