Document Detail


Ex vivo effect of varespladib on secretory phospholipase A2 alveolar activity in infants with ARDS.
MedLine Citation:
PMID:  23071714     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Secretory phospholipase A2 (sPLA2) plays a pivotal role in acute respiratory distress syndrome (ARDS). This enzyme seems an interesting target to reduce surfactant catabolism and lung tissue inflammation. Varespladib is a specifically designed indolic sPLA2 inhibitor, which has shown promising results in animals and adults. No specific data in pediatric ARDS patients are yet available.
METHODS: We studied varespladib in broncho-alveolar lavage (BAL) fluids obtained ex vivo from pediatric ARDS patients. Clinical data and worst gas exchange values during the ARDS course were recorded. Samples were treated with saline or 10-40-100 µM varespladib and incubated at 37°C. Total sPLA2 activity was measured by non-radioactive method. BAL samples were subjected to western blotting to identify the main sPLA isotypes with different sensitivity to varespladib. Results was corrected for lavage dilution using the serum-to-BAL urea ratio and for varespladib absorbance.
RESULTS: Varespladib reduces sPLA2 activity (p<0.0001) at 10,40 and 100 µM; both sPLA2 activity reduction and its ratio to total proteins significantly raise with increasing varespladib concentrations (p<0.001). IC(50) was 80 µM. Western blotting revealed the presence of sPLA2-IIA and -IB isotypes in BAL samples. Significant correlations exist between the sPLA2 activity reduction/proteins ratio and PaO(2) (rho = 0.63;p<0.001), PaO(2)/FiO(2) (rho = 0.7; p<0.001), oxygenation (rho = -0.6; p<0.001) and ventilation (rho = -0.4;p = 0.038) indexes.
CONCLUSIONS: Varespladib significantly inhibits sPLA2 in BAL of infants affected by post-neonatal ARDS. Inhibition seems to be inversely related to the severity of gas exchange impairment.
Authors:
Daniele De Luca; Angelo Minucci; Marco Piastra; Paola E Cogo; Francesca Vendittelli; Laura Marzano; Leonarda Gentile; Bruno Giardina; Giorgio Conti; Ettore D Capoluongo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-10-11
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-10-16     Completed Date:  2013-05-01     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e47066     Citation Subset:  IM    
Affiliation:
Laboratory of Clinical Molecular Biology, Department of Biochemistry, University Hospital A. Gemelli, Catholic University of the Sacred Heart, Rome, Italy. dm.deluca@fastwebnet.it
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MeSH Terms
Descriptor/Qualifier:
Acetates / pharmacology*
Bronchoalveolar Lavage Fluid*
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology*
Humans
Indoles / pharmacology*
Infant
Infant, Newborn
Phospholipases A2, Secretory / antagonists & inhibitors*,  metabolism*
Respiratory Distress Syndrome, Newborn / enzymology*
Chemical
Reg. No./Substance:
0/Acetates; 0/Enzyme Inhibitors; 0/Indoles; 0/varespladib; EC 3.1.1.4/Phospholipases A2, Secretory
Comments/Corrections

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