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The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis
  1. Güralp Onur Ceyhan (gueralp.ceyhan{at}med.uni-heidelberg.de)
  1. Department of Surgery, University of Heidelberg, Germany
    1. Frank Bergmann (frank.bergmann{at}med.uni-heidelberg.de)
    1. Institute of Pathology, University of Heidelberg, Germany
      1. Mustafa Kadihasanoglu (kadihasanoglu{at}gmail.com)
      1. Department of Surgery, University of Heidelberg, Germany
        1. Mert Erkan (mert.erkan{at}med.uni-heidelberg.de)
        1. Department of Surgery, University of Heidelberg, Germany
          1. Weon Park (wpark{at}ix.urz.uni-heidelberg.de)
          1. Department of Surgery, University of Heidelberg, Germany
            1. Ulf Hinz (ulf.hinz{at}med.uni-heidelberg.de)
            1. Department of Surgery, University of Heidelberg, Germany
              1. Michael W Müller (michael.mueller{at}med.uni-heidelberg.de)
              1. Department of Surgery, University of Heidelberg, Germany
                1. Thomas Giese (thomas.giese{at}urz.uni-heidelberg.de)
                1. Institute for Immunology, University of Heidelberg, Germany
                  1. Markus W Büchler (markus.buechler{at}med.uni-heidelberg.de)
                  1. Department of Surgery, University of Heidelberg, Germany
                    1. Nathalia A Giese (nathalia.giese{at}med.uni-heidelberg.de)
                    1. Department of Surgery, University of Heidelberg, Germany
                      1. Helmut Friess (helmut.friess{at}med.uni-heidelberg.de)
                      1. Department of Surgery, University of Heidelberg, Germany

                        Abstract

                        Background: Chronic pancreatitis (CP) is characterized by severe abdominal neuropathic pain, perineural inflammatory cell infiltrations, and intrapancreatic neural growth. Artemin was recently shown to eliminate neuropathic pain and reverse neuro-chemical damage after nerve injury. The role of artemin and its receptor GFRalpha3 was investigated in CP patients.

                        Methods: The expression of artemin and its receptor GFRalpha3 was studied in CP (n=66) and normal (n=22) pancreatic tissues by QRT-PCR and Western-blot analysis. Artemin expression was correlated with pain, and pathomorphological changes (inflammation, perineural inflammatory cell infiltration, neural alterations and fibrosis). Immunohistochemistry was used to localize artemin and GFRalpha3 in the tissues. To detect sources of artemin, primary human pancreatic stellate cells (hPSCs) were isolated and analysed by QRT-PCR and immunocytology analysis.

                        Results: In CP, artemin and GFRalpha3 are significantly overexpressed and are located in smooth- muscle cells of arteries, Schwann cells and neural ganglia. Increased levels of artemin-mRNA correlated with pain severity, inflammation, perineural inflammatory cell infiltration, neural density and hypertrophy. Furthermore, the severity of fibrosis was positively related to artemin expression and neural alterations. Activated hPSCs expressed low basal levels of artemin- mRNA which were up-regulated by exposure to TGF-beta1.

                        Conclusions: Overexpression of artemin in CP might function as a compensatory up-regulation in order to repair neural damage incurred by ongoing pancreatic inflammation. Upregulation of TGF-beta1 seems not only to increase pancreatic fibrosis, but also to contribute to neural alteration by stimulating artemin expression in hPSCs. However, overexpression of endogenous artemin seems not to be sufficient to prevent pain in CP.

                        • Artemin
                        • GFRalpha3
                        • chronic pancreatitis
                        • neural alteration
                        • pain

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