title: Long-term proton pump induced hypergastrinaemia does induce lineage-specific restitution but not clonal expansion in benign Barrett's oesophagus in vivo.
abstract: BACKGROUND
  Barrett's oesophagus is a common premalignant lesion caused partly by acid reflux. Although the requisite therapy, proton pump inhibitors (PPIs), have been implicated in the progression of Barrett's oesophagus in animal models, harmful effects of prolonged PPI therapy in Barrett's oesophagus is both inconclusive and controversial. We therefore aimed to test the role of PPI-induced hypergastrinaemia in vitro and see whether any biological parameters were useful surrogates of long-term therapy in man.
  
  
  METHODS
  We undertook detailed serological and tissue assessment of gastrin and CCK(2) receptors in 90 patients randomised to different doses of PPI therapy during a detailed 2-year follow-up. We also undertook a comprehensive study of cell models to study the consequential biological effects of gastrin on the mucosa.
  
  
  RESULTS
  Gastrin and its cognate receptor CCK(2)R were expressed highest in the stomach, then less in Barrett's oesophagus and least in squamous oesophagus (SqE) (n=20 paired t-test, p<0.01). Analysis of the change in Barrett's oesophagus segment length change in 70 patients who were randomised to high or low PPI dose showed no difference over 2 years (n=70 t-test, p=0.8). Prolonged PPI use did, however, increase the serum gastrin, (36 pg/ml+/-57 pg/ml to 103 pg/ml+/-94 pg/ml (paired t test, p<0.05)). In vitro gastrin also induced changes in OE33(E)(cckr) Barrett's oesophagus cells, but not OE21(E)(cckr) squamous cells, transfected with CCK(2)R; migration was induced by 1 ng/ml of gastrin but proliferation only increased with 100 ng/ml (paired t-test, p<0.01) and both were abolished by antagonists.
  
  
  CONCLUSIONS
  While the short-term effects of gastrin enhance epithelial restitution in Barrett's oesophagus (but not squamous mucosa) there is no clinical evidence that Barrett's oesophagus length expands over time. This study, which is the largest and longest term randomised controlled trial of gastrin biology in Barrett's oesophagus, is further proof of the clinical safety of PPI therapy.
authors: Digestive Diseases Centre, Level 4 Windsor Building, Leicester Royal Infirmary, Leicester, UK. j.a.jankowski@qmul.ac.uk
authors: Jolanta A
authors: JA
authors: Obszynska
authors: Paul A
authors: PA
authors: Atherfold
authors: Manoj
authors: M
authors: Nanji
authors: Deborah
authors: D
authors: Glancy
authors: Sonia
authors: S
authors: Santander
authors: Trevor A
authors: TA
authors: Graham
authors: William R
authors: WR
authors: Otto
authors: Kevin
authors: K
authors: West
authors: Rebecca F
authors: RF
authors: Harrison
authors: Janusz A Z
authors: JA
authors: Jankowski
mesh_terms: D000328:Adult; D000368:Aged; D001471:Barrett Esophagus / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004947:Esophagus / Q000378:metabolism; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D005755:Gastrins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D043887:Receptor, Cholecystokinin B / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014407:Tumor Cells, Cultured
chemical_list: D005755:Gastrins; D054328:Proton Pump Inhibitors; D012333:RNA, Messenger; D043887:Receptor, Cholecystokinin B