The Pannexin-1 Channel Inhibitor Probenecid Attenuates Skeletal Muscle Cellular Energy Crisis and Histopathological Injury in a Rabbit Endotoxemia Model

This study aimed to investigate the effect of probenecid (Pro) as an inhibitor of the pannexin-1 (Panx-1) channel-mediated release of intracellular ATP to the extracellular compartment on inflammation, cellular energy crisis, and organ injury in a rabbit sepsis model induced by Escherichia coli lipopolysaccharides (LPS). A total of 24 anesthetized and ventilated rabbits were randomly assigned to receive one of four treatments: infusion of LPS without Pro (LPS group), infusion of LPS with Pro (LPS + Pro group), sham operation without Pro (normal group), and sham operation with Pro (normal + Pro group). The LPS group had significantly higher serum ATP levels, serum inflammatory factor levels (TNF-, IL-6, and IL-1), and lower ATP concentrations and ATP/ADP ratios in the skeletal muscle tissue than the normal group. Compared to that at baseline, the expression of Panx-1 in peripheral blood cells increased significantly after the infusion of LPS (fluorescence intensity of Panx-1: T0 (baseline) vs. T1 (post-LPS)=10 +/- 1.2 vs. 84 +/- 48, P<0.0001; paired differences 73 +/- 46, P=0.024). Moreover, the LPS group exhibited higher expression of Panx-1 in the skeletal muscle tissue than the normal group. The serum ATP level was significantly positively correlated with IL-1 (R=0.602, P=0.001), IL-6 (R=0.381, P=0.033), and TNF- (R=0.514, P=0.005) in 24 paired measurements. Compared to the LPS group, the LPS + Pro group had significantly lower levels of inflammatory factors (TNF-, IL-6, and IL-1) and serum ATP. In the skeletal muscle tissue, the LPS + Pro group also had a higher ATP concentration (1.1 +/- 0.15 vs. 1.33 +/- 0.17, P=0.041) and ATP/ADP ratio (0.37 +/- 0.03 vs. 0.51 +/- 0.06, P=0.002) and a lower histopathological damage score (4.67 +/- 0.52 vs. 3 +/- 0.63, P=0.004). An overexpression of Panx-1 channel might be responsible for the strong inflammatory response, high serum ATP level, and skeletal muscle cellular energy crisis and histopathological damages in sepsis. Inhibiting Panx-1 channel-mediated release of intracellular ATP could decrease the above-mentioned injuries, and Panx-1 might be a potential therapeutic target in sepsis.