.. selleck Discussion and conclusions Signalling mechanisms regulating pathophysiological processes in acute pancreatitis are incompletely understood. The present study reveals that Rho-kinase signalling plays an integral part in the pathophysiology of SAP. In fact, inhibition of Rho-kinase activity markedly reduced acinar cell necrosis and blood amylase levels in acute pancreatitis. Our findings show that inhibition of Rho-kinase activity abolishes trypsinogen activation in the pancreas, which helps to explain the attenuated inflammatory response and tissue damage in SAP. These novel findings indicate that targeting Rho-kinase activity may be a useful approach to protect against SAP.

Rho-kinase activity is generally considered to regulate cytoskeletal dynamics, including cell contraction and vesicular trafficking, but there is increasing evidence also implicating Rho-kinase signalling in numerous features of inflammatory reactions, such as leucocyte migration, phagocytosis and cytokine formation (Riento and Ridley, 2003; Bokoch, 2005). In the present study, we observed that administration of Y-27632, a specific Rho-kinase inhibitor, markedly decreased tissue damage in SAP. For example, inhibition of Rho-kinase signalling reduced the taurocholate-induced increase in blood amylase by 83% and acinar cell necrosis by more than 90%, indicating that Rho-kinase indeed controls a substantial part of the tissue injury in pancreatitis. It should be mentioned that a previous study reported that Y-27632 increased secretion of amylase from acinar cells in cerulein-induced pancreatitis (Kusama et al.

, 2003). That observation may seem to be in contrast to our present findings but the reduction of blood amylase in our present work is more likely to be related to the protective effect of Y-27632 against taurocholate-induced cell injury in the pancreas. Nonetheless, our present data constitutes the first evidence in the literature that inhibition of the Rho-kinase signalling pathway protects against SAP. Thus, our data add SAP to the growing list of conditions, which may be ameliorated by interference with Rho-kinase signalling, including ischaemia-reperfusion (Bao et al., 2004; Shiotani et al., 2004), endotoxaemia (Thorlacius et al., 2006), septic lung injury (Tasaka et al., 2005), tissue fibrosis (Bourgier et al., 2005) and obstructive cholestasis (Laschke et al.

, 2009). In this context, it is interesting to note that the present findings show that inhibition of Rho-kinase attenuates TAP levels in animals with pancreatitis, suggesting that Rho-kinase is involved in the conversion of trypsinogen to active trypsin. This caused us to ask whether Cilengitide Rho-kinase may regulate trypsinogen activation in acinar cells in the pancreas. Interestingly, we found that Y-27632 abolished secretagogue-induced activation of trypsinogen in vitro, suggesting that Rho-kinase indeed regulates trypsinogen activation in acinar cells.