Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice
Acetaminophen; Connexin; Gap junction; Hemichannel; Hepatotoxicity; Inflammation
© 2017 Elsevier B.V. Historically, connexin hemichannels have been considered as structural precursors of gap junctions. However, accumulating evidence points to independent roles for connexin hemichannels in cellular signaling by connecting the intracellular compartment with the extracellular environment. Unlike gap junctions, connexin hemichannels seem to be mainly activated in pathological processes. The present study was set up to test the potential involvement of hemichannels composed of connexin32 and connexin43 in acute hepatotoxicity induced by acetaminophen. Prior to this, in vitro testing was performed to confirm the specificity and efficacy of TAT-Gap24 and TAT-Gap19 in blocking connexin32 and connexin43 hemichannels, respectively. Subsequently, mice were overdosed with acetaminophen followed by treatment with TAT-Gap24 or TAT-Gap19 or a combination of both after 1.5 h. Sampling was performed 3, 6, 24 and 48 h following acetaminophen administration. Evaluation of the effects of connexin hemichannel inhibition was based on a series of clinically relevant read-outs, measurement of inflammatory cytokines and oxidative stress. Subsequent treatment of acetaminophen-overdosed mice with TAT-Gap19 only marginally affected liver injury. In contrast, a significant reduction in serum alanine aminotransferase activity was found upon administration of TAT-Gap24 to intoxicated animals. Furthermore, co-treatment of acetaminophen-overdosed mice with both peptides revealed an additive effect as even lower serum alanine aminotransferase activity was observed. Blocking of connexin32 or connexin43 hemichannels individually was found to decrease serum quantities of pro-inflammatory cytokines, while no effects were observed on the occurrence of hepatic oxidative stress. This study shows for the first time a role for connexin hemichannels in acetaminophen-induced acute liver failure.
Maes, M., Crespo Yanguas, S., Willebrords, J., Weemhoff, J., da Silva, T., Decrock, E., Lebofsky, M., Pereira, I., Leybaert, L., Farhood, A., Jaeschke, H., Cogliati, B., & Vinken, M. (2017). Connexin hemichannel inhibition reduces acetaminophen-induced liver injury in mice. Toxicology Letters, 278 (). http://dx.doi.org/10.1016/j.toxlet.2017.07.007