Nuclear factor-kappa B (NF-κB) activation is a key early signal regulating 
inflammatory and cell death responses in acute pancreatitis. Our previous in 
vitro studies with molecular approaches on AR42J cell showed that protein kinase 
D (PKD/PKD1) activation was required in NF-κB activation induced by 
cholecystokinin 8 (CCK) or carbachol (CCh) in pancreatic acinar cells. Recently 
developed small molecule PKD inhibitors, CID755673 and CRT0066101, provide 
potentially important pharmacological approaches to further investigate the 
effect of PKD in pancreatitis therapy. The aim of this study was to explore 
whether CID755673 and CRT0066101 block NF-κB activation with in vitro and in 
vivo models of experimental pancreatitis and whether the small molecule PKD 
inhibitors have therapeutic effects when given before or after the initiation of 
experimental pancreatitis. Freshly prepared pancreatic acini were incubated with 
CID755673 or CRT006101, followed by hyperstimulation with CCK or CCh. For in 
vivo experimental pancreatitis, rats were treated with intraperitoneal injection 
of CID755673 or CRT0066101 prior to or after administering cerulein or saline. 
PKD activation and NF-κB-DNA binding activity in nuclear extracts from 
pancreatic acini and tissue were measured. The effects of PKD inhibitors on 
pancreatitis responses were evaluated. Our results showed that both CID755673 or 
CRT0066101 selectively and specifically inhibited PKD without effects on related 
protein kinase Cs. Inhibition of PKD resulted in significantly attenuation of 
NF-κB activation in both in vitro and in vivo models of experimental 
pancreatitis. NF-κB inhibition by CID755673 was associated with decreased 
inflammatory responses and attenuated severity of the disease, which were 
indicated by less inflammatory cell infiltration, reduced pancreatic 
interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), decreased 
intrapancreatic trypsin activation, and alleviation in pancreatic necrosis, 
edema and vacuolization. Furthermore, PKD inhibitor CID755673, given after the 
initiation of pancreatitis in experimental rat model, significantly attenuated 
the severity of acute pancreatitis. Therapies for acute pancreatitis are 
limited. Our results indicate that small chemical PKD inhibitors have 
significant potential as therapeutic interventions by suppressing NF-κB 
activation.