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, TH2 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 TH2 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.
| Original language | English |
|---|---|
| Pages (from-to) | 403-409 |
| Number of pages | 7 |
| Journal | Journal of Allergy and Clinical Immunology |
| Volume | 118 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2006 Jan 1 |
| Externally published | Yes |
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Keywords
- Airway
- PI3K-δ
- vascular permeability
- VEGF
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
Phosphoinositide 3-kinase-δ inhibitor reduces vascular permeability in a murine model of asthma. / Lee, Kyung Sun; Park, Seoung Ju; Kim, So Ri; Min, Kyung-Hoon; Jin, Sun Mi; Puri, Kamal D.; Lee, Yong Chul.
In: Journal of Allergy and Clinical Immunology, Vol. 118, No. 2, 01.01.2006, p. 403-409.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phosphoinositide 3-kinase-δ inhibitor reduces vascular permeability in a murine model of asthma
AU - Lee, Kyung Sun
AU - Park, Seoung Ju
AU - Kim, So Ri
AU - Min, Kyung-Hoon
AU - Jin, Sun Mi
AU - Puri, Kamal D.
AU - Lee, Yong Chul
PY - 2006/1/1
Y1 - 2006/1/1
N2 - 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, TH2 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 TH2 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.
AB - 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, TH2 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 TH2 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.
KW - Airway
KW - PI3K-δ
KW - vascular permeability
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=33746581368&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33746581368&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2006.04.041
DO - 10.1016/j.jaci.2006.04.041
M3 - Article
C2 - 16890765
AN - SCOPUS:33746581368
VL - 118
SP - 403
EP - 409
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 2
ER -