Mitochondria-targeted H2S suppresses and reverses cigarette smoke-induced inflammasome activity and lung injury in experimental COPD

Background: Hydrogen sulifde (H2S) is an endogenous anti-inflammatory signalling molecule and the only inorganic electron source for mitochondrial ATP synthesis. Lung H2S levels are depleted in COPD and negatively correlate with smoking pack years. Interventions restoring mitochondrial H2S levels and mitochondrial function could offer a novel COPD treatment option. Objectives: We developed novel molecules (MHD) to target mitochondria by a variety of mechanisms using distinct approaches to deliver minute fluxes of H2S. We examined the effects of MHD at suppressing and reversing CS-induced lung damage, inflammation and lung function in experimental COPD. Methods: Suppression of COPD development-Female C57Bl/6 mice (n=8) were exposed to CS (12 cigarettes,b.i.d.,5 days/week) or air for 8 weeks with mtH (1.0mg/kg,i.p.,q.d). Reversal of COPD-Mice were exposed to CS for 8 weeks followed by either 4 weeks of rest or continued CS exposure with MHD (1.0mg/kg i.n.,q.d). Inflammation (BALF inflammatory cells, H2S and IL-1β) and lung function (forced oscillation and manoeuvre) were assessed. Results: CS exposure depleted lung and mitochondrial H2S levels, induced mitochondrial oxidant production and inflammasome induction. Each MHD significantly suppressed CS-induced IL-1β synthesis, alveolar destruction, fibrosis and improved lung gas exchange (DFCO);each p Conclusion: MHD may be a novel therapeutic approach to treat COPD and related conditions.