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  • Title: Phosphoinositide 3-kinase-delta inhibitor reduces vascular permeability in a murine model of asthma.
    Author: Lee KS, Park SJ, Kim SR, Min KH, Jin SM, Puri KD, Lee YC.
    Journal: J Allergy Clin Immunol; 2006 Aug; 118(2):403-9. PubMed ID: 16890765.
    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 p110delta on VEGF-mediated signaling is unknown. Recently, an isoform-specific small molecule inhibitor, IC87114, which is selective for p110delta catalytic activity, has been identified. OBJECTIVE: We have sought to investigate the role of PI3K-delta, 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 1alpha 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 p110delta reduces ovalbumin-induced upregulation of VEGF level. CONCLUSION: These results suggest that PI3K-delta 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-delta in asthma and other airway inflammatory disorders.
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