Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 746, Issue -, Pages 245-251Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejphar.2014.11.020
Keywords
Amylase; Chemokines; Inflammation; Neutrophils; Pancreatitis
Categories
Funding
- Swedish Medical Research Council [2012-3685]
- Hawler Medical University, College of Pharmacy, Kurdistan Regional Government
- Nanakaly Group
- Einar och Inga Nilssons stiftelse
- Harald och Greta Jaenssons stiftelse
- Greta och Johan Kocks stiftelser
- Froken Agnes Nilssons stiftelse
- Franke och Margareta Bergqvists stiftelse for framjande av cancerforskning
- Magnus Bergvalls stiftelse
- Mossfelts stiftelse
- Nanna Svartz stiftelse
- Ruth och Richard Julins stiftelse
- Svenska Lakaresallskapet
- Allmana sjukhusets i Malmo stiftelse for bekampande av cancer
- MAS fonder
- Malmo University Hospital
- Lund University
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Neutrophil recruitment is known to be a rate limiting step in mediating tissue injury in severe acute pancreatitis (AP). However, the signalling mechanisms controlling inflammation and organ damage in AP remain elusive. Herein, we examined the role of Ras signalling in AP. Male C57BL/6 mice were treated with a Ras inhibitor (farnesylthiosalicylic acid, FTS) before infusion of taurocholate into the pancreatic duct. Pancreatic and lung tissues as well as blood were collected 24 h after pancreatitis induction. Pretreatment with FTS decreased serum amylase levels by 82% and significantly attenuated acinar cell necrosis, tissue haemorrhage and oedema formation in taurocholate-induced pancreatitis. Inhibition of Ras signalling reduced myeloperoxidase (MPO) levels in the inflamed pancreas by 42%. In addition, administration of FTS decreased pancreatic levels of CXC chemokines as well as circulating levels of interleukin-6 and high-mobility group box 1 in animals exposed to taurocholate. Moreover, treatment with FTS reduced taurocholate-induced MPO levels in the lung. Inhibition of Ras signalling had no effect on neutrophil expression of Mac-1 in mice with pancreatitis. Moreover, FTS had no direct impact on trypsin activation in isolated pancreatic acinar cells. These results indicate that Ras signalling controls CXC chemokine formation, neutrophil recruitment and tissue injury in severe AP. Thus, our findings highlight a new signalling mechanism regulating neutrophil recruitment in the pancreas and suggest that inhibition of Ras signalling might be a useful strategy to attenuate local and systemic inflammation in severe AP. (C) 2014 Elsevier B.V. All rights reserved.
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