肿瘤坏死因子α在人免疫缺陷病毒相关神经病变机制中的作用研究
摘要
大约40%的HIV患者出现不同程度的远端对称性多神经病变(Distal symmetrical polyneuropathy,DSP)。他们具有明显的感觉异常,持续性和阵发性疼痛。目前认为造成HIV-DSP的原因主要有两个:第一,HIV病毒本身,尤其是衣壳蛋白gp120;第二,抗艾滋病药物,艾滋病人使用抗逆转录药物(nucleoside reverse transcriptase inhibitors,NRTI),尤其是双脱氧类药物比如zalcitabine (ddC),didanosine (ddI)和stavudine (d4T)等等,这些药物是鸡尾酒疗法疗法(highly active anti-retroviral therapy, HAART)的重要组成部分。HAART疗法的应用延长了病人寿命,但也加剧了HIV-DSP病变。这个缺陷使得病毒抑制策略受到局限,甚至中断抗病毒治疗。因此,针对DSP病变的疗法亟待开发。然而,HIV及NRTI引起DSP的具体机制尚不清楚。
HIV不直接感染神经元,而是与胶质细胞CXCR4或CCR5受体结合,释放细胞因子,例如肿瘤坏死因子(TNFα)白介素1 (IL-1β)等,间接与神经元相互作用,引起神经毒性。TNFα在炎症,脊髓损伤,以及脊髓神经结扎等模型中起着起着重要作用。为了了解HIV和NRTI导致神经病变的机制,我们建立了三个大鼠模型,将HIV糖蛋白gp120施用于坐骨神经,腹腔注射ddC以及gp120+ddC共同施用模型,然后通过行为学评定,以及Western Blots,定量PCR,免疫组化等方法检测中枢神经和外周神经病理学和细胞因子的变化,探索胶质细胞与神经元细胞的关系以及TNFα在HIV相关神经疼痛中的作用。
实验结果显示,单独使用gp120或ddC即可导致大鼠异常疼痛,将gp120和ddC联合施用后,相比单独使用时疼痛加剧。免疫组化发现,三个大鼠模型中,外周神经纤维密度出现不同程度的减少,且gp120+ddC联合使用模型中减少最为明显;Western Blots和定量PCR结果显示gp120和ddC模型中腰4/5脊髓和背根经节中的GFAP和TNFα蛋白水平和mRNA水平都上调,在gp120和ddC共同施模型中显著上升。多重免疫组化染色发现,TNFα在背根神经节中主要由神经元细胞表达,在脊髓中则由神经胶质细胞表达。
大鼠蛛网膜下腔注射TNFSR或TNF-siRNA都能够逆转异常机械疼痛,恢复趋性运动。此外,蛛网膜下腔注射胶质细胞抑制剂己酮可可碱,也能有效的抑制异常疼痛。
这些结果表明,我们成功建立了HIV-gp120施用于坐骨神经,腹腔注射ddC以及gp120+ddC共同施用三个大鼠DSP模型;同时也发现在HIV和NRTI的神经病变过程中存在胶质细胞活化增生和外周神经纤维的枯萎;TNFα在HIV-DSP疼痛中起着重要作用,且在TNFα炎性通路中gp120,ddC具有协同加强作用。本研究对阐明HIV相关神经病变机制,验证和评估抗DSP药物,减轻HIV病人痛苦奠定基础。
Distal symmetrical polyneuropathy afflicts about 40% of people living with Human Immunodeficiency Virus (HIV), most of whom have measurable sensory abnormalities and on-going, paroxysmal pain. Currently two reasons are thought to induce HIV-related neuropathy. First, a disease-related DSP associated with HIV-infection itself, especially the coat protein gp120; or secondly a drug- induced DSP associated with the use of nucleoside reverse transcriptase inhibitors (NRTI), particularly the dideoxynuleosides; zalcitabine (ddC), didanosine (ddI) and stavudine (d4T), as part of highly active anti-retroviral therapy (HAART). The use of HAART has markedly increased patient survival making, painful DSP an important source of morbidity in otherwise reasonably healthy HIV-infected individuals. This limits viral suppression strategies and may precipitate discontinuation of anti-retroviral therapy. Therefore, it is important that analgesic strategies are developed to combat this pain. The exact pathogenesis of HIV-associated neuropathies is unclear
Direct infection of the nervous system by HIV is thought to be unlikely. Instead, HIV appears to interact with the nervous system via binding of the external envelope protein, gp120, to the chemokine receptors CXCR4 and/or CCR5 expressed on glial cells. Such interactions can result in neurotoxocity. Previous studies indicate that HIV virus infection is able to increase the production and utilization of several cytokines, such as TNFαand IL-1β. Cerebrospinal fluid from most of the patients with AIDS has increased levels of TNFα, TNFαis involved in the development of pain shown in