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Mucus secretion of pancreatic ductal epithelium increases in chronic pancreatitis
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Abstracts / Pancreatology 14 (2014) S1eS129
O-39. Mucus secretion of pancreatic ductal epithelium increases in chronic pancreatitis zs a, Duerr Julia b, Zhe Zhou-Suckow b, Jolanthe Schatterny b, Anita Bala szlo n Rakonczay a, Marcus A. n Bala zs N c, Zolta Istva emeth c, Tiszlavicz La b a Mall , Peter Hegyi a
First Department of Medicine, University of Szeged, Szeged, Hungary Department of Translational Pulmonology, Translational Lung Research Center, University of Heidelberg, Heidelberg, Germany c Department of Pathology University of Szeged, Szeged, Hungary b
Background: Mucoprotein plug formation within the pancreatic ducts is one of the early events of chronic pancreatitis (CP), but little is known about its pathogenesis. Recent evidence suggests impaired ion- and fluid secretion of pancreatic ductal epithelial cells (PDEC) in CP, which together with increased mucus secretion may alter mucus hydration and subsequently lead to plug formation. Aims: We aimed to invesigate mucus secretion of PDEC in CP. Materials & methods: Human and mouse pancreata were investigated. Human CP tissue samples were collected from surgically resected pancreata, whereas CP was induced by administration of 6x50mg/kg cerulein, 3 series/week for 4 weeks in mice. Morphometric analysis of mucus was carried out by CellF software. Total RNA was isolated from human and mouse tissue. The mRNA levels of different mucin subtypes were analysed by quantitative RT-PCR. Results: We found that mucus volume density (Vdmuc) of human PDEC was significantly higher in CP than in controls, in case of smaller ducts (ductal diameter <100mm: 1.21±0.13nl/mm2 and 0.37±0.05nl/mm2, respectively). Similarily, mouse PDEC showed significantly higher Vdmuc in CP than in controls, especially in ducts with smaller diameter (ductal diameter <80mm: 0.72±0.06nl/mm2 vs. 0.005±0.0002nl/mm2, ductal diameter >80mm: 0.075±0.020nl/mm2 vs. 0.016±0.004nl/mm2). Mucin gene expression analysis showed, that muc6 was ~1000-fold upregulated in mouse and 17-fold upregulated in human CP. Conclusion: There is a substantial mucus hypersecretion in CP localized to the small ducts. Obstruction of the small ducts by mucus in CP may contribute to the pathogenesis of the disease. Supported by EPC Travel Fellowship.
O-40. Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects and an increased risk for chronic pancreatitis e a genetic association study F. Ulrich Weiss a, Claudia Schurmann b, Annett Guenther a, Florian Ernst b, €lzke c, Do €rte Alexander Teumer b, Julia Mayerle a, Peter Simon a, Henry Vo Radke c, Andreas Greinacher d, Jens-Peter Kuehn e, Martin Zenker f, Uwe €lker b, Georg Homuth b, Markus Lerch a Vo a
University Medicine Greifswald, Internal Medicine A, Germany University Medicine Greifswald, Department of functional Genomics, Germany c University Medicine Greifswald, Institute for Community Medicine, Germany d University Medicine Greifswald, Institute of Immunology and Transfusion, Germany e University Medicine Greifswald, Department of Diagnostic Radiology and Neuroradiology, Germany f Otto-von-Guericke-University Magdeburg, Institute of Human Genetics, Germany b
Background: The definition of acute pancreatitis includes characteristic clinical symptoms in combination with above three-fold elevated serum lipase activities. Elevated lipase levels below this cut-off are not considered diagnostic for pancreatitis.
