title: Alcohol and cigarette smoke components activate human pancreatic stellate cells: implications for the progression of chronic pancreatitis.
abstract: BACKGROUND
  Chronic pancreatitis, a known complication of alcohol abuse, is characterized histopathologically by prominent fibrosis. Pancreatic stellate cells (PSCs) are responsible for producing this fibrous tissue in chronic pancreatitis and are activated by alcohol. Progression of alcoholic chronic pancreatitis (as assessed by calcification and fibrosis) is thought to be facilitated by concurrent smoking, but the mechanisms are unknown. This study aimed to (a) determine whether human PSCs (hPSCs) and rat PSCs express nicotinic acetylcholine receptors (nAChRs), which are known to bind 2 important components of cigarette smoke, namely nicotine and nicotine-derived nitrosamine ketone (NNK), and (b) examine the effects of cigarette smoke components in the presence and absence of alcohol on PSC activation in vitro.
  
  
  METHODS
  Western blotting was used to detect the presence of nAChRs in primary cultures of PSCs. Clinically relevant concentrations of cigarette smoke components (either cigarette smoke extract [CSE], NNK, or nicotine) ± ethanol (EtOH) were used to treat primary cultures of PSCs, and stellate cell activation was assessed by cell migration, proliferation, collagen production, and apoptosis.
  
  
  RESULTS
  We demonstrate, for the first time, that PSCs express nAChRs (isoforms α3, α7, β, ε) and that the expression of the α7 isoform in hPSCs is induced by CSE + EtOH. We also provide novel findings that PSCs are activated by CSE and NNK (both alone and in combination with EtOH) as evidenced by an increase in cell migration and/or proliferation. Further, we demonstrate that activation of PSCs by CSE + EtOH and NNK + EtOH may be mediated via nAChRs on the cells.
  
  
  CONCLUSIONS
  PSCs are activated by clinically relevant concentrations of cigarette smoke components (CSE and NNK), alone and in combination with EtOH. Thus, in alcoholics who smoke, progression of pancreatic fibrosis may be facilitated by the combined effects of alcohol and cigarette smoke components on hPSC behavior.
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.|School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Alexandra T K
authors.initials: AT
authors.lastname: Lee
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Srinivasa P
authors.initials: SP
authors.lastname: Pothula
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.|School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Mishaal B
authors.initials: MB
authors.lastname: Patel
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Romano C
authors.initials: RC
authors.lastname: Pirola
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Wilson
authors.affiliation: Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine, Ingham Institute for Applied Medical Research, Liverpool, New South Wales, Australia.
authors.forename: Minoti V
authors.initials: MV
authors.lastname: Apte
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000473:pathology*; D019512:Pancreatitis, Alcoholic / Q000139:chemically induced / Q000473:pathology*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects / Q000473:pathology; D014026:Nicotiana / Q000633:toxicity*
chemical_list: D012906:Smoke; D000431:Ethanol
keywords: Alcohol; Chronic Pancreatitis; Pancreatic Fibrosis; Pancreatic Stellate Cells; Smoking