腺苷A2A受体在创伤性颅脑损伤中的双向作用及机制研究
摘要
现代社会,创伤性颅脑损伤(traumatic brain injury,TBI)具有高发生率、高致残率及高死亡率的特点,严重威胁着人类生命及生活质量。颅脑创伤的损害分为原发性损伤和继发性损伤,前者无法逆转,而后者却是可逆并对预后具有决定性作用。目前,对于继发性损伤机制的认识主要有兴奋性氨基酸毒性、过度炎症以及钙超载三方面。颅脑创伤后,损伤组织由于ATP的崩解而释放大量腺苷并激活腺苷受体发挥生物学效应。而近来研究发现,腺苷A2A受体活化可以通过调节谷氨酸释放、炎性反应及钙离子内流而在多种中枢损伤模型(如:帕金森氏病模型、缺血性脑损伤模型及兴奋性毒性脑损伤模型等)中发挥保护或加重损伤的双向作用。但是,就A2A受体在颅脑创伤中的作用,少有报道。
因此,为阐明A2A受体在颅脑创伤中是否同样存在双向作用以及其作用的机制,在本研究中,我们首先利用重力撞击致伤法构建了小鼠TBI模型并在TBI后15min、3h、6h和12h分别应用A2A受体激动剂CGS21680和拮抗剂ZM241385处理TBI小鼠,观察了其对TBI后24h时的伤情的影响,结合对小鼠TBI后24h内脑脊液谷氨酸浓度的动态检测,分析其作用与内环境谷氨酸浓度的关系。然后,我们检测了体外实验中,不同浓度(0, 0.1, 0.5和5.0 mmol/L)谷氨酸条件下,小鼠小胶质细胞及中性粒细胞上A2A受体活化后分别对LPS诱导的小胶质细胞NOS产生及LPS诱导的TNF-αmRNA表达的影响,并探讨了其可能涉及的主要信号通路;进而通过观察联合应用谷氨酸释放抑制剂及A2A受体激动剂对小鼠TBI模型伤情的影响,以期通过细胞及整体动物实验阐明谷氨酸调控A2A受体双向作用的具体机制。最后,为证实骨髓来源细胞上的A2A受体是否是谷氨酸调控的主要靶标,我们利用骨髓移植的方法构建了选择性敲除及选择性重建骨髓来源细胞上A2A受体的小鼠模型,并观察了其对伤后内环境中存在较高浓度谷氨酸的TBI及无谷氨酸存在的ALI的伤情影响。
主要实验结果及结论:
1、在较低谷氨酸浓度的TBI后3h时间点,激活A2A受体产生保护,拮抗A2A受体加重损伤;而在较高浓度的TBI后15min、6h时间点,激活A2A受体则加重损伤,反而拮抗A2A受体产生保护;而在谷氨酸浓度达到峰值的TBI后12h时间点激活A2A受体使伤情加重更为剧烈,甚至引起动物死亡,但拮抗A2A受体却不再具有明显保护作用。这提示A2A受体活化后效应的走向与内环境中谷氨酸浓度的高低存在密切联系。进一步对各组TBI后24h时脑脊液中谷氨酸浓度及炎性因子表达的检测结果表明:激活或拮抗A2A受体对伤情的加重或减轻与其对脑脊液中谷氨酸浓度及炎性因子TNF-α、IL-1的表达的上调或降低基本成正相关。根据神经元、星型胶质细胞上A2A受体活化促谷氨酸释放的文献报道,以上结果初步提示:低浓度谷氨酸时激活A2A受体可能主要通过抑制炎性因子表达减轻损伤,从而使谷氨酸水平下降;反之,高浓度谷氨酸时激活A2A受体,则可能主要通过促进谷氨酸及炎性因子释放而加重损伤。
2、在无谷氨酸及较低浓度(0.1 mmol/L)谷氨酸条件下,激活A2A受体可以显著抑制LPS诱导的小胶质细胞NOS活性,并伴随着cAMP的上调。这种效应可以被PKA抑制剂H-89所阻断。而在较高浓度(0.5mmol/L及5.0mmol/L)的谷氨酸条件下,A2A受体活化则显著促进LPS诱导的小胶质细胞NOS活性,但与LPS组比较,并不伴随cAMP的改变。这种效应可被PKC抑制剂GF109203X而非PKA抑制剂H-89所拮抗。这表明A2A受体活化后,在无谷氨酸及低浓度谷氨酸条件下,可能主要通过PKA途径发挥作用;而在高浓度谷氨酸条件下,则主要通过PKC途径发挥作用。此外,我们在中性粒细胞上,通过检测LPS诱导的中性粒细胞TNF-α表达再次证实了不同浓度谷氨酸对A2A受体活化后效应的调控:与在小胶质细胞中观察的结果相一致,在无谷氨酸及较低浓度(0.1 mmol/L)谷氨酸条件下,激活A2A受体可以显著抑制LPS诱导的中性粒细胞TNF-α表达;而在较高浓度(0.5mmol/L及5.0mmol/L)的谷氨酸条件下,A2A受体活化则显著促进LPS诱导的中性粒细胞TNF-α表达。进一步通过联合应用谷氨酸释放抑制剂与A2A受体激动剂的整体动物TBI实验发现,在抑制谷氨酸释放的前提下,激活A2A受体可以使其在高浓度谷氨酸条件下的促炎损伤作用又重新转变为抑炎保护效应。通过上述细胞及整体动物实验证实:谷氨酸浓度的高低确实调控着TBI后A2A受体激活后的效应走向,高浓度的谷氨酸可以使A2A受体活化后从PKA途径的抑炎保护作用转变为PKC的促炎损伤效应,即谷氨酸浓度的高低可能是A2A受体产生双向作用的重要原因之一。
