Carcinogenesis, Vol 19, 1445-1449, Copyright © 1998 by Oxford University Press
SR Goldstein, GY Yang, X Chen, SK Curtis and CS Yang
A rat model was developed recently in our laboratory to study the
pathogenesis of Barrett's esophagus (BE) and its progression to esophageal
adenocarcinoma (EAC). Eight-week-old male Sprague-Dawley rats underwent
esophagoduodenal anastomosis (EDA) to produce gastric and duodenal reflux
in their distal esophagi. The rats were given iron dextran (50 mg of Fe/kg,
i.p.) starting 2 weeks after surgery and this was continued once a month.
BE was observed as early as week 3 and the incidence of BE and EAC
increased with time: 58 and 17% at week 23; 91 and 73% at week 31. There
was a progression in epithelial cell proliferation and inflammation from
mild to severe in the distal one- third of the esophagus. Iron deposition
in the esophagus also increased with time. Iron deposits in the stromal
tissue adjacent to the epithelium in the distal one-third of the esophagus
were associated with areas of severe inflammation. Immunohistochemical
analysis showed positive inducible nitric oxide synthase (iNOS) expression
in the stromal macrophages directly beneath the epithelium in the distal
one- third of the esophagus in 36, 83 and 100% of the rats at weeks 17, 23
and 31, respectively. A significant increasing linear trend (P=0.001) was
seen in nitrotyrosine immunostaining (number of positive cells/high power
field) in the distal esophagus. Strong positive nitrotyrosine staining was
seen in the macrophages and weaker positive staining was seen in the
adjacent epithelium starting at week 17. Furthermore, iron supplemented
rats killed at week 31 had significantly higher (P < 0.05) levels of
inflammation, cell proliferation, iNOS and nitrotyrosine as well as more
tumors in their distal esophagi than did rats that received no iron
supplement. These results suggest that iron supplementation enhanced
inflammation and the production of reactive oxygen and nitrogen species in
the esophageal epithelium. These processes could contribute to the
formation of BE and its progression to EAC.
ARTICLES
Studies of iron deposits, inducible nitric oxide synthase and nitrotyrosine in a rat model for esophageal adenocarcinoma
Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854-8020, USA.
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