Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease
Received 16 December 2008; received in revised form 10 August 2009; accepted 12 August 2009. published online 28 October 2009. Corrected Proof
Background
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.
Objective
This study aimed to investigate the role of SIRT1 and the related molecular mechanisms in the pathogenesis of allergic airway disease.
Methods
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.
Results
In this study with mice after inhalation of OVA, the increased levels of SIRT1, hypoxia-inducible factor 1α (HIF-1α), 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-1α in airway epithelial cells.
Conclusions
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-1α in mice.
aThe Department of Internal Medicine, Jeonju, South Korea
bThe Department of Pharmacology, Jeonju, South Korea
cThe Research Center for Pulmonary Disorders, Jeonju, South Korea
dThe Department of Microbiology, Chonbuk National University Medical School, Jeonju, South Korea
Reprint requests: Yong Chul Lee, MD, PhD, Department of Internal Medicine, Chonbuk National University Medical School, San 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea.
Supported by a grant from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A084144); by the Korea Science and Engineering Foundation (KOSEF) through the National Research Laboratory Program funded by the Ministry of Education, Science and Technology (R0A-2005-000-10052-0[2008]); and by a Korea Research Foundation Grant funded by the Korean Government (KRF-2008-313-E00249).
Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.
ABSTRACT