Protein kinase D: A therapeutic target in experimental alcoholic pancreatitis

Background: Alcohol abuse, a main cause of pancreatitis, has been known to augment NF-KB activation and cell necrosis in pancreatitis. However, the underlying mechanisms are unclear. We recently reported that inhibition of protein kinase D (PKD) alleviated NF-KB activation and severity of experimental pancreatitis. Here we investigated whether PKD signaling mediated the modulatory effects of alcohol abuse on pathological responses in alcoholic pancreatitis. Methods: Alcoholic pancreatitis was provoked in two rodent models with pair-feeding control and ethanolcontaining Lieber-DeCarli diets for up to 8 weeks followed by up to 7 hourly intraperitoneal injections of cerulein at 1 mu g/kg (rats) or 3 mu g/kg (mice). Effects of PKD inhibition by PKD inhibitors or genetic deletion of pancreatic PKD isoform (PKD3 Delta panc mice) on alcoholic pancreatitis parameters were determined. Results: Ethanol administration amplified PKD signaling by promoting expression and activation of pancreatic PKD, resulted in augmented/promoted pancreatitis responses. Pharmacological inhibition of PKD or with PKD3 Delta panc mice prevented the augmenting/sensitizing effect of ethanol on NF-KB activation and inflammatory responses, cell necrotic death and the severity of disease in alcoholic pancreatitis. PKD inhibition prevented alcohol-enhanced trypsinogen activation, mRNA expression of multiple inflammatory molecules, the receptorinteracting protein kinase activation, ATP depletion, and downregulation of pro-survival Bcl-2 protein in alcoholic pancreatitis. Furthermore, PKD inhibitor CID755673 or CRT0066101, administrated after the induction of pancreatitis in mouse and rat alcoholic pancreatitis models, significantly mitigated the severity of pancreatitis.Conclusion: PKD mediates effect of alcohol abuse on pathological process of pancreatitis and constitutes a novel therapeutic target to treat this disease.

Automated summary

The study reveals that alcohol abuse can enhance PKD signaling in pancreatitis, leading to exacerbated pathological responses. Inhibition of PKD activation through pharmacological means or genetic deletion prevents the detrimental effects of alcohol on NF-KB activation, inflammatory responses, and cell necrosis, thereby mitigating the severity of alcoholic pancreatitis.