Involvement of sirtuin 1 in airway inflammation and hyperresponsiveness of allergic airway disease.
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 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.


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-1alpha in mice.
Department of Internal Medicine, Chonbuk National University Medical School, Jeonju 561-180, South Korea.
So Ri
SR
Kim
Kyung Sun
KS
Lee
Seoung Ju
SJ
Park
Kyung Hoon
KH
Min
Yeong Hun
YH
Choe
Hee
H
Moon
Wan Hee
WH
Yoo
Han-Jung
HJ
Chae
Myung Kwan
MK
Han
Yong Chul
YC
Lee
D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D015870:Gene Expression; D020869:Gene Expression Profiling; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009284:Naphthols / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism
D000485:Allergens; D001549:Benzamides; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009284:Naphthols; D042461:Vascular Endothelial Growth Factor A; C439060:sirtinol; D010047:Ovalbumin; D056564:Sirtuin 1