3、在TBI模型中,选择性敲除或重建骨髓来源细胞上的A2A受体均具有同整体A2A受体敲除一致的保护作用,虽然三者在对谷氨酸释放抑制上作用相当,但选择性敲除A2A受体却体现出更显著的抑炎效应。相反,在ALI模型中,选择性敲除骨髓来源细胞上的A2A受体与整体A2A受体敲除却能通过促炎作用显著加重肺损伤,而选择性重建骨髓来源细胞上的A2A受体却对伤情影响不大。以上结果提示:骨髓来源细胞上的A2A受体在较高浓度谷氨酸环境中主要发挥促炎损伤效应,而在无谷氨酸存在时发挥抑炎保护作用。这与2中细胞实验结果一致,从而证实:骨髓来源细胞上的A2A受体可能是TBI后谷氨酸调控A2A受体的主要靶标,而其受谷氨酸浓度调控而产生的不同生物学效应可能是A2A受体在TBI及其它中枢损伤中产生双向作用的重要细胞机制。
上述研究结果表明:A2A受体活化在颅脑创伤模型中同样存在双向作用;高浓度的谷氨酸可以使A2A受体活化后从抑炎保护效应转变为促炎损伤效应,这种效应的偏转可能与其从PKA到PKC信号通路的偏转有关;而骨髓来源细胞上的A2A受体可能是受谷氨酸上述调节的主要靶标,即谷氨酸对骨髓来源细胞上A2A受体激活后效应走向的调节可能是A2A受体双向作用的重要细胞机制。以上发现不仅为阐明A2A受体在TBI中的作用与机制奠定了基础,而且可以为临床通过调节A2A受体而治疗TBI的新策略提供可靠的实验依据和理论支持。
Traumatic brain injury (TBI) is a severe human injury condition with high incidence, disability and fatality in modern society, which is known to result from neurological deficits through both primary and secondary (delayed) events. While primary damage to the brain cells and tissues is irreversible and incurable, secondary damage results from a potentially reversible process, and the extent of secondary damage closely correlates with clinical prognosis. Three possible mechanisms have been proposed for such secondary brain injury, including glutamate release, cytokine production and Ca2+ overload. Interfering with any of these three pathological processes may reduce TBI-induced brain damage. During brain injury, adenosine levels increase rapidly and markedly to make adenosine receptors active. Recent studies have showed that activation of the adenosine A2A receptors (A2ARs) exert both attenuation and aggravation with regulation of glutamate release, inflammation and Ca2+ influx in a lot of brain injury models, such as Parkinson's disease, ischemic brain injury and excitotoxicity and experimental allergic encephalitis (EAE). However, the role of A2ARs in TBI is unknown.