Aims: We investigated whether high lipase activity - within the reference range and in the absence of pancreatitis - are associated with genetic polymorphisms (SNPs) and whether these identified SNPs are also associated with clinical pancreatitis. Patients & methods: Genome-wide association studies (GWAS) on phenotypes “serum lipase activity” and “high serum lipase activity” were conducted including 3966 German volunteers from the population-based Study-of-Health-in-Pomerania (SHIP). Lead SNPs associated on a genomewide significance level were replicated in two cohorts, 1444 blood donors and 1042 pancreatitis patients. Results: Initial GWAS detected SNPs in genes encoding the ABO blood group transferases A/B, Fucosyltransferase-2 (FUT2), and Chymotrypsinogen-B2 (CTRB2), to be significantly associated with lipase activity levels in asymptomatic subjects. Replication analyses in blood donors confirmed the association of FUT-2 non-secretor status (OR¼1.49; p¼0.012) and ABO blood-type-B (OR¼2.48; p¼7.29x10-8) with high lipase activity levels. In pancreatitis patients FUT-2 non secretor status (OR¼1.53; p¼8.56x10-4) and ABO-B (OR¼1.69, p¼1.0x10-4) were significantly associated with chronic, but not acute pancreatitis. Carriers of blood group O were less frequently affected by chronic pancreatitis (OR¼0.62; p¼1.22x10-05) and less likely to have high lipase activities (OR¼0.59; p¼8.14x10-05). Conclusion: These data indicate that blood type-B as well as FUT2 nonsecretor status are common population-wide risk factors for developing chronic pancreatitis. They also imply that, even within the reference range, elevated lipase activities may indicate subclinical pancreatic injury in asymptomatic subjects.
O-41. Neural remodeling in pancreatic neuropathy is characterized by neurotrophin-3-mediated increase in the pancreatic nociceptive innervation, demyelination and selective glial activation Ihsan Ekin Demir, Dominique Carty, Kun Wang, Christine Waldbaur, Lea Krauss, Elke Tieftrunk, Helmut Friess, Güralp O. Ceyhan Department of Surgery, Klinikum Rechts der Isar, Technische €t München, Munich, Germany, Germany Universita Background: Neural remodelling in pancreatic cancer (PDAC) and chronic pancreatitis (CP) is characterized by reduced sympathetic pancreas innervation among patients with severe pain. Aims: Here we aimed to identify whether sympathetic innervation in PDAC and CP is replaced by increased nociceptive innervation and glial activation. Patients & methods: Normal human pancreas (NP, n¼16), CP (n¼ 26) and PCa (n¼25) tissues were quantitatively analyzed for the neuroimmunoreactivity of a) nociceptive fiber markers substance-P (SP) and calcitonin-gene-related-peptide (CGRP), b) myelination markers neurofilament-H (NFH) and peripheral-myelin-protein-22 (PMP22), c) glial activation markers p75NTR and glial-fibrillary-acidic-protein (GFAP) and correlated to pain, neural invasion (NI) and pancreatic neuritis. Nociceptive neurite density of dorsal-root-ganglia-(DRG)-neurons that were cultivated in human NP, CP or PDAC tissue extracts was analyzed in the presence of neutralizing antibodies against nerve-growth-factor (NGF), neurotrophin-3 (NT-3) or brain-derived-neurotrophic-factor (BDNF). Results: SP- and CGRP-containing nerve fibers were prominently increased in CP independently of the pain status. Accordingly, the neuroimmunoreactivity of NFH and PMP22 was remarkably decreased in CP and PCa. NI and pancreatic neuritis were more pronounced around nerves with decreasing SP- and CGRP-content, increasing myelination and enhanced glial activation. Cultivation of DRG neurons in CP extracts induced the sprouting of SP- and CGRP-containing neurites, which was reversed upon blockade of NT-3 within CP extracts. Conclusion: Neural remodeling in CP and PDAC involves pain-independent, NT-3-mediated upregulation of nociceptive innervation, loss of myelination, and glial activation around nerves with NI and pancreatic neuritis. These alterations in nociception, myelination and glial activity may be the determinants of the pathologic pain response in PDAC and CP.
