The effect of selective cyclooxygenase-2 inhibition in Barrett's esophagus epithelium: an in vitro study.
The effect of selective cyclooxygenase-2 inhibition in Barrett's esophagus epithelium: an in vitro study.
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DOI：
10.1093/jnci/94.6.422
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发表时间：
2002-03
期刊：
影响因子：
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通讯作者：
N. Buttar;Kenneth K Wang;Marlys A. Anderson;R. Dierkhising;R. Pacifico;Krishnawatie K. Krishnadath;L. Lut
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文献类型：
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作者：
N. Buttar;Kenneth K Wang;Marlys A. Anderson;R. Dierkhising;R. Pacifico;Krishnawatie K. Krishnadath;L. Lut
背景：Barrett食管患者（正常鳞状食管上皮被柱状粘膜取代）患食管腺癌的风险增加。粘液损伤可能通过合成胰高血糖素和其他炎症介质参与肿瘤形成的进展。环氧合酶（考克斯）-2是前列腺素合成的限速酶。我们检测了抑制Barrett食管细胞中考克斯-2活性的效果。方法：从20例Barrett食管患者的内镜活检标本中建立原代食管上皮细胞和成纤维细胞培养物。分别用逆转录聚合酶链反应和前列腺素E（2）（PGE（2））酶免疫测定法测定混合细胞培养物中考克斯-2的表达和活性。增殖通过Ki-67染色测量。用选择性考克斯-2抑制剂NS-398、促炎细胞因子（白细胞介素1 β和肿瘤坏死因子-α）和成纤维细胞培养物的条件培养基（未刺激和用促炎细胞因子刺激）处理上皮细胞的上清液，测定PGE（2）水平。结果食管上皮细胞和成纤维细胞表达考克斯2信使RNA。与对照处理的细胞相比，NS-398使Barrett食管上皮细胞的增殖降低了55%（95%置信区间= 47.1%至63.8%; P<0.001），并降低了考克斯-2活性。外源性PGE（2）的加入逆转了NS-398对Barrett食管上皮细胞的抗增殖作用。促炎细胞因子不影响食管上皮细胞中的考克斯-2活性，但刺激成纤维细胞中的考克斯-2活性。然而，未刺激和刺激的成纤维细胞的条件培养基增加食管上皮细胞中的考克斯-2活性。结论考克斯-2在巴雷特食管中具有功能活性，因为用考克斯-2抑制剂处理会阻碍培养物中巴雷特食管上皮细胞的增殖，但用前列腺素处理可以恢复增殖。这些结果提高了抑制考克斯-2可能对Barrett食管具有化学预防潜力的可能性。
BACKGROUND Individuals with Barrett's esophagus, in which the normal squamous esophageal epithelium is replaced with a columnar mucosa, are at increased risk for esophageal adenocarcinoma. Mucosal injury may be involved in the progression to neoplasia via the synthesis of prostaglandins and other mediators of inflammation. Cyclooxygenase (COX)-2 is the rate-limiting enzyme involved in prostaglandin synthesis. We examined the effect of inhibiting COX-2 activity in Barrett's esophageal cells. METHODS Primary esophageal epithelial and fibroblast cell cultures were established from endoscopic biopsy specimens from 20 consecutive patients with Barrett's esophagus. COX-2 expression and activity were determined on pooled cell cultures by reverse transcription-polymerase chain reaction and prostaglandin E(2) (PGE(2)) enzyme immunoassay, respectively. Proliferation was measured by Ki-67 staining. PGE(2) levels were determined in supernatants from epithelial cells treated with the selective COX-2 inhibitor NS-398, proinflammatory cytokines (interleukin 1beta and tumor necrosis factor-alpha), and conditioned medium from fibroblast cultures (both unstimulated and stimulated with proinflammatory cytokines). RESULTS Esophageal epithelial cells and fibroblasts expressed COX-2 messenger RNA. Compared with control-treated cells, NS-398 decreased proliferation of Barrett's esophageal epithelial cells by 55% (95% confidence interval = 47.1% to 63.8%; P<.001) and decreased COX-2 activity. The addition of exogenous PGE(2) reversed the antiproliferative effect of NS-398 on Barrett's esophageal epithelial cells. Proinflammatory cytokines did not affect COX-2 activity in esophageal epithelial cells but stimulated COX-2 activity in fibroblasts. However, conditioned medium from unstimulated and stimulated fibroblasts increased COX-2 activity in esophageal epithelial cells. CONCLUSION COX-2 is functionally active in Barrett's esophagus because treatment with the COX-2 inhibitor hinders proliferation of Barrett's esophageal epithelial cells in culture, but proliferation is restored by treatment with prostaglandin. These results raise the possibility that inhibition of COX-2 may have chemopreventive potential for Barrett's esophagus.