Anti-inflammatory properties of desipramine and fluoxetine.
Anti-inflammatory properties of desipramine and fluoxetine.
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DOI：
10.1186/1465-9921-8-35
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发表时间：
2007-05-03
影响因子：
5.8
通讯作者：
Mathieu M
中科院分区：
文献类型：
--
作者：
Roumestan C;Michel A;Bichon F;Portet K;Detoc M;Henriquet C;Jaffuel D;Mathieu M
抗抑郁药是大量处方的药物，已被证明会影响炎症信号。我们在感染性休克和过敏性哮喘的动物模型中检测了这些化合物是否具有抗炎特性。我们还分析了抗抑郁药是否直接作用于参与这些疾病炎症反应的外周细胞类型。在体内将抗抑郁药地昔帕明和氟西汀与抗炎药糖皮质激素强的松龙进行比较。在脂多糖(LPS)诱导败血症休克的小鼠模型中，动物在注射LPS之前或之后接受药物治疗。检测循环肿瘤坏死因子-α水平和死亡率。在卵蛋白致敏的大鼠中，通过计数支气管肺泡灌洗液中的白细胞来评估药物治疗对肺部炎症的影响。用气压体积描记仪测量支气管高反应性。用免疫分析法检测活化的单核细胞和肺上皮细胞在体外产生肿瘤坏死因子-α和激活后调节的正常T细胞表达和推测分泌的T细胞(RANTES)。用报告基因分析法检测抗抑郁药物对参与调控κ-α和RANTES表达的核因子-RANTES B和激活蛋白-1活性的影响。在感染性休克模型中，预防性给予三种药物均显著降低循环中肿瘤坏死因子-α水平和死亡率(氟西汀组死亡率为50%，地塞帕明和强的松龙组死亡率为30%，对照组为90%)。在治疗试验中，抗抑郁药没有统计上的显著效果，而强的松龙仍然降低了死亡率(60%的死亡率，而对照组为95%)。在卵蛋白致敏的大鼠中，这三种药物降低了肺部炎症，尽管程度不同。强的松龙和氟西汀减少巨噬细胞、淋巴细胞、中性粒细胞和嗜酸性粒细胞的数量，而地昔帕明只减少巨噬细胞和淋巴细胞的数量。然而，与强的松龙相反，抗抑郁药并不能减轻支气管的高反应性。在体外，地塞帕明和氟西汀可剂量依赖性地抑制脂多糖刺激的单核细胞释放肿瘤坏死因子α。在肺上皮细胞中，这些化合物降低了肿瘤坏死因子-α诱导的RANTES的表达以及核因子-κB和激活蛋白-1的活性。地塞帕明和氟西汀可减少两种人类疾病动物模型的炎症反应。这些抗抑郁药直接作用于相关的外周细胞类型，以减少炎症介质的表达，可能是通过影响其基因转录。对这些观察的临床意义进行了讨论。
Antidepressants are heavily prescribed drugs and have been shown to affect inflammatory signals. We examined whether these have anti-inflammatory properties in animal models of septic shock and allergic asthma. We also analysed whether antidepressants act directly on peripheral cell types that participate in the inflammatory response in these diseases. The antidepressants desipramine and fluoxetine were compared in vivo to the glucocorticoid prednisolone, an anti-inflammatory drug of reference. In a murine model of lipopolysaccharides (LPS)-induced septic shock, animals received the drugs either before or after injection of LPS. Circulating levels of tumour necrosis factor (TNF)-α and mortality rate were measured. In ovalbumin-sensitized rats, the effect of drug treatment on lung inflammation was assessed by counting leukocytes in bronchoalveolar lavages. Bronchial hyperreactivity was measured using barometric plethysmography. In vitro production of TNF-α and Regulated upon Activation, Normal T cell Expressed and presumably Secreted (RANTES) from activated monocytes and lung epithelial cells, respectively, was analysed by immunoassays. Reporter gene assays were used to measure the effect of antidepressants on the activity of nuclear factor-κB and activator protein-1 which are involved in the control of TNF-α and RANTES expression. In the septic shock model, all three drugs given preventively markedly decreased circulating levels of TNF-α and mortality (50% mortality in fluoxetine treated group, 30% in desipramine and prednisolone treated groups versus 90% in controls). In the curative trial, antidepressants had no statistically significant effect, while prednisolone still decreased mortality (60% mortality versus 95% in controls). In ovalbumin-sensitized rats, the three drugs decreased lung inflammation, albeit to different degrees. Prednisolone and fluoxetine reduced the number of macrophages, lymphocytes, neutrophils and eosinophils, while desipramine diminished only the number of macrophages and lymphocytes. However, antidepressants as opposed to prednisolone did not attenuate bronchial hyperreactivity. In vitro, desipramine and fluoxetine dose-dependently inhibited the release of TNF-α from LPS-treated monocytes. In lung epithelial cells, these compounds decreased TNF-α-induced RANTES expression as well as the activity of nuclear factor-κB and activator protein-1. Desipramine and fluoxetine reduce the inflammatory reaction in two animal models of human diseases. These antidepressants act directly on relevant peripheral cell types to decrease expression of inflammatory mediators probably by affecting their gene transcription. Clinical implications of these observations are discussed.
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影响因子：
4.7
作者：
Okamoto, H;Shino, Y;Iyo, M
通讯作者：
Iyo, M
DOI：
10.1073/pnas.0437889100
发表时间：
2003-02-04
影响因子：
11.1
作者：
Nguyen, C;Teo, JL;Kahn, M
通讯作者：
Kahn, M
影响因子：
5
作者：
Hurwitz, EL;Morgenstern, H
通讯作者：
Morgenstern, H
DOI：
10.1124/jpet.104.067835
发表时间：
2004-09-01
影响因子：
3.5
作者：
Reynolds, JL;Ignatowski, TA;Spengler, RN
通讯作者：
Spengler, RN
影响因子：
11.2
作者：
Peer, D;Dekel, Y;Margalit, R
通讯作者：
Margalit, R