Goldstein S R, Yang G Y, Chen X, Curtis S K, Yang C S
Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway 08854-8020, USA.
Carcinogenesis. 1998 Aug;19(8):1445-9. doi: 10.1093/carcin/19.8.1445.
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.
最近我们实验室建立了一种大鼠模型，用于研究巴雷特食管（BE）的发病机制及其向食管腺癌（EAC）的进展。8周龄雄性Sprague-Dawley大鼠接受食管十二指肠吻合术（EDA），以使其远端食管产生胃和十二指肠反流。术后2周开始给大鼠腹腔注射右旋糖酐铁（50mg Fe/kg），并每月持续给药一次。早在第3周就观察到了BE，且BE和EAC的发生率随时间增加：第23周时分别为58%和17%；第31周时分别为91%和73%。食管远端三分之一处的上皮细胞增殖和炎症从轻度发展到重度。食管中的铁沉积也随时间增加。食管远端三分之一处上皮附近基质组织中的铁沉积与严重炎症区域相关。免疫组织化学分析显示，在第17、23和31周时，分别有36%、83%和100%的大鼠食管远端三分之一处上皮正下方的基质巨噬细胞中诱导型一氧化氮合酶（iNOS）表达呈阳性。食管远端硝基酪氨酸免疫染色（阳性细胞数/高倍视野）呈显著增加的线性趋势（P = 0.001）。从第17周开始，巨噬细胞中可见强阳性硝基酪氨酸染色，相邻上皮中可见弱阳性染色。此外，在第31周处死的补充铁的大鼠，其远端食管中的炎症、细胞增殖、iNOS和硝基酪氨酸水平显著高于（P < 0.05）未补充铁的大鼠，且肿瘤更多。这些结果表明，补充铁增强了食管上皮中的炎症以及活性氧和氮物种的产生。这些过程可能有助于BE的形成及其向EAC的进展。
