Mitochondria-targeted Sulfide Delivery Molecules – New and Novel Players that can Suppress and Reverse Cigarette Smoke-induced Inflammasome Activity

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Abstract RATIONALE Cigarette smoke (CS) is the major risk factor in development of chronic obstructive pulmonary disease (COPD). Interventions that can prevent and/or reverse disease are urgently needed. Hydrogen sulfide (H2S) is generated in mitochondria (mt) and crucial in maintaining mt respiration, suppressing oxidative stress/inflammation. Lung H2S levels are reduced after CS exposure. Lung inflammation, mitochondrial damage and oxidative injury are exacerbated as a result of inhibition/silencing of H2S enzymes, suggesting impairment of H2S synthesis/loss of bioavailability is detrimental in COPD and negatively impacts mitochondrial health. METHODS We have produced novel mt-targeted H2S donors (mtH2SD) AP39 and RT01 to investigate whether these molecules could suppress and/or reverse CS-induced inflammation and lung injury. To investigate suppression, mice were exposed to CS (or air) for 8 wks (with 1.0 mg/kg). To investigate reversal, mice were exposed to CS for 8 wks followed by either 4 wks rest or continued CS exposure, each with mtH2SD (1.0 mg/kg). Airway inflammation (BALF differential cell counts, IL-1β by ELISA) and lung function were assessed. RESULTS Lung H2S levels were reduced and inflammasome activity increased in response to CS exposure. mtH2SD significantly suppressed CS-induced alveolar destruction, fibrosis and improved lung function. mtH2SD treatment reversed CS-induced lung neutrophil, eosinophil and macrophage infiltration, loss of lung function, and partially reversed airway resistance in both models. CONCLUSIONS Targeting H2S to mitochondria may be a novel therapeutic approach to prevent and/or reverse mitochondria-driven inflammation and lung injury in COPD and related diseases.