The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis
- Güralp O Ceyhan1,
- Frank Bergmann2,
- Mustafa Kadihasanoglu1,
- Mert Erkan1,
- Weon Park1,
- Ulf Hinz3,
- Thomas Giese4,
- Michael W Müller1,
- Markus W Büchler1,
- Nathalia A Giese1,
- Helmut Friess1
- 1Department of General Surgery, University of Heidelberg, Heidelberg, Germany
- 2Institute of Pathology, University of Heidelberg, Heidelberg, Germany
- 3Unit for Documentation and Statistics, Department of Surgery, University of Heidelberg, Heidelberg, Germany
- 4Institute for Immunology, University of Heidelberg, Heidelberg, Germany
- Correspondence to:
Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany; helmut_
- Accepted 26 September 2006
- Revised 18 September 2006
- Published Online First 17 October 2006
Background and aim: Chronic pancreatitis is characterised by severe abdominal neuropathic pain, perineural inflammatory cell infiltrations and intrapancreatic neural growth. Artemin was recently shown to eliminate neuropathic pain and reverse neurochemical damage after nerve injury. The role of artemin and its receptor GFRα3 was investigated in patients with chronic pancreatitis.
Methods: Expression of artemin and its receptor GFRα3 was studied in chronic pancreatitis (n = 66) and normal (n = 22) pancreatic tissues by quantitative reverse transcription-polymerase chain reaction (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 localise artemin and GFRα3 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 chronic pancreatitis, artemin and GFRα3 were significantly overexpressed and 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 with artemin expression and neural alterations. Activated hPSCs expressed low basal levels of artemin mRNA which were upregulated by exposure to transforming growth factor (TGF)β1.
Conclusions: Overexpression of artemin in chronic pancreatitis might function as a compensatory upregulation in order to repair neural damage incurred by ongoing pancreatic inflammation. Upregulation of TGFβ1 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 does not seem to be sufficient to prevent pain in chronic pancreatitis.
- FCS, fetal calf serum
- FGF, fibroblast growth factor
- GDNF, glial derived neurotrophic factor
- GFR, GDNF family receptor
- hPSC, human pancreatic stellate cell
- NHY, neural hypertrophy
- PDGF, platelet derived growth factor
- QRT-PCR, quantitative reverse transcription-polymerase chain reaction
- TGF, transforming growth factor
Published Online First 15 October 2006
Competing interests: None declared.