脂氧素和阿司匹林触发的脂氧素通过抑制脊髓前炎症细胞因子的表达缓解骨癌痛。
Lipoxins and aspirin-triggered lipoxin alleviate bone cancer pain in association with suppressing expression of spinal proinflammatory cytokines.
机构信息
Institute of Acupuncture Research-WHO Collaborating Center for Traditional Medicine, School of Basic Medical Sciences, Shanghai Medical College, Institutes of Brain Science, Fudan University, 138 Yi Xue Yuan Road, PO Box 291, Shanghai 200032, China.
出版信息
J Neuroinflammation. 2012 Dec 26;9:278. doi: 10.1186/1742-2094-9-278.
BACKGROUND
The neuroinflammatory responses in the spinal cord following bone cancer development have been shown to play an important role in cancer-induced bone pain (CIBP). Lipoxins (LXs), endogenous lipoxygenase-derived eicosanoids, represent a unique class of lipid mediators that possess a wide spectrum of anti-inflammatory and pro-resolving actions. In this study, we investigated the effects of intrathecal injection with lipoxin and related analogues on CIBP in rats.
METHODS
The CIBP model was induced by intra-tibia inoculation of Walker 256 mammary gland carcinoma cells. Mechanical thresholds were determined by measuring the paw withdrawal threshold to probing with a series of calibrated von Frey filaments. Lipoxins and analogues were administered by intrathecal (i.t.) or intravenous (i.v.) injection. The protein level of LXA4 receptor (ALX) was tested by western blot. The localization of lipoxin receptor in spinal cord was assessed by fluorescent immunohistochemistry. Real-time PCR was carried out for detecting the expression of pro-inflammatory cytokines.
RESULTS
Our results demonstrated that: 1) i.t. injection with the same dose (0.3 nmol) of lipoxin A4 (LXA4), lipoxin B4 (LXB4) or aspirin-triggered-15-epi-lipoxin A4 (ATL) could alleviate the mechanical allodynia in CIBP on day 7 after surgery. ATL showed a longer effect than the others and the effect lasted for 6 hours. ATL administered through i.v. injection could also attenuate the allodynia in cancer rats. 2) The results from western blot indicate that there is no difference in the expression of ALX among the naive, sham or cancer groups. 3) Immunohistochemistry showed that the lipoxin receptor (ALX)-like immunoreactive substance was distributed in the spinal cord, mainly co-localized with astrocytes, rarely co-localized with neurons, and never co-localized with microglia. 4) Real-time PCR analysis revealed that, compared with vehicle, i.t. injection with ATL could significantly attenuate the expression of the mRNA of proinflammatory cytokines (IL-1β and TNF-α) in the spinal cord in CIBP.
CONCLUSIONS
Taken together, the results of our study suggest that LXs and analogues exert strong analgesic effects on CIBP. These analgesic effects in CIBP are associated with suppressing the expression of spinal proinflammatory cytokines.
背景
骨癌发展后脊髓中的神经炎症反应被证明在癌性骨痛（CIBP）中起重要作用。脂氧素（LXs）是内源性脂氧合酶衍生的类二十烷酸，代表了一类具有广泛抗炎和促解决作用的独特脂质介质。在这项研究中，我们研究了鞘内注射脂氧素及其相关类似物对大鼠 CIBP 的影响。
方法
通过胫骨内接种 Walker 256 乳腺癌细胞诱导 CIBP 模型。通过使用一系列校准的 von Frey 细丝探测来测量爪退缩阈值来确定机械阈值。通过鞘内（i.t.）或静脉内（i.v.）注射给予脂氧素和类似物。通过 Western blot 测试 LXA4 受体（ALX）的蛋白水平。通过荧光免疫组织化学评估脂氧素受体在脊髓中的定位。进行实时 PCR 以检测促炎细胞因子的表达。
结果
我们的结果表明：1）鞘内注射相同剂量（0.3 nmol）的脂氧素 A4（LXA4）、脂氧素 B4（LXB4）或阿司匹林触发的 15-epi-脂氧素 A4（ATL）均可减轻手术后第 7 天 CIBP 的机械性痛觉过敏。ATL 的作用比其他两种更长，作用持续 6 小时。静脉内给予 ATL 也可减轻癌症大鼠的痛觉过敏。2）Western blot 结果表明，在正常、假手术或癌症组之间，ALX 的表达没有差异。3）免疫组织化学显示，脂氧素受体（ALX）样免疫反应物质分布在脊髓中，主要与星形胶质细胞共定位，很少与神经元共定位，从未与小胶质细胞共定位。4）实时 PCR 分析显示，与载体相比，鞘内注射 ATL 可显著减轻 CIBP 脊髓中促炎细胞因子（IL-1β和 TNF-α）mRNA 的表达。
结论
综上所述，本研究结果表明 LXs 及其类似物对 CIBP 具有强烈的镇痛作用。这些在 CIBP 中的镇痛作用与抑制脊髓促炎细胞因子的表达有关。
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