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Rho‐kinase signalling regulates trypsinogen activation and tissue damage in severe acute pancreatitis
Author(s) -
Awla D,
Hartman H,
Abdulla A,
Zhang S,
Rahman M,
Regnér S,
Thorlacius H
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01060.x
Subject(s) - trypsinogen , pancreatitis , acute pancreatitis , pancreas , acinar cell , myeloperoxidase , endocrinology , medicine , kinase , rho kinase inhibitor , inflammation , rho associated protein kinase , chemistry , biology , microbiology and biotechnology , biochemistry , trypsin , enzyme
BACKGROUND AND PURPOSE Severe acute pancreatitis (SAP) is characterized by trypsinogen activation, infiltration of leucocytes and tissue necrosis but the intracellular signalling mechanisms regulating organ injury in the pancreas remain elusive. Rho‐kinase is a potent regulator of specific cellular processes effecting several pro‐inflammatory activities. Herein, we examined the role of Rho‐kinase signalling in acute pancreatitis. EXPERIMENTAL APPROACH Pancreatitis was induced by infusion of taurocholate into the pancreatic duct in C57BL/6 mice. Animals were treated with a Rho‐kinase inhibitor Y‐27632 (0.5–5 mg·kg −1 ) before induction of pancreatitis. KEY RESULTS Taurocholate infusion caused a clear‐cut increase in blood amylase, pancreatic neutrophil infiltration, acinar cell necrosis and oedema formation in the pancreas. Levels of pancreatic myeloperoxidase (MPO), macrophage inflammatory protein‐2 (MIP‐2), trypsinogen activation peptide (TAP) and lung MPO were significantly increased, indicating local and systemic disease. Inhibition of Rho‐kinase activity dose‐dependently protected against pancreatitis. For example, 5 mg·kg −1 Y‐27632 reduced acinar cell necrosis, leucocyte infiltration and pancreatic oedema by 90%, 89% and 58%, respectively, as well as tissue levels of MPO by 75% and MIP‐2 by 84%. Moreover, Rho‐kinase inhibition decreased lung MPO by 75% and blood amylase by 83%. Pancreatitis‐induced TAP levels were reduced by 61% in Y‐27632‐treated mice. Inhibition of Rho‐kinase abolished secretagogue‐induced activation of trypsinogen in pancreatic acinar cells in vitro . CONCLUSIONS AND IMPLICATIONS Our novel data suggest that Rho‐kinase signalling plays an important role in acute pancreatitis by regulating trypsinogen activation and subsequent CXC chemokine formation, neutrophil infiltration and tissue injury. Thus, these results indicate that Rho‐kinase may constitute a novel target in the management of SAP.