In this study, to investigate the effects and mechanisms of A2ARs in TBI, we constructed a cortical impact injury model of TBI in mice by weight-dropped method and firstly investigated the effect of A2ARs on the injury at 24h post-TBI by use of the selective agonist CGS21680 and antagonist ZM241385 at 15min, 3h, 6h and 12h after TBI, respectively. Together with the assay of glutamate levels in cerebral spinal fluid (CSF) at the medicine treatment time described above, we analyzed the relationship of the effects of A2ARs-activation and the concentration of glutamate in internal environment in TBI. Secondly, we assayed the effect of CGS21680 on LPS-induced NOS activity of cultured microglia cells and LPS-induced TNF-αmRNA expression of peripheral blood polymorphonuclear neutrophils (PMN) in the presence of increased concentrations of glutamate (0, 0.1, 0.5 and 5.0 mmol/L) and examined the signal transduction of PKA and PKC pathway associated differential regulation of inflammation by A2ARs. We further observed the effect of A2ARs activation after inhibition of glutamate release in mouse TBI model to explore the possible mechanisms of the bi-directional effects of A2ARs regulated by glutamate. Finally, to prove whether the A2ARs on bone marrow-derived cells (BMDCs) were the main targets of glutamate regulation, we constructed two transgenic mouse models: selective inactivation and reconstruction of A2ARs on BMDCs by bone marrow transplantation. Then we investigated their effects in TBI model, which was a injury with high level of glutamate in internal surrounding and in acute lung injury (ALI) model, which was a injury without glutamate in circumstance.
The main results and conclusions are summarized as follows:
1. In TBI model of mouse, activation A2ARs by CGS21680 at 3h post-TBI , which time the glutamate level in CSF was relative low, attenuated the neurological deficits, cerebral edema, glutamate release as well as cytokine expressions of mice at 24h post-TBI significantly; while inactivation of A2ARs by ZM241385 performed aggravation. However, CGS21680 treatment at 15min, 6h post-TBI, which time the glutamate level in CSF was relative high, significantly accelerated the brain damage with upregulation of glutamate concentration and cytokine expressions of mice at 24h post-TBI, while ZM241385 showed protection. In addition, administration of CGS21680 at 12h post-TBI which the glutamate level was much higher than that of 15min, 6h post-TBI, even caused mice dead and ZM241385 didn't show significant protective effect. These results prove that A2ARs also have bi-directional effects in TBI which is connected with the concentration of glutamate in internal environment.
2. In primarily cultured microglia cells from wild type mice, CGS21680 inhibited LPS-induced NOS production significantly in parallel with increased level of cAMP in the glutamate level at 0 and 0.1mM when compared with the LPS alone group. This effect was completely abolished by the PKA inhibitor H-89. In the presence of 0.5mM and 5.0 mM of glutamate, LPS-induced NOS production was enhanced rather than inhibited by CGS21680. This enhancement effect was not inhibited by associated with the cAPM level and not affected by H-89, but was blocked by the PKC inhibitor GF109203X. The differential modulation of CGS21680 on NO activity in the increased concentration of glutamate is mediated by the A2AR since CGS21680 failed to inhibit LPS-induced NOS production and cAMP levels (in the presence or absence of glutamate) in microglial cells derived from A2AR-deficient mice. And the different role of A2AR on inflammation regulated by glutamate were confirmed in LPS-induced neutrophil TNF-αexpression These results demonstrate that, increased extracellular glutamate switches the cAMP-mediated inhibition by adenosine A2ARs agonist to the PKC-mediated potentiation on inflammation in cultured microglia and neutrophil.
3. At 15min post-TBI, CGS21680 treatment accelerated brain damage of mice at 24hs post-TBI as described above. However, after treating the mice with antagonist of glutamate release (s)-4c3HPG at 30 min before TBI, CGS21680 treatment at 15min post-TBI attenuated brain injury, glutamate level in CSF and cytokine mRNA expressions of mice at 24h post-TBI. This result is consistent with previously cell experimental results and confirms that high level of glutamate switches the protective role to the damaging effect of A2ARs activation.
4. Mice models of selective inactivation and reconstruction of A2ARs on BMDCs were constructed and applied to different injury conditions with or without glutamate in circumstance. In TBI model, which was a condition with high level of glutamate, both selective inactivation and reconstruction of A2ARs on BMDCs played protective role, just like global A2ARs inactivation. All of the three could reduce the concentration of glutamate in CSF of mice at 24h post-TBI, but the effect on inhibition of cytokine expressions by selective inactivation A2ARs was much better than the other two. However, in ALI model, which was a injury without glutamate in circumstance, selective inactivation of A2ARs on BMDCs and global A2ARs inactivation promoted lung damage by promotion of inflammatory cytokine expressions, while selective reconstruction of A2ARs on BMDCs didn't show any significant difference compared with injured wild type mice. These results showthat high level of glutamate may switch the effect of A2ARs on BMDCs from suppression inflammation to promotion inflammation, and suggest that A2ARs on BMDCs regulation by glutamate may be the important cell mechanism of A2ARs’bi-directional in TBI.
