The major goal of this proposal is to understand the role of Sirtuin1 in lung premature aging (apoptosis/senescence), emphysema and inflammation in response to cigarette smoke and in patients with COPD. The proposal will identify key intracellular signaling events in the SIRT1 pathway and will allow us to identify therapeutic targets for CS-mediated abnormal lung inflammation and airway injury in pathogenesis of COPD. These studies have high translational potential as SIRT1 is implicated in control of aging, senescence and inflammation.
Pictured Right: Schematic showing the role of SIRT1/FOXO3 pathway in protecting against pulmonary emphysema. (A) Lung level of SIRT1 is reduced in response to cigarette smoke or oxidative/carbonyl stress, which leads to acetylation and degradation of FOXO3, culminating in stress-induced premature senescence. The senescence of lung cells is a contributing factor in causing airspace enlargement and pulmonary emphysema. NF-κB is also acetylated and activated in response to cigarette smoke exposure due to SIRT1 reduction. However, the inhibition of NF-κB-dependent lung inflammation does not prevent the progression of airspace enlargement. SIRT1 activation by overexpression and pharmacological means protects the lungs against cellular senescence and emphysematous changes. (B) Treatment of SRT1720 after the development of emphysema for 2 wk ameliorated elastase-induced increase in lung SA-b-gal activity. (C) The activity of SA-β-gal was increased in lungs of patients with COPD as compared to non-smokers by staining.