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CXCR2 inhibition protects against chronic pancreatitis in a murine model
Abstracts / Pancreatology 13 (2013) e1–e20
Conclusion: Components of the metabolic syndrome, which are associated with insulin resistance, namely elevated diastolic blood pressure, elevated serum HbA1c and decreased serum HDL were positively associated with large increases in the risk of pancreatic cancer. Factors influencing these parameters should be measured in future aetiological work and may suggest mechanisms for carcinogenesis, but support an aetiological role for insulin resistance in pancreatic cancer. Take-home message: Metabolic factors and serum HDL may be predicitve of the risk of developing pancreatic cancer. Abstract previously presented? yes (BSG) Any disclosures? no ()
O10. Long-term follow-up of patients with IgG4-related disease M.T. Huggett, S.P. Pereira, M.H. Chapman, G.J. Johnson, G.J. Webster. University College Hospital, London, UK Category: Benign and Inflammatory Abstract The long-term clinical course of IgG4-related disease is still being defined. Here we report data from a large European cohort of prospectively followed patients. 63 patients (48M, 15F; median age 59 years) were included, with a median follow-up from diagnosis of 35 months. 68% were jaundiced at presentation and 14% had undergone surgery for suspected pancreaticobiliary cancer. HISORt criteria were fulfilled in 92% patients. 27% had associated autoimmune disease (19% Sjögren's,11% thyroid disease,10% IBD, and 2% each for vitiligo, coeliac, psoriasis, alopecia and polymyalgia rheumatica).79% patients had extrapancreatic disease: biliary involvement in 71% (3 patients developed cirrhosis and one underwent liver transplantation); renal or retroperitoneal disease in 17%; arthropathy/arthralgia in 6%; and pulmonary inflitrates in 3%. Two patients developed IgG4-related cerebral involvement, one with encephalitis, the other a pituitary mass. Exocrine insufficiency occurred in 49% patients, as did diabetes. Portal and/or splenic vein thrombosis developed in 13%. 92% patients received an initial steroid course for a median of 5.1 months, with a good response in 95% of these. Disease relapse occurred in 50%, and median time to relapse was 4.5 months. Extrapancreatic disease at presentation predicted relapse (P¼0.01), but elevated serum IgG4 did not (P¼0.92). Four patients died during follow-up, three from probable IgG4-related disease (autoimmune encephalitis, progressive liver disease, and hilar cholangiocarcinoma), and the other from cancer of unknown primary. Conclusion: IgG4-related disease may be associated with multi-organ complications, which cause significant morbidity, and a small but significant mortality. Extrapancreatic involvement at presentation predicts a complicated course. Take-home message: IgG4-related disease is highly steroid responsive but relapse is common and there is now recognised to be a significant associated morbidity. Abstract previously presented? no () Any disclosures? no ()
O11. CXCR2 inhibition protects against chronic pancreatitis in a murine model C.W. Steele 1, J.P. Morton 1, C.J. McKay 2, T.R.J. Evans 1, C.R. Carter 2, O.J. Sansom 1. 1 2
Beatson Institute for Cancer Research, UK Glasgow Royal Infirmary, UK
Category: Benign and Inflammatory Abstract Patients presenting with chronic pancreatitis (CP) often have little functional pancreas with the majority being replaced with fibrous tissue.