our previous studies of neuropathic pain induced by spinal cord injury, spinal nerve ligation, and of inflammatory pain. In order to elucidate the mechanisms underlying drug-induced neuropathy in the context of HIV infection, we have characterized pathological events in the peripheral and central nervous system following peripheral gp120 application, anti-retroviral agent, ddC (Zalcitabine) with or without the concomitant delivery of HIV-gp120 to the rat sciatic nerve (gp120+ddC). The results showed that HIV-gp120 or systemic ddC treatment alone is associated with a persistent mechanical hypersensitivity that when combined with perineural HIV-gp120 is exacerbated. We found that chemokine GFAP and TNFαare significantly expressed in the DRG and spinal cord of rats treated with perineural HIV-gp120 and/or ddC and there is a reduction in intraepidermal nerve fiber density. Furthermore, a spinal gliosis is apparent at times of peak behavior sensitivity that is exacerbated in gp120+ddC as compared to either treatment alone.
Moreover, intrathecal administration of TNF siRNA or soluble TNF receptor reversed mechanical allodynia in these three models. Treatment with the glial inhibitor, pentoxifylline, is associated with delayed onset of hypersensitivity to mechanical stimuli in the gp120, ddC and gp120+ddC models and reversal of some measures of thigmotaxis.
These data suggests that HIV-gp120 and ddC may have a synergistic effect on neuropathic pain. They therefore merit further investigation for the elucidation of underlying mechanisms and may provide useful evidence for preclinical assessment of drugs for the treatment of HIV-related peripheral neuropathic pain.
HIV不直接感染神经元,而是与胶质细胞CXCR4或CCR5受体结合,释放细胞因子,例如肿瘤坏死因子(TNFα)白介素1 (IL-1β)等,间接与神经元相互作用,引起神经毒性。TNFα在炎症,脊髓损伤,以及脊髓神经结扎等模型中起着起着重要作用。为了了解HIV和NRTI导致神经病变的机制,我们建立了三个大鼠模型,将HIV糖蛋白gp120施用于坐骨神经,腹腔注射ddC以及gp120+ddC共同施用模型,然后通过行为学评定,以及Western Blots,定量PCR,免疫组化等方法检测中枢神经和外周神经病理学和细胞因子的变化,探索胶质细胞与神经元细胞的关系以及TNFα在HIV相关神经疼痛中的作用。
实验结果显示,单独使用gp120或ddC即可导致大鼠异常疼痛,将gp120和ddC联合施用后,相比单独使用时疼痛加剧。免疫组化发现,三个大鼠模型中,外周神经纤维密度出现不同程度的减少,且gp120+ddC联合使用模型中减少最为明显;Western Blots和定量PCR结果显示gp120和ddC模型中腰4/5脊髓和背根经节中的GFAP和TNFα蛋白水平和mRNA水平都上调,在gp120和ddC共同施模型中显著上升。多重免疫组化染色发现,TNFα在背根神经节中主要由神经元细胞表达,在脊髓中则由神经胶质细胞表达。
大鼠蛛网膜下腔注射TNFSR或TNF-siRNA都能够逆转异常机械疼痛,恢复趋性运动。此外,蛛网膜下腔注射胶质细胞抑制剂己酮可可碱,也能有效的抑制异常疼痛。
这些结果表明,我们成功建立了HIV-gp120施用于坐骨神经,腹腔注射ddC以及gp120+ddC共同施用三个大鼠DSP模型;同时也发现在HIV和NRTI的神经病变过程中存在胶质细胞活化增生和外周神经纤维的枯萎;TNFα在HIV-DSP疼痛中起着重要作用,且在TNFα炎性通路中gp120,ddC具有协同加强作用。本研究对阐明HIV相关神经病变机制,验证和评估抗DSP药物,减轻HIV病人痛苦奠定基础。
