title: The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis.
abstract: OBJECTIVE
  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 GFRalpha3 was investigated in patients with chronic pancreatitis.
  
  
  METHODS
  Expression of artemin and its receptor GFRalpha3 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 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 chronic pancreatitis, artemin and GFRalpha3 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)beta1.
  
  
  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 TGFbeta1 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.
authors.affiliation: Department of General Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Güralp O
authors.initials: GO
authors.lastname: Ceyhan
authors.forename: Frank
authors.initials: F
authors.lastname: Bergmann
authors.forename: Mustafa
authors.initials: M
authors.lastname: Kadihasanoglu
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.forename: Weon
authors.initials: W
authors.lastname: Park
authors.forename: Ulf
authors.initials: U
authors.lastname: Hinz
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.forename: Michael W
authors.initials: MW
authors.lastname: Müller
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Nathalia A
authors.initials: NA
authors.lastname: Giese
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
mesh_terms: D015746:Abdominal Pain / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D005260:Female; D005355:Fibrosis; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000473:pathology; D010147:Pain Measurement / Q000379:methods; D010179:Pancreas / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012720:Severity of Illness Index; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: C490886:ARTN protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1