e5
However, patients with hereditary pancreatitis, mainly caused by PRSS1 mutations, often have a milder form of the disease providing a potential window of opportunity for therapeutic intervention. The molecular mechanism by which factors, such as alcohol, induce CP remains poorly elucidated. It is known acinar damage induces an inflammatory response resulting in the influx of granulocytes. Macrophages play an important role in pancreatic stellate cell activation resulting in fibrotic tissue production. Chemokine signalling is instrumental in the mediation of chronic inflammation, and CXCR2, a chemokine receptor expressed by granulocytes, is likely to contribute to CP associated inflammation. To assess the role of CXCR2 in this process we induced CP experimentally in wild type (WT) and CXCR2 knockout (KO) mice over 6 weeks. CXCR2 KO mice were completely protected from pancreatic damage. This protection was both neutrophil and macrophage dependent. Extension of studies to 9 months demonstrated WT mice had developed severe atrophy and significant fibrosis while CXCR2 KO mice were again protected. Furthermore, treatment of WT mice with CXCR2 inhibiting peptide protected the pancreas from chronic inflammation. To examine the importance of neutrophils in this process we used a neutrophil blocking antibody and found that there was significant pancreatic damage from macrophage infiltration despite neutrophil blockade. Thus CXCR2 inhibition may protect patients with early chronic pancreatitis from pancreatic damage in a process dependent on both neutrophil and macrophage chemotaxis. Take-home message: CXCR2 inhibition may protect patients at high risk of chronic pancreatitis, such as those with PRSS1 mutations from pancreatic damage. Abstract previously presented? no () Any disclosures? no ()
O12. Evidence of epithelial-to-mesenchymal transition in the normal human endocrine pancreas Katherine E. Jones, Hannah J. Wills, Anne Clark, Paul R.V. Johnson. Academic Paediatric Surgery Unit, Nuffield Department of Surgical Sciences, University of Oxford, UK Category: Benign and Inflammatory Abstract Islet transplantation achieves insulin-independence in 80-85% of selected adult patients with type 1 diabetes mellitus. One limiting factor is donor pancreas shortage and hence there is a need for a renewable islet source. Progenitor cells within the adult islet could provide this source via epithelial-to-mesenchymal transition (EMT). Cultured islets undergo EMT into cells capable of re-differentiating into islets. EMT has yet to be identified in vivo in the human endocrine pancreas. This study aimed to investigate the prevalence of EMT in the normal human pancreas, and to establish whether this is influenced by prolonged cold ischaemia time (CIT). With consent and ethical approval, sections of pancreas were prepared from heart-beating donors referred into our transplant programme (n¼20). Sections were analysed for EMT using antibodies including insulin, glucagon and the mesenchymal marker vimentin. Morphometric analysis of vimentin and endocrine co-localisation was performed using a Zeiss 710 confocal microscope (12-20 islets per sample), and samples quantified in Volocity (Improvision 2006). The prevalence of EMT was correlated with CIT following correction for BMI and age. Islet cells co-expressing insulin and vimentin were observed, but were rare (1.08 0.27%, SEM). Co-expression of glucagon and vimentin was observed significantly more frequently (2.62 0.56%, p<0.05). The prevalence of EMT was not influenced by CIT. EMT occurs in normal adult islets in vivo. The trigger for EMT in islets is yet to be identified, but CIT does not appear to influence this. EMT may offer a therapuetic strategy to generate novel islet sources for transplantation. Take-home message: EMT positive cells within islets could be a potential source of islet progenitor cells for expansion in vitro for therapeutic use. Abstract previously presented? yes (Internation Symposium of Paediatric Surgical Research) Any disclosures? no () Main Session Poster Abstracts (40)
Conclusion: Components of the metabolic syndrome, which are associated with insulin resistance, namely elevated diastolic blood pressure, elevated serum HbA1c and decreased serum HDL were positively associated with large increases in the risk of pancreatic cancer. Factors influencing these parameters should be measured in future aetiological work and may suggest mechanisms for carcinogenesis, but support an aetiological role for insulin resistance in pancreatic cancer. Take-home message: Metabolic factors and serum HDL may be predicitve of the risk of developing pancreatic cancer. Abstract previously presented? yes (BSG) Any disclosures? no ()
O10. Long-term follow-up of patients with IgG4-related disease M.T. Huggett, S.P. Pereira, M.H. Chapman, G.J. Johnson, G.J. Webster. University College Hospital, London, UK Category: Benign and Inflammatory Abstract The long-term clinical course of IgG4-related disease is still being defined. Here we report data from a large European cohort of prospectively followed patients. 63 patients (48M, 15F; median age 59 years) were included, with a median follow-up from diagnosis of 35 months. 68% were jaundiced at presentation and 14% had undergone surgery for suspected pancreaticobiliary cancer. HISORt criteria were fulfilled in 92% patients. 27% had associated autoimmune disease (19% Sjögren's,11% thyroid disease,10% IBD, and 2% each for vitiligo, coeliac, psoriasis, alopecia and polymyalgia rheumatica).79% patients had extrapancreatic disease: biliary involvement in 71% (3 patients developed cirrhosis and one underwent liver transplantation); renal or retroperitoneal disease in 17%; arthropathy/arthralgia in 6%; and pulmonary inflitrates in 3%. Two patients developed IgG4-related cerebral involvement, one with encephalitis, the other a pituitary mass. Exocrine insufficiency occurred in 49% patients, as did diabetes. Portal and/or splenic vein thrombosis developed in 13%. 92% patients received an initial steroid course for a median of 5.1 months, with a good response in 95% of these. Disease relapse occurred in 50%, and median time to relapse was 4.5 months. Extrapancreatic disease at presentation predicted relapse (P¼0.01), but elevated serum IgG4 did not (P¼0.92). Four patients died during follow-up, three from probable IgG4-related disease (autoimmune encephalitis, progressive liver disease, and hilar cholangiocarcinoma), and the other from cancer of unknown primary. Conclusion: IgG4-related disease may be associated with multi-organ complications, which cause significant morbidity, and a small but significant mortality. Extrapancreatic involvement at presentation predicts a complicated course. Take-home message: IgG4-related disease is highly steroid responsive but relapse is common and there is now recognised to be a significant associated morbidity. Abstract previously presented? no () Any disclosures? no ()
O11. CXCR2 inhibition protects against chronic pancreatitis in a murine model C.W. Steele 1, J.P. Morton 1, C.J. McKay 2, T.R.J. Evans 1, C.R. Carter 2, O.J. Sansom 1. 1 2
Beatson Institute for Cancer Research, UK Glasgow Royal Infirmary, UK
Category: Benign and Inflammatory Abstract Patients presenting with chronic pancreatitis (CP) often have little functional pancreas with the majority being replaced with fibrous tissue.
