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.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Serrano, Jose
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Chandra, Rashmi; Liddle, Rodger A (2014) Recent advances in the regulation of pancreatic secretion. Curr Opin Gastroenterol 30:490-4
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
Romac, Joelle M-J; Shahid, Rafiq A; Choi, Steve S et al. (2012) Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1? in the pancreas. Am J Physiol Gastrointest Liver Physiol 302:G535-41
Chandra, Rashmi; Liddle, Rodger A (2011) Recent advances in pancreatic endocrine and exocrine secretion. Curr Opin Gastroenterol 27:439-43
Vigna, Steven R; Shahid, Rafiq A; Nathan, Jaimie D et al. (2011) Leukotriene B4 mediates inflammation via TRPV1 in duct obstruction-induced pancreatitis in rats. Pancreas 40:708-14
Nathan, Jaimie D; Romac, Joelle; Peng, Ruth Y et al. (2010) Protection against chronic pancreatitis and pancreatic fibrosis in mice overexpressing pancreatic secretory trypsin inhibitor. Pancreas 39:e24-30
Liddle, Rodger A (2010) Pancreatitis: the acid test. Gastroenterology 139:1457-60
Chandra, Rashmi; Liddle, Rodger A (2009) Neural and hormonal regulation of pancreatic secretion. Curr Opin Gastroenterol 25:441-6
Noble, M D; Romac, J; Vigna, S R et al. (2008) A pH-sensitive, neurogenic pathway mediates disease severity in a model of post-ERCP pancreatitis. Gut 57:1566-71
Romac, Joelle M J; McCall, Shannon J; Humphrey, John E et al. (2008) Pharmacologic disruption of TRPV1-expressing primary sensory neurons but not genetic deletion of TRPV1 protects mice against pancreatitis. Pancreas 36:394-401

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