Abstracts / Pancreatology 14 (2014) S1eS129
O-39. Mucus secretion of pancreatic ductal epithelium increases in chronic pancreatitis zs a, Duerr Julia b, Zhe Zhou-Suckow b, Jolanthe Schatterny b, Anita Bala szlo n Rakonczay a, Marcus A. n Bala zs N c, Zolta Istva emeth c, Tiszlavicz La b a Mall , Peter Hegyi a
First Department of Medicine, University of Szeged, Szeged, Hungary Department of Translational Pulmonology, Translational Lung Research Center, University of Heidelberg, Heidelberg, Germany c Department of Pathology University of Szeged, Szeged, Hungary b
Background: Mucoprotein plug formation within the pancreatic ducts is one of the early events of chronic pancreatitis (CP), but little is known about its pathogenesis. Recent evidence suggests impaired ion- and fluid secretion of pancreatic ductal epithelial cells (PDEC) in CP, which together with increased mucus secretion may alter mucus hydration and subsequently lead to plug formation. Aims: We aimed to invesigate mucus secretion of PDEC in CP. Materials & methods: Human and mouse pancreata were investigated. Human CP tissue samples were collected from surgically resected pancreata, whereas CP was induced by administration of 6x50mg/kg cerulein, 3 series/week for 4 weeks in mice. Morphometric analysis of mucus was carried out by CellF software. Total RNA was isolated from human and mouse tissue. The mRNA levels of different mucin subtypes were analysed by quantitative RT-PCR. Results: We found that mucus volume density (Vdmuc) of human PDEC was significantly higher in CP than in controls, in case of smaller ducts (ductal diameter <100mm: 1.21±0.13nl/mm2 and 0.37±0.05nl/mm2, respectively). Similarily, mouse PDEC showed significantly higher Vdmuc in CP than in controls, especially in ducts with smaller diameter (ductal diameter <80mm: 0.72±0.06nl/mm2 vs. 0.005±0.0002nl/mm2, ductal diameter >80mm: 0.075±0.020nl/mm2 vs. 0.016±0.004nl/mm2). Mucin gene expression analysis showed, that muc6 was ~1000-fold upregulated in mouse and 17-fold upregulated in human CP. Conclusion: There is a substantial mucus hypersecretion in CP localized to the small ducts. Obstruction of the small ducts by mucus in CP may contribute to the pathogenesis of the disease. Supported by EPC Travel Fellowship.
O-40. Fucosyltransferase 2 (FUT2) non-secretor status and blood group B are associated with elevated serum lipase activity in asymptomatic subjects and an increased risk for chronic pancreatitis e a genetic association study F. Ulrich Weiss a, Claudia Schurmann b, Annett Guenther a, Florian Ernst b, €lzke c, Do €rte Alexander Teumer b, Julia Mayerle a, Peter Simon a, Henry Vo Radke c, Andreas Greinacher d, Jens-Peter Kuehn e, Martin Zenker f, Uwe €lker b, Georg Homuth b, Markus Lerch a Vo a
University Medicine Greifswald, Internal Medicine A, Germany University Medicine Greifswald, Department of functional Genomics, Germany c University Medicine Greifswald, Institute for Community Medicine, Germany d University Medicine Greifswald, Institute of Immunology and Transfusion, Germany e University Medicine Greifswald, Department of Diagnostic Radiology and Neuroradiology, Germany f Otto-von-Guericke-University Magdeburg, Institute of Human Genetics, Germany b
Background: The definition of acute pancreatitis includes characteristic clinical symptoms in combination with above three-fold elevated serum lipase activities. Elevated lipase levels below this cut-off are not considered diagnostic for pancreatitis.
