Suppression of sirtuin 1 alleviates airway inflammation through mTOR-mediated autophagy

Sirtuin 1 (SIRT1) is involved in the pathogenesis of allergic asthma. This study aimed to investigate whether EX-527, a specific SIRT1 inhibitor, exerted suppressive effects on allergic airway inflammation in mice submitted to ovalbumin (OVA) inhalation. In addition, this study assessed whether such a protective role was mediated by autophagy suppression though mammalian target of rapamycin (mTOR) activation. Female C57BL/6 mice were sensitized to OVA and EX-527 (10 mg/kg) was administered prior to OVA challenge. The study found that EX-527 reversed OVA-induced airway inflammation, and reduced OVA-induced increases in inflammatory cytokine expression, and total cell and eosinophil counts in bronchoalveolar lavage fluid. In addition, EX-527 enhanced mTOR activation, thereby suppressing autophagy in allergic mice. To assess whether EX-527 inhibited airway inflammation in asthma through the mTOR-mediated autophagy pathway, rapamycin was administered to mice treated with EX-527 after OVA sensitization. All effects induced by EX-527, including increased phosphorylated-mTOR and decreased autophagy, were abrogated by rapamycin treatment. Taken together, the present findings indicated that EX-527 may inhibit allergic airway inflammation by suppressing autophagy, an effect mediated by mTOR activation in allergic mice.