In summary, we demonstrated the bi-directional effects of A2ARs in the mouse TBI model and that high level of glutamate in internal enviroment might switch the effects of A2ARs, mainly on BMDCs, on inflammation and glutamate release from inhibition to promotion in accompany with the signal pathway switch from PKA to PKC activation. These findings may provide some experimental evidence and a new strategy for clinical treatment by regulation of A2ARs.
因此,为阐明A2A受体在颅脑创伤中是否同样存在双向作用以及其作用的机制,在本研究中,我们首先利用重力撞击致伤法构建了小鼠TBI模型并在TBI后15min、3h、6h和12h分别应用A2A受体激动剂CGS21680和拮抗剂ZM241385处理TBI小鼠,观察了其对TBI后24h时的伤情的影响,结合对小鼠TBI后24h内脑脊液谷氨酸浓度的动态检测,分析其作用与内环境谷氨酸浓度的关系。然后,我们检测了体外实验中,不同浓度(0, 0.1, 0.5和5.0 mmol/L)谷氨酸条件下,小鼠小胶质细胞及中性粒细胞上A2A受体活化后分别对LPS诱导的小胶质细胞NOS产生及LPS诱导的TNF-αmRNA表达的影响,并探讨了其可能涉及的主要信号通路;进而通过观察联合应用谷氨酸释放抑制剂及A2A受体激动剂对小鼠TBI模型伤情的影响,以期通过细胞及整体动物实验阐明谷氨酸调控A2A受体双向作用的具体机制。最后,为证实骨髓来源细胞上的A2A受体是否是谷氨酸调控的主要靶标,我们利用骨髓移植的方法构建了选择性敲除及选择性重建骨髓来源细胞上A2A受体的小鼠模型,并观察了其对伤后内环境中存在较高浓度谷氨酸的TBI及无谷氨酸存在的ALI的伤情影响。
主要实验结果及结论:
1、在较低谷氨酸浓度的TBI后3h时间点,激活A2A受体产生保护,拮抗A2A受体加重损伤;而在较高浓度的TBI后15min、6h时间点,激活A2A受体则加重损伤,反而拮抗A2A受体产生保护;而在谷氨酸浓度达到峰值的TBI后12h时间点激活A2A受体使伤情加重更为剧烈,甚至引起动物死亡,但拮抗A2A受体却不再具有明显保护作用。这提示A2A受体活化后效应的走向与内环境中谷氨酸浓度的高低存在密切联系。进一步对各组TBI后24h时脑脊液中谷氨酸浓度及炎性因子表达的检测结果表明:激活或拮抗A2A受体对伤情的加重或减轻与其对脑脊液中谷氨酸浓度及炎性因子TNF-α、IL-1的表达的上调或降低基本成正相关。根据神经元、星型胶质细胞上A2A受体活化促谷氨酸释放的文献报道,以上结果初步提示:低浓度谷氨酸时激活A2A受体可能主要通过抑制炎性因子表达减轻损伤,从而使谷氨酸水平下降;反之,高浓度谷氨酸时激活A2A受体,则可能主要通过促进谷氨酸及炎性因子释放而加重损伤。
2、在无谷氨酸及较低浓度(0.1 mmol/L)谷氨酸条件下,激活A2A受体可以显著抑制LPS诱导的小胶质细胞NOS活性,并伴随着cAMP的上调。这种效应可以被PKA抑制剂H-89所阻断。而在较高浓度(0.5mmol/L及5.0mmol/L)的谷氨酸条件下,A2A受体活化则显著促进LPS诱导的小胶质细胞NOS活性,但与LPS组比较,并不伴随cAMP的改变。这种效应可被PKC抑制剂GF109203X而非PKA抑制剂H-89所拮抗。这表明A2A受体活化后,在无谷氨酸及低浓度谷氨酸条件下,可能主要通过PKA途径发挥作用;而在高浓度谷氨酸条件下,则主要通过PKC途径发挥作用。此外,我们在中性粒细胞上,通过检测LPS诱导的中性粒细胞TNF-α表达再次证实了不同浓度谷氨酸对A2A受体活化后效应的调控:与在小胶质细胞中观察的结果相一致,在无谷氨酸及较低浓度(0.1 mmol/L)谷氨酸条件下,激活A2A受体可以显著抑制LPS诱导的中性粒细胞TNF-α表达;而在较高浓度(0.5mmol/L及5.0mmol/L)的谷氨酸条件下,A2A受体活化则显著促进LPS诱导的中性粒细胞TNF-α表达。进一步通过联合应用谷氨酸释放抑制剂与A2A受体激动剂的整体动物TBI实验发现,在抑制谷氨酸释放的前提下,激活A2A受体可以使其在高浓度谷氨酸条件下的促炎损伤作用又重新转变为抑炎保护效应。通过上述细胞及整体动物实验证实:谷氨酸浓度的高低确实调控着TBI后A2A受体激活后的效应走向,高浓度的谷氨酸可以使A2A受体活化后从PKA途径的抑炎保护作用转变为PKC的促炎损伤效应,即谷氨酸浓度的高低可能是A2A受体产生双向作用的重要原因之一。
3、在TBI模型中,选择性敲除或重建骨髓来源细胞上的A2A受体均具有同整体A2A受体敲除一致的保护作用,虽然三者在对谷氨酸释放抑制上作用相当,但选择性敲除A2A受体却体现出更显著的抑炎效应。相反,在ALI模型中,选择性敲除骨髓来源细胞上的A2A受体与整体A2A受体敲除却能通过促炎作用显著加重肺损伤,而选择性重建骨髓来源细胞上的A2A受体却对伤情影响不大。以上结果提示:骨髓来源细胞上的A2A受体在较高浓度谷氨酸环境中主要发挥促炎损伤效应,而在无谷氨酸存在时发挥抑炎保护作用。这与2中细胞实验结果一致,从而证实:骨髓来源细胞上的A2A受体可能是TBI后谷氨酸调控A2A受体的主要靶标,而其受谷氨酸浓度调控而产生的不同生物学效应可能是A2A受体在TBI及其它中枢损伤中产生双向作用的重要细胞机制。
上述研究结果表明:A2A受体活化在颅脑创伤模型中同样存在双向作用;高浓度的谷氨酸可以使A2A受体活化后从抑炎保护效应转变为促炎损伤效应,这种效应的偏转可能与其从PKA到PKC信号通路的偏转有关;而骨髓来源细胞上的A2A受体可能是受谷氨酸上述调节的主要靶标,即谷氨酸对骨髓来源细胞上A2A受体激活后效应走向的调节可能是A2A受体双向作用的重要细胞机制。以上发现不仅为阐明A2A受体在TBI中的作用与机制奠定了基础,而且可以为临床通过调节A2A受体而治疗TBI的新策略提供可靠的实验依据和理论支持。
