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Phosphoinositide 3-kinase-δ inhibitor reduces vascular permeability in a murine model of asthma

Authors :
Kamal D. Puri
Sun Mi Jin
Kyung Sun Lee
Seoung Ju Park
Kyung Hoon Min
So Ri Kim
Yong Chul Lee
Source :
Journal of Allergy and Clinical Immunology. 118:403-409
Publication Year :
2006
Publisher :
Elsevier BV, 2006.

Abstract

Background Bronchial asthma is characterized by inflammation of the airways, which is usually accompanied by increased vascular permeability, resulting in plasma exudation. Vascular endothelial growth factor (VEGF) has been implicated in contributing to asthmatic tissue edema through its effect on vascular permeability. Many cellular responses of VEGF are regulated by the lipid products of phosphoinositide 3-kinase (PI3K). However, the effect of PI3K catalytic subunit p110δ on VEGF-mediated signaling is unknown. Recently, an isoform-specific small molecule inhibitor, IC87114, which is selective for p110δ catalytic activity, has been identified. Objective We have sought to investigate the role of PI3K-δ, more specifically in the increase of vascular permeability. Methods Female BALB/c mice were sensitized and challenged with ovalbumin. We have investigated the effect of IC87114 on airway inflammation, T H 2 cytokines expression, airway hyperresponsiveness, plasma extravasation, hypoxia-inducible factor 1α expression, and VEGF expression in a murine model of asthma. Results Our current study has revealed that IC87114 reduces antigen-induced airway infiltration of inflammatory cells, secretion of T H 2 cytokines in lungs, airway hyperresponsiveness, and vascular permeability. Moreover, we have found that inhibition of p110δ reduces ovalbumin-induced upregulation of VEGF level. Conclusion These results suggest that PI3K-δ inhibitor attenuates antigen-induced airway inflammation and hyperresponsiveness by preventing vascular leakage in mice. Clinical implications These findings provide a crucial molecular mechanism for the potential role of PI3K-δ in asthma and other airway inflammatory disorders.

Details

ISSN :
00916749
Volume :
118
Database :
OpenAIRE
Journal :
Journal of Allergy and Clinical Immunology
Accession number :
edsair.doi.dedup.....f94a4f85238dd435c2c738889bf8f3f4
Full Text :
https://doi.org/10.1016/j.jaci.2006.04.041