Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation.
Microglia cyclooxygenase-2 activity in experimental gliomas: possible role in cerebral edema formation.
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发表时间：
2003-02
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通讯作者：
B. Badie;J. Schartner;A. Hagar;S. Prabakaran;Todd R Peebles;Becky Bartley;S. Lapsiwala;D. Resnick;Jessica Vorpahl
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作者：
B. Badie;J. Schartner;A. Hagar;S. Prabakaran;Todd R Peebles;Becky Bartley;S. Lapsiwala;D. Resnick;Jessica Vorpahl
脑水肿是恶性胶质瘤患者发病率和死亡率的重要原因。为了研究炎症细胞在脑水肿形成中的作用，我们研究了花生四烯酸代谢关键酶环加氧酶(COX)-2在C6啮齿动物胶质瘤模型中在小胶质细胞中的表达。实验设计采用逆转录pcr、Western分析和前列腺素E(2) （PGE(2)）酶免疫分析法检测颅内大鼠C6胶质瘤原代小胶质细胞培养物中COX-2的表达。采用磁共振成像技术对同一肿瘤模型的血肿瘤屏障通透性进行研究。结果：与C6胶质瘤细胞相比，从颅内C6肿瘤中分离的小胶质细胞通过cox -2依赖性途径产生高水平的PGE(2)。为了测试所观察到的小胶质细胞COX-2活性是否在胶质瘤脑水肿形成中起作用，我们用选择性COX-2抑制剂罗非昔布治疗荷瘤大鼠。在减少造影剂向脑实质扩散方面，罗非昔布与地塞米松一样有效（P = 0.01，罗非昔布与对照动物相比），表明血液肿瘤屏障通透性降低。结论：这些研究结果表明，胶质瘤浸润性小胶质细胞是通过COX-2途径产生PGE(2)的主要来源，并支持使用COX-2抑制剂作为糖皮质激素治疗恶性脑肿瘤患者瘤周水肿的可能替代方案。
PURPOSE Cerebral edema is responsible for significant morbidity and mortality in patients harboring malignant gliomas. To examine the role of inflammatory cells in brain edema formation, we studied the expression cyclooxygenase (COX)-2, a key enzyme in arachidonic acid metabolism, by microglia in the C6 rodent glioma model. EXPERIMENTAL DESIGN The expression of COX-2 in primary microglia cultures obtained from intracranial rat C6 gliomas was examined using reverse transcription-PCR, Western analysis, and prostaglandin E(2) (PGE(2)) enzyme immunoassay. Blood-tumor barrier permeability was studied in the same tumor model using magnetic resonance imaging. RESULTS In contrast to C6 glioma cells, microglia isolated from intracranial C6 tumors produced high levels of PGE(2) through a COX-2-dependent pathway. To test whether the observed microglia COX-2 activity played a role in brain edema formation in gliomas, tumor-bearing rats were treated with rofecoxib, a selective COX-2 inhibitor. Rofecoxib was as effective as dexamethasone in decreasing the diffusion of contrast material into the brain parenchyma (P = 0.01, rofecoxib versus control animals), suggesting a reduction in blood-tumor barrier permeability. CONCLUSIONS These findings suggest that glioma-infiltrating microglia are a major source of PGE(2) production through the COX-2 pathway and support the use of COX-2 inhibitors as possible alternatives to glucocorticoids in the treatment of peritumoral edema in patients with malignant brain tumors.