Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis
| Autor: | Henrik Thorlacius, Lingtao Luo, Mohammed Merza, Changhui Yu |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Neutrophils Macrophage-1 Antigen Inflammation Acinar Cells Proto-Oncogene Proteins p21(ras) medicine Acinar cell Animals Molecular Targeted Therapy Enzyme Inhibitors HMGB1 Protein Pancreas Pharmacology Pancreatic duct Ras Inhibitor biology business.industry Interleukin-6 Pancreatitis Acute Necrotizing Anti-Inflammatory Agents Non-Steroidal medicine.disease Farnesol Salicylates Mice Inbred C57BL medicine.anatomical_structure Neutrophil Infiltration Myeloperoxidase Immunology Cancer research biology.protein Pancreatitis Acute pancreatitis medicine.symptom Chemokines business Signal Transduction |
| Zdroj: | European journal of pharmacology. 746 |
| ISSN: | 1879-0712 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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