title: Inhibition of Ras signalling reduces neutrophil infiltration and tissue damage in severe acute pancreatitis.
abstract: 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.
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden; Department of Gastroenterology, Zhujiang Hospital of Southern Medical University, 510282 Guangzhou, China.
authors.forename: Changhui
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Merza
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Clinical Sciences, Section of Surgery, Malmö, Lund University, 20502 Malmö, Sweden. Electronic address: henrik.thorlacius@med.lu.se.
authors.forename: Henrik
authors.initials: H
authors.lastname: Thorlacius
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005204:Farnesol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D024243:HMGB1 Protein / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D016177:Macrophage-1 Antigen / Q000097:blood / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012459:Salicylates / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018925:Chemokines; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D015850:Interleukin-6; D016177:Macrophage-1 Antigen; D012459:Salicylates; C093323:farnesylthiosalicylic acid; C577686:interleukin-6, mouse; D005204:Farnesol; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Amylase; Chemokines; Inflammation; Neutrophils; Pancreatitis