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


CONCLUSIONS
These results suggest that PI3K-delta inhibitor attenuates antigen-induced airway inflammation and hyperresponsiveness by preventing vascular leakage in mice.


CONCLUSIONS
These findings provide a crucial molecular mechanism for the potential role of PI3K-delta in asthma and other airway inflammatory disorders.
Lee
Kyung Sun
KS
Department of Internal Medicine, Chonbuk National University Medical School, San 2-20, Geunam-dong, Deokjin-gu, Jeonju 561-180, South Korea.
Park
Seoung Ju
SJ
Kim
So Ri
SR
Min
Kyung Hoon
KH
Jin
Sun Mi
SM
Puri
Kamal D
KD
Lee
Yong Chul
YC
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects*; D002934:Cinnamates / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D011799:Quinazolines / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D002934:Cinnamates; D016207:Cytokines; D004791:Enzyme Inhibitors; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C477872:IC 87114; D007211:Indoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011799:Quinazolines; C483044:SU 1498; C416849:SU 5614; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D010047:Ovalbumin; D058534:Class I Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse; D040262:Receptors, Vascular Endothelial Growth Factor; D000225:Adenine