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: 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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Authors | Kyung Sun Lee, Seoung Ju Park, So Ri Kim, Kyung Hoon Min, Sun Mi Jin, Kamal D Puri, Yong Chul Lee |
Journal | The Journal of allergy and clinical immunology
(J Allergy Clin Immunol)
Vol. 118
Issue 2
Pg. 403-9
(Aug 2006)
ISSN: 0091-6749 [Print] United States |
PMID | 16890765
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Cinnamates
- Cytokines
- Enzyme Inhibitors
- Hif1a protein, mouse
- Hypoxia-Inducible Factor 1, alpha Subunit
- IC 87114
- Indoles
- Phosphoinositide-3 Kinase Inhibitors
- Quinazolines
- SU 1498
- SU 5614
- Vascular Endothelial Growth Factor A
- vascular endothelial growth factor A, mouse
- Ovalbumin
- Class I Phosphatidylinositol 3-Kinases
- Pik3cd protein, mouse
- Receptors, Vascular Endothelial Growth Factor
- Adenine
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Topics |
- Adenine
(analogs & derivatives, pharmacology)
- Animals
- Asthma
(immunology, metabolism)
- Bronchial Hyperreactivity
(immunology, metabolism, prevention & control)
- Bronchoalveolar Lavage Fluid
(chemistry, cytology)
- Capillary Permeability
(drug effects)
- Cinnamates
(pharmacology)
- Class I Phosphatidylinositol 3-Kinases
- Cytokines
(metabolism)
- Disease Models, Animal
- Enzyme Inhibitors
(pharmacology)
- Female
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Indoles
(pharmacology)
- Leukocyte Count
- Lung
(drug effects, metabolism)
- Mice
- Mice, Inbred BALB C
- Ovalbumin
- Phosphoinositide-3 Kinase Inhibitors
- Pneumonia
(immunology, metabolism, prevention & control)
- Quinazolines
(pharmacology)
- Receptors, Vascular Endothelial Growth Factor
(antagonists & inhibitors)
- Vascular Endothelial Growth Factor A
(metabolism)
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