Aims: We investigated whether high lipase activity - within the reference range and in the absence of pancreatitis - are associated with genetic polymorphisms (SNPs) and whether these identified SNPs are also associated with clinical pancreatitis. Patients & methods: Genome-wide association studies (GWAS) on phenotypes “serum lipase activity” and “high serum lipase activity” were conducted including 3966 German volunteers from the population-based Study-of-Health-in-Pomerania (SHIP). Lead SNPs associated on a genomewide significance level were replicated in two cohorts, 1444 blood donors and 1042 pancreatitis patients. Results: Initial GWAS detected SNPs in genes encoding the ABO blood group transferases A/B, Fucosyltransferase-2 (FUT2), and Chymotrypsinogen-B2 (CTRB2), to be significantly associated with lipase activity levels in asymptomatic subjects. Replication analyses in blood donors confirmed the association of FUT-2 non-secretor status (OR¼1.49; p¼0.012) and ABO blood-type-B (OR¼2.48; p¼7.29x10-8) with high lipase activity levels. In pancreatitis patients FUT-2 non secretor status (OR¼1.53; p¼8.56x10-4) and ABO-B (OR¼1.69, p¼1.0x10-4) were significantly associated with chronic, but not acute pancreatitis. Carriers of blood group O were less frequently affected by chronic pancreatitis (OR¼0.62; p¼1.22x10-05) and less likely to have high lipase activities (OR¼0.59; p¼8.14x10-05). Conclusion: These data indicate that blood type-B as well as FUT2 nonsecretor status are common population-wide risk factors for developing chronic pancreatitis. They also imply that, even within the reference range, elevated lipase activities may indicate subclinical pancreatic injury in asymptomatic subjects.
O-41. Neural remodeling in pancreatic neuropathy is characterized by neurotrophin-3-mediated increase in the pancreatic nociceptive innervation, demyelination and selective glial activation Ihsan Ekin Demir, Dominique Carty, Kun Wang, Christine Waldbaur, Lea Krauss, Elke Tieftrunk, Helmut Friess, Güralp O. Ceyhan Department of Surgery, Klinikum Rechts der Isar, Technische €t München, Munich, Germany, Germany Universita Background: Neural remodelling in pancreatic cancer (PDAC) and chronic pancreatitis (CP) is characterized by reduced sympathetic pancreas innervation among patients with severe pain. Aims: Here we aimed to identify whether sympathetic innervation in PDAC and CP is replaced by increased nociceptive innervation and glial activation. Patients & methods: Normal human pancreas (NP, n¼16), CP (n¼ 26) and PCa (n¼25) tissues were quantitatively analyzed for the neuroimmunoreactivity of a) nociceptive fiber markers substance-P (SP) and calcitonin-gene-related-peptide (CGRP), b) myelination markers neurofilament-H (NFH) and peripheral-myelin-protein-22 (PMP22), c) glial activation markers p75NTR and glial-fibrillary-acidic-protein (GFAP) and correlated to pain, neural invasion (NI) and pancreatic neuritis. Nociceptive neurite density of dorsal-root-ganglia-(DRG)-neurons that were cultivated in human NP, CP or PDAC tissue extracts was analyzed in the presence of neutralizing antibodies against nerve-growth-factor (NGF), neurotrophin-3 (NT-3) or brain-derived-neurotrophic-factor (BDNF). Results: SP- and CGRP-containing nerve fibers were prominently increased in CP independently of the pain status. Accordingly, the neuroimmunoreactivity of NFH and PMP22 was remarkably decreased in CP and PCa. NI and pancreatic neuritis were more pronounced around nerves with decreasing SP- and CGRP-content, increasing myelination and enhanced glial activation. Cultivation of DRG neurons in CP extracts induced the sprouting of SP- and CGRP-containing neurites, which was reversed upon blockade of NT-3 within CP extracts. Conclusion: Neural remodeling in CP and PDAC involves pain-independent, NT-3-mediated upregulation of nociceptive innervation, loss of myelination, and glial activation around nerves with NI and pancreatic neuritis. These alterations in nociception, myelination and glial activity may be the determinants of the pathologic pain response in PDAC and CP.