Phosphodiesterase 4 Inhibition as a Therapeutic Target for Alcoholic Liver Disease: From Bedside to Bench.

ABSTRACT

Alcoholic liver disease (ALD) is a major cause of liver-related mortality. There is still no US Food and Drug Administration-approved therapy for ALD, and therefore, identifying therapeutic targets is needed. Our previous work demonstrated that ethanol exposure leads to up-regulation of cAMP-degrading phosphodiesterase 4 (PDE4) expression, which compromises normal cAMP signaling in monocytes/macrophages and hepatocytes. This effect of ethanol on cAMP signaling contributes to dysregulated inflammatory response and altered lipid metabolism. It is unknown whether chronic alcohol consumption in humans alters hepatic PDE4 expression and cAMP signaling and whether inadequate cAMP signaling plays a pathogenic role in alcohol-induced liver injury. Our present work shows that expression of the PDE4 subfamily of enzymes is significantly up-regulated and cAMP levels are markedly decreased in hepatic tissues of patients with severe ALD. We also demonstrate the anti-inflammatory efficacy of roflumilast, a clinically available PDE4 inhibitor, on endotoxin-inducible proinflammatory cytokine production ex vivo in whole blood of patients with alcoholic hepatitis. Moreover, we demonstrate that ethanol-mediated changes in hepatic PDE4 and cAMP levels play a causal role in liver injury in in vivo and in vitro models of ALD. This study employs a drug delivery system that specifically delivers the PDE4 inhibitor rolipram to the liver to avoid central nervous system side effects associated with this drug. Our results show that PDE4 inhibition significantly attenuates ethanol-induced hepatic steatosis and injury through multiple mechanisms, including reduced oxidative and endoplasmic reticulum stress both in vivo and in vitro. Conclusion: Increased PDE4 plays a pathogenic role in the development of ALD; hence, directed interventions aimed at inhibiting PDE4 might be an effective treatment for ALD.