Acute pancreatitis is poorly understood and there are no good treatments for it. New insight into y mechanisms by which the pancreas is damaged by inflammatory insults may lead to better treatments for acute pancreatitis in people. There is strong evidence that neurogenic inflammation mediated by TRPV1 cation channels in a class of sensory neurons that innervate the pancreas play a role in acute pancreatitis, but the source of activation of TRPV1 is unknown. We have recently discovered that leukotriene B4 (LTB4), an endogenous agonist ligand of TRPV1, is produced by pancreatic acinar cells. Moreover, we have shown that LTB4 can induce pancreatitis an effect that is blocked by TRPV1 antagonists. In the current proposal we will test the hypothesis that LTB4 mediates acute pancreatic inflammation using several animal models: (1) caerulein hyperstimulation, (2) intraductal bile acid infusion, and (3) ethanol plus fatty acid ethyl ester administration. The intraductal bile aci infusion model is considered to be a good model of human gallstone- induced pancreatitis and the ethanol plus fatty acid ethyl ester model may be relevant to human alcohol- induced pancreatitis. The first specific aim is to test the hypothesis that 5-lipoxygenase (5-LO) and LTB4 mediate neurogenic inflammation in the three animal models described above. The second specific aim is to test the hypothesis that calcium-dependent and calcium-independent pathways are involved in 5-LO activation in these models. The third specific aim is to test the hypothesis that TRPV1 expressed by pancreatic acinar cells plays a role in acute pancreatitis in animal models. Experimental approaches to testing these hypotheses include in vivo induction of pancreatitis in mice, pharmacological stimulation and inhibition of various pathways of regulation, use of mouse strains with genetic deletions of TRPV1 and 5-LO genes, including pancreas specific knockouts of these genes, and in vitro studies of signal transduction mechanisms and regulation of 5- LO activity in pancreatic acini. We expect these studies will unveil a novel pathway critical to the pathogenesis of neurogenic pancreatitis. Importantly, these results may identify novel therapeutic targets for treating human acute pancreatitis.

Public Health Relevance

Pancreatitis is an inflammatory disease of the pancreas that causes intense pain and, in severe cases, death. Although some predisposing factors (such as gallstones and alcohol) are known, the exact mechanisms leading to pancreatitis are not well understood. Pain-sensing nerves release transmitters that may actually cause inflammation and preliminary data indicate that these nerves play a role in pancreatitis. This proposal will characterize the neural mechanisms that contribute to pancreatitis and may lead to improved treatments of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK064213-11
Application #
8702876
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Serrano, Jose
Project Start
2003-04-01
Project End
2018-02-28
Budget Start
2014-06-01
Budget End
2015-02-28
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
Anderson, Michelle A; Akshintala, Venkata; Albers, Kathryn M et al. (2016) Mechanism, assessment and management of pain in chronic pancreatitis: Recommendations of a multidisciplinary study group. Pancreatology 16:83-94
Kanju, Patrick; Chen, Yong; Lee, Whasil et al. (2016) Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. Sci Rep 6:26894
Bohórquez, Diego; Haque, Fariha; Medicetty, Satish et al. (2015) Correlative Confocal and 3D Electron Microscopy of a Specific Sensory Cell. J Vis Exp :e52918
Shahid, Rafiq A; Vigna, Steven R; Layne, Amanda C et al. (2015) Acinar Cell Production of Leukotriene B4 Contributes to Development of Neurogenic Pancreatitis in Mice. Cell Mol Gastroenterol Hepatol 1:75-86
Shahid, Rafiq A; Wang, David Q-H; Fee, Brian E et al. (2015) Endogenous elevation of plasma cholecystokinin does not prevent gallstones. Eur J Clin Invest 45:237-46
Chandra, Rashmi; Liddle, Rodger A (2014) Recent advances in the regulation of pancreatic secretion. Curr Opin Gastroenterol 30:490-4
Vigna, Steven R; Shahid, Rafiq A; Liddle, Rodger A (2014) Ethanol contributes to neurogenic pancreatitis by activation of TRPV1. FASEB J 28:891-6
Chandra, Rashmi; Liddle, Rodger A (2013) Modulation of pancreatic exocrine and endocrine secretion. Curr Opin Gastroenterol 29:517-22
Chandra, Rashmi; Wang, Yu; Shahid, Rafiq A et al. (2013) Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion. J Clin Invest 123:3343-52
Forsmark, Chris E; Liddle, Rodger A (2012) The challenging task of treating painful chronic pancreatitis. Gastroenterology 143:533-5

Showing the most recent 10 out of 27 publications