Distal symmetrical polyneuropathy afflicts about 40% of people living with Human Immunodeficiency Virus (HIV), most of whom have measurable sensory abnormalities and on-going, paroxysmal pain. Currently two reasons are thought to induce HIV-related neuropathy. First, a disease-related DSP associated with HIV-infection itself, especially the coat protein gp120; or secondly a drug- induced DSP associated with the use of nucleoside reverse transcriptase inhibitors (NRTI), particularly the dideoxynuleosides; zalcitabine (ddC), didanosine (ddI) and stavudine (d4T), as part of highly active anti-retroviral therapy (HAART). The use of HAART has markedly increased patient survival making, painful DSP an important source of morbidity in otherwise reasonably healthy HIV-infected individuals. This limits viral suppression strategies and may precipitate discontinuation of anti-retroviral therapy. Therefore, it is important that analgesic strategies are developed to combat this pain. The exact pathogenesis of HIV-associated neuropathies is unclear
Direct infection of the nervous system by HIV is thought to be unlikely. Instead, HIV appears to interact with the nervous system via binding of the external envelope protein, gp120, to the chemokine receptors CXCR4 and/or CCR5 expressed on glial cells. Such interactions can result in neurotoxocity. Previous studies indicate that HIV virus infection is able to increase the production and utilization of several cytokines, such as TNFαand IL-1β. Cerebrospinal fluid from most of the patients with AIDS has increased levels of TNFα, TNFαis involved in the development of pain shown in our previous studies of neuropathic pain induced by spinal cord injury, spinal nerve ligation, and of inflammatory pain. In order to elucidate the mechanisms underlying drug-induced neuropathy in the context of HIV infection, we have characterized pathological events in the peripheral and central nervous system following peripheral gp120 application, anti-retroviral agent, ddC (Zalcitabine) with or without the concomitant delivery of HIV-gp120 to the rat sciatic nerve (gp120+ddC). The results showed that HIV-gp120 or systemic ddC treatment alone is associated with a persistent mechanical hypersensitivity that when combined with perineural HIV-gp120 is exacerbated. We found that chemokine GFAP and TNFαare significantly expressed in the DRG and spinal cord of rats treated with perineural HIV-gp120 and/or ddC and there is a reduction in intraepidermal nerve fiber density. Furthermore, a spinal gliosis is apparent at times of peak behavior sensitivity that is exacerbated in gp120+ddC as compared to either treatment alone.
Moreover, intrathecal administration of TNF siRNA or soluble TNF receptor reversed mechanical allodynia in these three models. Treatment with the glial inhibitor, pentoxifylline, is associated with delayed onset of hypersensitivity to mechanical stimuli in the gp120, ddC and gp120+ddC models and reversal of some measures of thigmotaxis.
These data suggests that HIV-gp120 and ddC may have a synergistic effect on neuropathic pain. They therefore merit further investigation for the elucidation of underlying mechanisms and may provide useful evidence for preclinical assessment of drugs for the treatment of HIV-related peripheral neuropathic pain.
引文
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