Sustained Adenosine Caused Endothelial Mitochondrial Dysfunction: Implications for Cigarette Smoke-Induced Increased Susceptibility to Acute Lung Injury

Cigarette smoke (CS) has been independently associated with the development of acute lung injury (ALI). We have previously demonstrated that CS exposure increases lung adenosine levels in mice and that sustained exposure to adenosine causes lung endothelial injury by equilibrative nucleoside transporter (ENT) 1/2-dependent mechanism. In this study we hypothesize that CS-induced increased adenosine causes lung endothelial injury, leading to increased susceptibility to ALI, via ENT1/2- mediated mitochondrial dysfunction. Using inhaled Pseudomonas aeruginosa, a clinically relevant model of ALI, we found that CS pre-exposure exacerbated P. aeruginosa-induced lung injury. Pharmacological inhibition of ENT1 attenuated P. aeruginosa-induced lung edema and inflammation. Using cultured lung endothelial cells, we found that sustained exposure to adenosine decreased mitochondrial basal respiration, increased mitochondrial reactive oxygen species (ROS), enhanced expression of fission/fusion markers (Drp1 and Mfn1) an...