title: Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury.
abstract: OBJECTIVE
  Reflux esophagitis is believed to be caused by the caustic effects of refluxed gastric acid on esophageal epithelial cells. However, caustic chemical injuries develop rapidly whereas esophagitis might not appear until weeks after the induction of reflux in animal models. We studied early histologic events in the development of reflux esophagitis in a rat model and performed in vitro experiments to determine whether exposure to acidified bile salts causes esophageal epithelial cells to secrete chemokines that might contribute to inflammation.
  
  
  METHODS
  At various time points after esophagoduodenostomy, the rat esophagus was removed and inflammatory changes were analyzed by histologic analyses. Human esophageal squamous cell lines were exposed to acidified bile salts to evaluate their effects on cytokine production and immune-cell migration.
  
  
  RESULTS
  Reflux esophagitis started at postoperative day 3 with lymphocytic infiltration of the submucosa that progressed to the epithelial surface-these findings contradicted those expected from a caustic chemical injury. Basal cell and papillary hyperplasia preceded the development of surface erosions. Exposure of squamous cells to acidified bile salts significantly increased the secretion of interleukin-8 and interleukin-1beta; conditioned media from these cells caused significant increases in the migration rates of T cells and neutrophils.
  
  
  CONCLUSIONS
  These findings support, but do not prove, an alternative concept for the development of reflux esophagitis in which refluxed gastric juice does not directly damage the esophagus, but rather stimulates esophageal epithelial cells to secrete chemokines that mediate damage of esophageal tissue.
authors: Department of Medicine, VA North Texas Health Care System and University of Texas Southwestern Medical School, Irving, Texas, USA. rhonda.souza@utsouthwestern.edu
authors: Rhonda F
authors: RF
authors: Souza
authors: Xiaofang
authors: X
authors: Huo
authors: Vivek
authors: V
authors: Mittal
authors: Christopher M
authors: CM
authors: Schuler
authors: Susanne W
authors: SW
authors: Carmack
authors: Hui Ying
authors: HY
authors: Zhang
authors: Xi
authors: X
authors: Zhang
authors: Chunhua
authors: C
authors: Yu
authors: Kathy
authors: K
authors: Hormi-Carver
authors: Robert M
authors: RM
authors: Genta
authors: Stuart J
authors: SJ
authors: Spechler
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D018929:Cell Culture Techniques; D002460:Cell Line; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004385:Duodenostomy; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D004942:Esophagitis, Peptic / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004946:Esophagostomy; D005764:Gastroesophageal Reflux / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D005765:Gastrointestinal Agents / Q000494:pharmacology; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001647:Bile Acids and Salts; D016207:Cytokines; D005765:Gastrointestinal Agents