Lee Kyung Sun, Park Seoung Ju, Kim So Ri, Min Kyung Hoon, Jin Sun Mi, Puri Kamal D, Lee Yong Chul
Department of Internal Medicine, Chonbuk National University Medical School, San 2-20, Geunam-dong, Deokjin-gu, Jeonju 561-180, South Korea.
J Allergy Clin Immunol. 2006 Aug;118(2):403-9. doi: 10.1016/j.jaci.2006.04.041. Epub 2006 Jun 6.
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.
We have sought to investigate the role of PI3K-delta, more specifically in the increase of vascular permeability.
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.
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.
These results suggest that PI3K-delta inhibitor attenuates antigen-induced airway inflammation and hyperresponsiveness by preventing vascular leakage in mice.
These findings provide a crucial molecular mechanism for the potential role of PI3K-delta in asthma and other airway inflammatory disorders.
支气管哮喘的特征是气道炎症，通常伴有血管通透性增加，导致血浆渗出。血管内皮生长因子（VEGF）通过其对血管通透性的影响，被认为与哮喘组织水肿的形成有关。VEGF的许多细胞反应受磷酸肌醇3激酶（PI3K）脂质产物的调节。然而，PI3K催化亚基p110δ对VEGF介导的信号传导的影响尚不清楚。最近，已鉴定出一种对p110δ催化活性具有选择性的亚型特异性小分子抑制剂IC87114。
我们试图研究PI3K-δ的作用，更具体地说是在血管通透性增加方面的作用。
用卵清蛋白对雌性BALB/c小鼠进行致敏和激发。我们研究了IC87114对哮喘小鼠模型气道炎症、T（H）2细胞因子表达、气道高反应性、血浆外渗、缺氧诱导因子1α表达和VEGF表达的影响。
我们目前的研究表明，IC87114可减少抗原诱导的炎症细胞气道浸润、肺中T（H）2细胞因子的分泌、气道高反应性和血管通透性。此外，我们发现抑制p110δ可降低卵清蛋白诱导的VEGF水平上调。
这些结果表明，PI3K-δ抑制剂通过防止小鼠血管渗漏来减轻抗原诱导的气道炎症和高反应性。
这些发现为PI3K-δ在哮喘和其他气道炎症性疾病中的潜在作用提供了关键的分子机制。
