title: Phosphoinositide 3-kinase-delta inhibitor reduces vascular permeability in a murine model of asthma.
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.
  
  
  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.
authors.affiliation: Department of Internal Medicine, Chonbuk National University Medical School, San 2-20, Geunam-dong, Deokjin-gu, Jeonju 561-180, South Korea.
authors.forename: Kyung Sun
authors.initials: KS
authors.lastname: Lee
authors.forename: Seoung Ju
authors.initials: SJ
authors.lastname: Park
authors.forename: So Ri
authors.initials: SR
authors.lastname: Kim
authors.forename: Kyung Hoon
authors.initials: KH
authors.lastname: Min
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Jin
authors.forename: Kamal D
authors.initials: KD
authors.lastname: Puri
authors.forename: Yong Chul
authors.initials: YC
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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