Traumatic brain injury (TBI) is a severe human injury condition with high incidence, disability and fatality in modern society, which is known to result from neurological deficits through both primary and secondary (delayed) events. While primary damage to the brain cells and tissues is irreversible and incurable, secondary damage results from a potentially reversible process, and the extent of secondary damage closely correlates with clinical prognosis. Three possible mechanisms have been proposed for such secondary brain injury, including glutamate release, cytokine production and Ca2+ overload. Interfering with any of these three pathological processes may reduce TBI-induced brain damage. During brain injury, adenosine levels increase rapidly and markedly to make adenosine receptors active. Recent studies have showed that activation of the adenosine A2A receptors (A2ARs) exert both attenuation and aggravation with regulation of glutamate release, inflammation and Ca2+ influx in a lot of brain injury models, such as Parkinson's disease, ischemic brain injury and excitotoxicity and experimental allergic encephalitis (EAE). However, the role of A2ARs in TBI is unknown.
In this study, to investigate the effects and mechanisms of A2ARs in TBI, we constructed a cortical impact injury model of TBI in mice by weight-dropped method and firstly investigated the effect of A2ARs on the injury at 24h post-TBI by use of the selective agonist CGS21680 and antagonist ZM241385 at 15min, 3h, 6h and 12h after TBI, respectively. Together with the assay of glutamate levels in cerebral spinal fluid (CSF) at the medicine treatment time described above, we analyzed the relationship of the effects of A2ARs-activation and the concentration of glutamate in internal environment in TBI. Secondly, we assayed the effect of CGS21680 on LPS-induced NOS activity of cultured microglia cells and LPS-induced TNF-αmRNA expression of peripheral blood polymorphonuclear neutrophils (PMN) in the presence of increased concentrations of glutamate (0, 0.1, 0.5 and 5.0 mmol/L) and examined the signal transduction of PKA and PKC pathway associated differential regulation of inflammation by A2ARs. We further observed the effect of A2ARs activation after inhibition of glutamate release in mouse TBI model to explore the possible mechanisms of the bi-directional effects of A2ARs regulated by glutamate. Finally, to prove whether the A2ARs on bone marrow-derived cells (BMDCs) were the main targets of glutamate regulation, we constructed two transgenic mouse models: selective inactivation and reconstruction of A2ARs on BMDCs by bone marrow transplantation. Then we investigated their effects in TBI model, which was a injury with high level of glutamate in internal surrounding and in acute lung injury (ALI) model, which was a injury without glutamate in circumstance.
