Morphine enhances macrophage apoptosis.
Morphine enhances macrophage apoptosis.
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DOI：
10.4049/jimmunol.160.4.1886
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发表时间：
1998-02
影响因子：
4.4
通讯作者：
Pravin C. Singhal;Puneet Sharma;Aditi A. Kapasi;Krishna Reddy;N. Franki;N. Gibbons
中科院分区：
文献类型：
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作者：
Pravin C. Singhal;Puneet Sharma;Aditi A. Kapasi;Krishna Reddy;N. Franki;N. Gibbons
实验室数据表明，吗啡降低了腹腔和肺泡巨噬细胞（Mphi）的数量，并损害了它们对免疫复合物和细菌的吞噬能力。我们假设吗啡通过编程死亡减少Mphi的数量，并损害Mphi的吞噬能力。我们研究了吗啡在体内和体外对Mphi细胞凋亡的影响。从吗啡处理的大鼠中收获的腹膜Mphi显示DNA片段化。吗啡以剂量依赖方式促进小鼠Mphi（J 774.16）细胞凋亡。吗啡处理的人单核细胞在凝胶电泳和末端标记研究中显示出经典的梯形图。吗啡促进基础状态和LPS激活状态下的一氧化氮（NO）产生。NO合成酶抑制剂N（G）-硝基-L-精氨酸甲酯（L-NAME）和N（G）-单甲基-L-精氨酸单乙酸酯（L-NMMA）可抑制吗啡诱导的Mphi产生NO。吗啡还增强诱导型一氧化氮合酶（iNOS）的Mphi mRNA表达。由于L-NAME和L-NMMA可抑制吗啡诱导的Mphi凋亡，因此吗啡诱导的Mphi凋亡可能是通过NO的产生介导的。此外，IL-转换酶（ICE）-1抑制剂减弱吗啡诱导的Mphi凋亡。这些研究表明，吗啡通过p53的积累激活凋亡途径的诱导期。吗啡诱导的细胞凋亡的效应期似乎是通过Bax的积累和ICE-1的激活来进行的。本研究提供了一个假设，吗啡可能直接损害免疫功能，促进阿片类药物成瘾患者的Mphi细胞凋亡的基础。
Laboratory data indicate that morphine decreases the numbier of peritoneal and alveolar macrophages (Mphi) and compromises their phagocytic capability for immune complexes and bacteria. We hypothesize that morphine decreases the number of, as well as compromises the phagocytic capability of, Mphi by programming their death. We studied the effect of morphine on Mphi apoptosis in vivo as well as in vitro. Peritoneal Mphi harvested from morphine-treated rats showed DNA fragmentation. Morphine enhanced murine Mphi (J 774.16) apoptosis in a dose-dependent manner. Human monocytes treated with morphine showed a classic ladder pattern in gel electrophoretic and end-labeling studies. Morphine promoted nitric oxide (NO) production both under basal and LPS-activated states. N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine monoacetate (L-NMMA), inhibitors of NO synthase, attenuated the morphine-induced generation of NO by Mphi. Morphine also enhanced Mphi mRNA expression of inducible NO synthase (iNOS). Since morphine-induced Mphi apoptosis was inhibited by L-NAME and L-NMMA, it appears that morphine-induced Mphi apoptosis may be mediated through the generation of NO. Morphine promoted the synthesis of Bax and p53 proteins by Mphi. Moreover, IL-converting enzyme (ICE)-1 inhibitor attenuated morphine-induced Mphi apoptosis. These studies suggest that morphine activates the induction phase of the apoptotic pathway through accumulation of p53. The effector phase of morphine-induced apoptosis appears to proceed through the accumulation of Bax and activation of ICE-1. The present study provides a basis for a hypothesis that morphine may be directly compromising immune function by promoting Mphi apoptosis in patients with opiate addiction.