Identification of Drug Candidates to Suppress Cigarette Smoke-induced Inflammation via cMap Analyses.
Cigarette smoking is the main risk factor for COPD, and to date, existing pharmacologic interventions have been ineffective at controlling inflammatory processes associated with the disease. To address this issue, we used the Connectivity Map (cMap) database to identify drug candidates with the potential to attenuate cigarette smoke-induced inflammation. We queried cMap using three independent, in house cohorts of healthy non-smokers and smokers. Potential drug candidates were validated against four publicly available human datasets, as well as six independent data sets from cigarette smoke-exposed mice. Overall, these analyses yielded two potential drug candidates: kaempferol and bethanechol. Subsequently, the efficacy of each drug was validated in vivo in a model of cigarette smoke-induced inflammation. BALB/c mice were exposed to room air or cigarette smoke and treated with each of the two candidate drugs either prophylactically or therapeutically. We found that kaempferol, but not bethanechol, was able to reduce cigarette smoke-induced neutrophilia both when administered prophylactically and therapeutically. Mechanistically, kaempferol decreased expression of IL-1α and CXCL-5 levels in the lung. Our data suggest that cMap analyses may serve as a useful tool to identify novel drug candidates against cigarette smoke-induced inflammation.