e5
However, patients with hereditary pancreatitis, mainly caused by PRSS1 mutations, often have a milder form of the disease providing a potential window of opportunity for therapeutic intervention. The molecular mechanism by which factors, such as alcohol, induce CP remains poorly elucidated. It is known acinar damage induces an inflammatory response resulting in the influx of granulocytes. Macrophages play an important role in pancreatic stellate cell activation resulting in fibrotic tissue production. Chemokine signalling is instrumental in the mediation of chronic inflammation, and CXCR2, a chemokine receptor expressed by granulocytes, is likely to contribute to CP associated inflammation. To assess the role of CXCR2 in this process we induced CP experimentally in wild type (WT) and CXCR2 knockout (KO) mice over 6 weeks. CXCR2 KO mice were completely protected from pancreatic damage. This protection was both neutrophil and macrophage dependent. Extension of studies to 9 months demonstrated WT mice had developed severe atrophy and significant fibrosis while CXCR2 KO mice were again protected. Furthermore, treatment of WT mice with CXCR2 inhibiting peptide protected the pancreas from chronic inflammation. To examine the importance of neutrophils in this process we used a neutrophil blocking antibody and found that there was significant pancreatic damage from macrophage infiltration despite neutrophil blockade. Thus CXCR2 inhibition may protect patients with early chronic pancreatitis from pancreatic damage in a process dependent on both neutrophil and macrophage chemotaxis. Take-home message: CXCR2 inhibition may protect patients at high risk of chronic pancreatitis, such as those with PRSS1 mutations from pancreatic damage. Abstract previously presented? no () Any disclosures? no ()
O12. Evidence of epithelial-to-mesenchymal transition in the normal human endocrine pancreas Katherine E. Jones, Hannah J. Wills, Anne Clark, Paul R.V. Johnson. Academic Paediatric Surgery Unit, Nuffield Department of Surgical Sciences, University of Oxford, UK Category: Benign and Inflammatory Abstract Islet transplantation achieves insulin-independence in 80-85% of selected adult patients with type 1 diabetes mellitus. One limiting factor is donor pancreas shortage and hence there is a need for a renewable islet source. Progenitor cells within the adult islet could provide this source via epithelial-to-mesenchymal transition (EMT). Cultured islets undergo EMT into cells capable of re-differentiating into islets. EMT has yet to be identified in vivo in the human endocrine pancreas. This study aimed to investigate the prevalence of EMT in the normal human pancreas, and to establish whether this is influenced by prolonged cold ischaemia time (CIT). With consent and ethical approval, sections of pancreas were prepared from heart-beating donors referred into our transplant programme (n¼20). Sections were analysed for EMT using antibodies including insulin, glucagon and the mesenchymal marker vimentin. Morphometric analysis of vimentin and endocrine co-localisation was performed using a Zeiss 710 confocal microscope (12-20 islets per sample), and samples quantified in Volocity (Improvision 2006). The prevalence of EMT was correlated with CIT following correction for BMI and age. Islet cells co-expressing insulin and vimentin were observed, but were rare (1.08 0.27%, SEM). Co-expression of glucagon and vimentin was observed significantly more frequently (2.62 0.56%, p<0.05). The prevalence of EMT was not influenced by CIT. EMT occurs in normal adult islets in vivo. The trigger for EMT in islets is yet to be identified, but CIT does not appear to influence this. EMT may offer a therapuetic strategy to generate novel islet sources for transplantation. Take-home message: EMT positive cells within islets could be a potential source of islet progenitor cells for expansion in vitro for therapeutic use. Abstract previously presented? yes (Internation Symposium of Paediatric Surgical Research) Any disclosures? no () Main Session Poster Abstracts (40)