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 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.

Key words: Allergic airway disease, histone deacetylase, hypoxia-inducible factor 1α, sirtuin 1, sirtinol, vascular endothelial growth factor

Abbreviations used: BAL, Bronchoalveolar lavage, EBD, Evans blue dye, HDAC, Histone deacetylase, HIF-1α, Hypoxia-inducible factor 1α, IC₅₀, Inhibitory concentration of 50, 2ME2, 2-Methoxyestradiol, NF-κB, Nuclear factor κB, OVA, Ovalbumin, PAS, Periodic acid–Schiff, p-Akt, Phosphorylated Akt, PI3K, Phosphoinositide 3-kinase, PPARγ, Peroxisome proliferator–activated receptor γ, R_rs, Respiratory system resistance, Sir2, Silent information regulator 2, SIRT1, Sirtuin 1, VEGF, Vascular endothelial growth factor