Department of Internal Medicine, Chonbuk National University Medical School, Jeonju 561-180, South Korea.
J Allergy Clin Immunol. 2010 Feb;125(2):449-460.e14. doi: 10.1016/j.jaci.2009.08.009. Epub 2009 Oct 27.
Bronchial asthma is a chronic inflammatory disorder of the airways characterized by increased expression of multiple inflammatory genes. Acetylation of histones by histone acetyltransferases is associated with increased gene transcription, whereas hypoacetylation induced by histone deacetylases is associated with suppression of gene expression. Sirtuin 1 (SIRT1) is a member of the silent information regulator 2 family that belongs to class III histone deacetylase.
This study aimed to investigate the role of SIRT1 and the related molecular mechanisms in the pathogenesis of allergic airway disease.
By using a murine model of ovalbumin (OVA)-induced allergic airway disease and murine tracheal epithelial cells, this study investigated the involvement of SIRT1 and its signaling networks in allergic airway inflammation and hyperresponsiveness.
In this study with mice after inhalation of OVA, the increased levels of SIRT1, hypoxia-inducible factor 1alpha (HIF-1alpha), and vascular endothelial growth factor protein in the lungs after OVA inhalation were decreased substantially by the administration of a SIRT1 inhibitor, sirtinol. We also showed that the administration of sirtinol reduced significantly the increased numbers of inflammatory cells of the airways; airway hyperresponsiveness; increased levels of IL-4, IL-5, and IL-13; and increased vascular permeability in the lungs after OVA inhalation. In addition, we have found that inhibition of SIRT1 reduced OVA-induced upregulation of HIF-1alpha in airway epithelial cells.
These results indicate that inhibition of SIRT1 might attenuate antigen-induced airway inflammation and hyperresponsiveness through the modulation of vascular endothelial growth factor expression mediated by HIF-1alpha in mice.
支气管哮喘是一种气道慢性炎症性疾病，其特征是多种炎症基因表达增加。组蛋白乙酰转移酶的组蛋白乙酰化与基因转录增加有关，而组蛋白去乙酰化酶诱导的低乙酰化与基因表达抑制有关。Sirtuin 1（SIRT1）是沉默信息调节因子 2 家族的成员，属于 III 类组蛋白去乙酰化酶。
本研究旨在探讨 SIRT1 及其相关分子机制在过敏性气道疾病发病机制中的作用。
本研究通过卵清蛋白（OVA）诱导的过敏性气道疾病小鼠模型和小鼠气管上皮细胞，研究了 SIRT1 及其信号网络在过敏性气道炎症和高反应性中的作用。
在本研究中，通过 OVA 吸入的小鼠模型，OVA 吸入后肺组织中 SIRT1、缺氧诱导因子 1α（HIF-1α）和血管内皮生长因子蛋白水平的增加，通过 SIRT1 抑制剂 sirtinol 的给药显著降低。我们还表明，sirtinol 的给药显著减少了 OVA 吸入后气道炎症细胞的增加、气道高反应性、IL-4、IL-5 和 IL-13 水平的增加以及肺血管通透性的增加。此外，我们发现抑制 SIRT1 可降低 OVA 诱导的气道上皮细胞中 HIF-1α的上调。
这些结果表明，抑制 SIRT1 可能通过调节 HIF-1α介导的血管内皮生长因子表达，减轻抗原诱导的气道炎症和高反应性。
