Back to Search
Start Over
Phosphoinositide 3-kinase-δ inhibitor reduces vascular permeability in a murine model of asthma
- 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.
- Subjects :
- Vascular Endothelial Growth Factor A
Indoles
Class I Phosphatidylinositol 3-Kinases
Ovalbumin
Immunology
Inflammation
Vascular permeability
Pharmacology
Capillary Permeability
Leukocyte Count
Mice
chemistry.chemical_compound
Airway resistance
medicine
Animals
Immunology and Allergy
Enzyme Inhibitors
Lung
Phosphoinositide-3 Kinase Inhibitors
Mice, Inbred BALB C
business.industry
Adenine
Pneumonia
respiratory system
Hypoxia-Inducible Factor 1, alpha Subunit
Asthma
Extravasation
respiratory tract diseases
Vascular endothelial growth factor
Disease Models, Animal
Vascular endothelial growth factor A
Receptors, Vascular Endothelial Growth Factor
chemistry
Hypoxia-inducible factors
Cinnamates
P110δ
Quinazolines
Cytokines
Female
Bronchial Hyperreactivity
medicine.symptom
business
Bronchoalveolar Lavage Fluid
Subjects
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