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Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models.

Wen L, Voronina S, Javed MA, Awais M, Szatmary P, Latawiec D, Chvanov M, Collier D, Huang W, Barrett J, Begg M, Stauderman K, Roos J, Grigoryev S, Ramos S, Rogers E, Whitten J, Velicelebi G, Dunn M, Tepikin AV, Criddle DN, Sutton R - Gastroenterology (2015)

Bottom Line: The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis.Cytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis.ORAI1 inhibitors might be developed for the treatment of patients with pancreatitis.

View Article: PubMed Central - PubMed

Affiliation: Pancreas Biomedical Research Unit, National Institute for Health Research Liverpool, Royal Liverpool University Hospital, Liverpool, United Kingdom; Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

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GSK-7975A markedly reduces all biochemical responses of TLCS-AP, CER-AP, and FAEE-AP. All models resulted in substantial increases of (A) serum amylase, (B) IL6, (C) pancreatic trypsin activity, (D) pancreatic activity, and (E) lung MPO activity. Subcutaneous osmotic minipump administration of GSK-7975A given as prodrug GSK-6288B at low (L) or high (H) doses significantly reduced all parameters, with a more marked reduction of serum amylase and IL6, pancreatic trypsin at the high dose (mean ± SEM ≥6 mice/group; *P < .05, control vs 3 models; †P < .05 TLCS-AP vs TLCS-AP plus GSK-7975A; ‡P < .05, CER-AP vs CER-AP plus GSK-7975A; and §P < .05, FAEE-AP vs FAEE-AP plus GSK-7975A).
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fig4: GSK-7975A markedly reduces all biochemical responses of TLCS-AP, CER-AP, and FAEE-AP. All models resulted in substantial increases of (A) serum amylase, (B) IL6, (C) pancreatic trypsin activity, (D) pancreatic activity, and (E) lung MPO activity. Subcutaneous osmotic minipump administration of GSK-7975A given as prodrug GSK-6288B at low (L) or high (H) doses significantly reduced all parameters, with a more marked reduction of serum amylase and IL6, pancreatic trypsin at the high dose (mean ± SEM ≥6 mice/group; *P < .05, control vs 3 models; †P < .05 TLCS-AP vs TLCS-AP plus GSK-7975A; ‡P < .05, CER-AP vs CER-AP plus GSK-7975A; and §P < .05, FAEE-AP vs FAEE-AP plus GSK-7975A).

Mentions: GSK-7975A was tested in 3 clinically representative mouse models of acute pancreatitis. TLCS-AP, which is representative of acute biliary pancreatitis from ampullary gallstone obstruction, was induced by pancreatic ductal infusion of TLCS13 and minipumps inserted 30 minutes later. At both doses GSK-7975A significantly reduced increases in serum amylase, IL6, and pancreatic MPO levels; lung MPO was reduced significantly by low dose only (Figure 4). There were consistent reductions in pancreatic edema, inflammatory cell infiltration, and acinar cell necrosis, with a marked reduction in overall histopathology score in the GSK-7975A–treated groups; inflammatory cell infiltration and histopathology score were reduced significantly more by the higher dose (Figure 5).


Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models.

Wen L, Voronina S, Javed MA, Awais M, Szatmary P, Latawiec D, Chvanov M, Collier D, Huang W, Barrett J, Begg M, Stauderman K, Roos J, Grigoryev S, Ramos S, Rogers E, Whitten J, Velicelebi G, Dunn M, Tepikin AV, Criddle DN, Sutton R - Gastroenterology (2015)

GSK-7975A markedly reduces all biochemical responses of TLCS-AP, CER-AP, and FAEE-AP. All models resulted in substantial increases of (A) serum amylase, (B) IL6, (C) pancreatic trypsin activity, (D) pancreatic activity, and (E) lung MPO activity. Subcutaneous osmotic minipump administration of GSK-7975A given as prodrug GSK-6288B at low (L) or high (H) doses significantly reduced all parameters, with a more marked reduction of serum amylase and IL6, pancreatic trypsin at the high dose (mean ± SEM ≥6 mice/group; *P < .05, control vs 3 models; †P < .05 TLCS-AP vs TLCS-AP plus GSK-7975A; ‡P < .05, CER-AP vs CER-AP plus GSK-7975A; and §P < .05, FAEE-AP vs FAEE-AP plus GSK-7975A).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4556985&req=5

fig4: GSK-7975A markedly reduces all biochemical responses of TLCS-AP, CER-AP, and FAEE-AP. All models resulted in substantial increases of (A) serum amylase, (B) IL6, (C) pancreatic trypsin activity, (D) pancreatic activity, and (E) lung MPO activity. Subcutaneous osmotic minipump administration of GSK-7975A given as prodrug GSK-6288B at low (L) or high (H) doses significantly reduced all parameters, with a more marked reduction of serum amylase and IL6, pancreatic trypsin at the high dose (mean ± SEM ≥6 mice/group; *P < .05, control vs 3 models; †P < .05 TLCS-AP vs TLCS-AP plus GSK-7975A; ‡P < .05, CER-AP vs CER-AP plus GSK-7975A; and §P < .05, FAEE-AP vs FAEE-AP plus GSK-7975A).
Mentions: GSK-7975A was tested in 3 clinically representative mouse models of acute pancreatitis. TLCS-AP, which is representative of acute biliary pancreatitis from ampullary gallstone obstruction, was induced by pancreatic ductal infusion of TLCS13 and minipumps inserted 30 minutes later. At both doses GSK-7975A significantly reduced increases in serum amylase, IL6, and pancreatic MPO levels; lung MPO was reduced significantly by low dose only (Figure 4). There were consistent reductions in pancreatic edema, inflammatory cell infiltration, and acinar cell necrosis, with a marked reduction in overall histopathology score in the GSK-7975A–treated groups; inflammatory cell infiltration and histopathology score were reduced significantly more by the higher dose (Figure 5).

Bottom Line: The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis.Cytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis.ORAI1 inhibitors might be developed for the treatment of patients with pancreatitis.

View Article: PubMed Central - PubMed

Affiliation: Pancreas Biomedical Research Unit, National Institute for Health Research Liverpool, Royal Liverpool University Hospital, Liverpool, United Kingdom; Department of Integrated Traditional and Western Medicine, Sichuan Provincial Pancreatitis Centre, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

Show MeSH
Related in: MedlinePlus