Sandeep Nadella1, Victor Ciofoaia1,2, Hong Cao1, Bhaskar Kallakury3, Robin D Tucker3, Jill P Smith4. 1. Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC, 20007, USA. 2. Mayo Clinic, Rochester, MN, USA. 3. Department of Pathology, Georgetown University, Washington, DC, USA. 4. Department of Medicine, Georgetown University, 4000 Reservoir Rd, NW, Building D, Room 338, Washington, DC, 20007, USA. jps261@georgetown.edu.
Abstract
BACKGROUND AND AIMS: Chronic pancreatitis is associated with recurrent inflammation, pain, fibrosis, and loss of exocrine and endocrine pancreatic function and risk of cancer. We hypothesized that activation of the CCK receptor contributes to pancreatitis and blockade of this pathway would improve chronic pancreatitis. METHODS: Two murine models were used to determine whether CCK receptor blockade with proglumide could prevent and reverse histologic and biochemical features of chronic pancreatitis: the 6-week repetitive chronic cerulein injection model and the modified 75% choline-deficient ethionine (CDE) diet. In the CDE-fed model, half the mice received water supplemented with proglumide, for 18 weeks. After chronic pancreatitis was established in the cerulein model, half the mice were treated with proglumide and half with water. Histology was scored in a blinded fashion for inflammation, fibrosis and acinar ductal metaplasia (ADM) and serum lipase levels were measured. RNA was extracted and examined for differentially expressed fibrosis genes. RESULTS: Proglumide therapy decreased pancreatic weight in the CDE diet study and the cerulein-induced chronic pancreatitis model. Fibrosis, inflammation, and ADM scores were significantly reduced in both models. Lipase values improved with proglumide but not in controls in both models. Proglumide decreased pancreas mRNA expression of amylase, collagen-4, and TGFβR2 gene expression by 44, 38, and 25%, respectively, compared to control mice. CONCLUSION: New strategies are needed to decreased inflammation and reduce fibrosis in chronic pancreatitis. CCK receptor antagonist therapy may improve chronic pancreatitis by reversing fibrosis and inflammation. The decrease in ADM may reduce the risk of the development of pancreatic cancer.
BACKGROUND AND AIMS: Chronic pancreatitis is associated with recurrent inflammation, pain, fibrosis, and loss of exocrine and endocrine pancreatic function and risk of cancer. We hypothesized that activation of the CCK receptor contributes to pancreatitis and blockade of this pathway would improve chronic pancreatitis. METHODS: Two murine models were used to determine whether CCK receptor blockade with proglumide could prevent and reverse histologic and biochemical features of chronic pancreatitis: the 6-week repetitive chronic cerulein injection model and the modified 75% choline-deficient ethionine (CDE) diet. In the CDE-fed model, half the mice received water supplemented with proglumide, for 18 weeks. After chronic pancreatitis was established in the cerulein model, half the mice were treated with proglumide and half with water. Histology was scored in a blinded fashion for inflammation, fibrosis and acinar ductal metaplasia (ADM) and serum lipase levels were measured. RNA was extracted and examined for differentially expressed fibrosis genes. RESULTS:Proglumide therapy decreased pancreatic weight in the CDE diet study and the cerulein-induced chronic pancreatitis model. Fibrosis, inflammation, and ADM scores were significantly reduced in both models. Lipase values improved with proglumide but not in controls in both models. Proglumide decreased pancreas mRNA expression of amylase, collagen-4, and TGFβR2 gene expression by 44, 38, and 25%, respectively, compared to control mice. CONCLUSION: New strategies are needed to decreased inflammation and reduce fibrosis in chronic pancreatitis. CCK receptor antagonist therapy may improve chronic pancreatitis by reversing fibrosis and inflammation. The decrease in ADM may reduce the risk of the development of pancreatic cancer.
Authors: Sandeep Nadella; Julian Burks; Abdulhameed Al-Sabban; Gloria Inyang; Juan Wang; Robin D Tucker; Marie E Zamanis; William Bukowski; Narayan Shivapurkar; Jill P Smith Journal: Am J Physiol Gastrointest Liver Physiol Date: 2018-06-21 Impact factor: 4.052
Authors: Marc J Berna; Oliver Seiz; Jan Friso Nast; Daniel Benten; Michael Bläker; Johannes Koch; Ansgar W Lohse; Andrea Pace Journal: J Biol Chem Date: 2010-09-14 Impact factor: 5.157
Authors: Adam M Passman; Robyn P Strauss; Sarah B McSpadden; Megan L Finch-Edmondson; Ken H Woo; Luke A Diepeveen; Roslyn London; Bernard A Callus; George C Yeoh Journal: Dis Model Mech Date: 2015-10-23 Impact factor: 5.758