Release of prostaglandin E-2 in bovine brain endothelial cells after exposure to three unique forms of the antifungal drug amphotericin-B: role of COX-2 in amphotericin-B induced fever.
Release of prostaglandin E-2 in bovine brain endothelial cells after exposure to three unique forms of the antifungal drug amphotericin-B: role of COX-2 in amphotericin-B induced fever.
复制标题
暴露于三种独特形式的抗真菌药物两性霉素 B 后，牛脑内皮细胞中前列腺素 E-2 的释放：COX-2 在两性霉素 B 诱导发热中的作用。
DOI：
10.1016/s0024-3205(03)00172-3
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发表时间：
2003
期刊：
影响因子：
6.1
通讯作者：
Miller,DonaldW
中科院分区：
文献类型：
--
作者：
McGuire,TimothyR;Trickler,WilliamJ;Hock,Lynette;Vrana,Amy;Hoie,EricB;Miller,DonaldW
两性霉素-B的常见配方包括脱氧胆酸胶体悬浮剂(d-Amph)、两性霉素-B脂质复合体(ABLC)和脂质体产品(L-Amph)。输液相关发热的临床发生率以d-Amph最高，ABLC居中，L-Amph最低。在本研究中，我们检测了这三种两性霉素-B制剂对脑微血管内皮细胞环氧合酶-2(COX-2)的激活和随后前列腺素E-2(PGE-2)的释放。将原代培养的牛脑微血管内皮细胞暴露于d-Amph、ABLC和L-Amph，其浓度与接受药物的患者血浆中的浓度相同。收集细胞的培养液样本，并分析PGE-2。经L-安非他明处理的BBMEC单层细胞释放前列腺素E-2的能力与单独使用培养液的细胞相似。相比之下，ABLC和d-Amph导致BBMEC单层细胞释放PGE-2的量显著高于单独接受培养基组的对照组。D-Amph处理后的PGE-2释放量与细菌脂多糖(LPS)处理后的PGE-2释放量相似。Western印迹分析显示，LPS、Ablc或d-Amph可显著诱导BBMEC COX-2的表达。此外，选择性COX-2抑制剂NS-398的加入减少了BBMEC单层暴露于脂多糖或各种两性霉素-B制剂后的PGE-2释放。这些研究表明，两性霉素-B诱导脑微血管内皮细胞COX-2的表达，导致发热产生PGE-2的释放。BBMEC在接触不同的两性霉素-B制剂后释放PGE-2的幅度反映了关于两性霉素-B诱导发热的临床观察，并为临床使用COX-2抑制剂来降低两性霉素-B发热提供了初步支持。
Common formulations of amphotericin-B include a deoxycholate colloidal suspension (d-Amph), an amphotericin-B lipid complex (Ablc), and a liposomal product (l-Amph). The clinical incidence of infusion related fever is highest with d-Amph, intermediate with Ablc, and lowest with l-Amph. In the present study, we measured the activation of cyclooxygenase-2 (COX-2) and subsequent release of prostaglandin E-2 (PgE-2) from brain microvessel endothelium treated with these three formulations of amphotericin-B. Primary cultured bovine brain microvessel endothelial cells (BBMEC) were exposed to d-Amph, Ablc and l-Amph at concentrations that can be achieved in the plasma of patients receiving the drug. Media samples from the cells were collected and analyzed for PgE-2. Release of PgE-2 from BBMEC monolayers treated with l-Amph was similar to cells receiving culture media alone. In contrast, Ablc and d-Amph caused significantly greater release of PgE-2 from BBMEC monolayers compared to controls receiving culture media alone. PgE-2 release after d-Amph treatment was similar in magnitude to that observed with bacterial lipopolysaccharide (LPS). Western blot analysis indicated significant induction of COX-2 expression in BBMEC following LPS, Ablc or d-Amph treatment. Furthermore, PgE-2 release following exposure of BBMEC monolayers to either LPS or the various amphotericin-B formulations was reduced by the addition of the selective COX-2 inhibitor, NS-398. These studies indicate that amphotericin-B induces COX-2 expression in brain microvessel endothelium resulting in release of fever producing PgE-2. The magnitude of PgE-2 release from BBMEC following exposure to various amphotericin-B formulations mirrors the clinical observations regarding amphotericin-B induced fever and serves as initial support for the clinical use of COX-2 inhibitors to reduce amphotericin-B fever.