The main results and conclusions are summarized as follows:
1. In TBI model of mouse, activation A2ARs by CGS21680 at 3h post-TBI , which time the glutamate level in CSF was relative low, attenuated the neurological deficits, cerebral edema, glutamate release as well as cytokine expressions of mice at 24h post-TBI significantly; while inactivation of A2ARs by ZM241385 performed aggravation. However, CGS21680 treatment at 15min, 6h post-TBI, which time the glutamate level in CSF was relative high, significantly accelerated the brain damage with upregulation of glutamate concentration and cytokine expressions of mice at 24h post-TBI, while ZM241385 showed protection. In addition, administration of CGS21680 at 12h post-TBI which the glutamate level was much higher than that of 15min, 6h post-TBI, even caused mice dead and ZM241385 didn't show significant protective effect. These results prove that A2ARs also have bi-directional effects in TBI which is connected with the concentration of glutamate in internal environment.
2. In primarily cultured microglia cells from wild type mice, CGS21680 inhibited LPS-induced NOS production significantly in parallel with increased level of cAMP in the glutamate level at 0 and 0.1mM when compared with the LPS alone group. This effect was completely abolished by the PKA inhibitor H-89. In the presence of 0.5mM and 5.0 mM of glutamate, LPS-induced NOS production was enhanced rather than inhibited by CGS21680. This enhancement effect was not inhibited by associated with the cAPM level and not affected by H-89, but was blocked by the PKC inhibitor GF109203X. The differential modulation of CGS21680 on NO activity in the increased concentration of glutamate is mediated by the A2AR since CGS21680 failed to inhibit LPS-induced NOS production and cAMP levels (in the presence or absence of glutamate) in microglial cells derived from A2AR-deficient mice. And the different role of A2AR on inflammation regulated by glutamate were confirmed in LPS-induced neutrophil TNF-αexpression These results demonstrate that, increased extracellular glutamate switches the cAMP-mediated inhibition by adenosine A2ARs agonist to the PKC-mediated potentiation on inflammation in cultured microglia and neutrophil.
3. At 15min post-TBI, CGS21680 treatment accelerated brain damage of mice at 24hs post-TBI as described above. However, after treating the mice with antagonist of glutamate release (s)-4c3HPG at 30 min before TBI, CGS21680 treatment at 15min post-TBI attenuated brain injury, glutamate level in CSF and cytokine mRNA expressions of mice at 24h post-TBI. This result is consistent with previously cell experimental results and confirms that high level of glutamate switches the protective role to the damaging effect of A2ARs activation.
4. Mice models of selective inactivation and reconstruction of A2ARs on BMDCs were constructed and applied to different injury conditions with or without glutamate in circumstance. In TBI model, which was a condition with high level of glutamate, both selective inactivation and reconstruction of A2ARs on BMDCs played protective role, just like global A2ARs inactivation. All of the three could reduce the concentration of glutamate in CSF of mice at 24h post-TBI, but the effect on inhibition of cytokine expressions by selective inactivation A2ARs was much better than the other two. However, in ALI model, which was a injury without glutamate in circumstance, selective inactivation of A2ARs on BMDCs and global A2ARs inactivation promoted lung damage by promotion of inflammatory cytokine expressions, while selective reconstruction of A2ARs on BMDCs didn't show any significant difference compared with injured wild type mice. These results showthat high level of glutamate may switch the effect of A2ARs on BMDCs from suppression inflammation to promotion inflammation, and suggest that A2ARs on BMDCs regulation by glutamate may be the important cell mechanism of A2ARs’bi-directional in TBI.
In summary, we demonstrated the bi-directional effects of A2ARs in the mouse TBI model and that high level of glutamate in internal enviroment might switch the effects of A2ARs, mainly on BMDCs, on inflammation and glutamate release from inhibition to promotion in accompany with the signal pathway switch from PKA to PKC activation. These findings may provide some experimental evidence and a new strategy for clinical treatment by regulation of A2ARs.
引文
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