Nrf2在大鼠肢体爆炸伤后短暂低温肺保护中的作用及机制
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摘要
现代战争中肢体爆炸伤发生率高,且多存在血管、神经和广泛的软组织损伤,是战时创伤性截肢的主要原因。肢体爆炸伤由于其特殊的致伤机理,常导致全身免疫系统过度激活,进而导致远隔器官损伤。其中,以肺损伤的发生率最高,且常常是多器官功能损害的先兆,因此减轻或预防肺损伤的发生成为改善肢体爆炸伤伤员预后的关键。
既往研究表明,控制性全身低温可明显减轻脓毒症、内毒素和缺血—再灌注等引起的肺损伤,但对于有活动性出血的肢体爆炸伤而言,长时间低温可能导致致命性出血。近期研究发现对于急性肺损伤的救治,低温维持时间并非越长越好,相反短时间全身低温(2h)肺保护作用优于长时间全身低温(5h)。全身降温30min也可明显增强组织对缺血的耐受。另外,前期研究提示损伤局部短暂低温可通过抑制全身失控性炎症反应和氧化损伤减轻肺和肠道屏障功能损害。因此,本研究拟通过制作肢体远端爆炸伤动物模型,观察全身短暂低温和损伤局部短暂低温对肺损伤的作用,并初步探讨其机制。
内源性保护机制受损在创伤后脏器功能损害中的作用日益受到人们的关注。NF-E2相关因子(Nrf2)是决定细胞内源性抗损伤能力的关键转录因子,具有抗氧化、抗炎等作用。最新研究发现Nrf2转录调节活性增强在动物冬眠时缺血缺氧的耐受过程中具有重要作用,提示控制性低温可能是通过增强Nrf2转录调节活性,进而发挥保护效应。但Nrf2在肢体爆炸伤后肺损伤及低温脏器保护作用中的相关研究目前尚未见报道。
针对上述问题,本研究分为四个部分:①采用80mg DDNP纸质点爆源紧贴大鼠左后肢下段引爆制作肢体爆炸伤动物模型,观察全身短暂低温(30min)或损伤局部短暂低温(30min)对肢体爆炸伤后肺损伤的作用。②全身短暂低温或损伤局部短暂低温对肢体爆炸伤后肺Nrf2转录调节活性的影响。③培养肺微血管内皮细胞,通过给予肺微血管内皮细胞不同剂量的H2O2或TNFα,观察Nrf2转录调节活性的变化,初步探讨全身短暂低温和损伤局部短暂低温是否通过减少肺自由基和炎症因子的产生,进而参与Nrf2转录调节活性的调控。④采用RNAi技术阻断肺微血管内皮细胞Nrf2表达,研究Nrf2在抗炎症损伤和抗氧化损伤中的作用;探讨Nrf2在低温肺保护中的作用。
主要结果结论如下:
1.大鼠肢体爆炸伤后早期可引起肺组织出现以炎症损伤、氧化损伤、炎症细胞浸润和肺水肿为主要表现的继发肺损伤早期改变;肺组织MDA含量和MPO活性明显升高(p<0.05),SOD活性明显下降;肺组织TNFα、IL-6和IL-10水平均明显升高(p<0.01)。
2.全身短暂低温或损伤局部短暂低温可明显减轻肢体爆炸伤后肺组织炎症细胞浸润,肺水肿;降低肺组织MDA含量和MPO活性(p<0.01),增高SOD活性;降低肺组织TNFα、IL-6和IL-10水平(p<0.01)。说明全身短暂低温或损伤局部短暂低温可通过抑制氧化应激和炎症反应,减轻肢体爆炸伤后肺损伤。
3.肢体爆炸伤后肺Nrf2转录调节活性增强,全身短暂低温或损伤局部短暂低温可进一步增强肺Nrf2的转录调节活性,但对肺Nrf2 mRNA表达水平没有明显影响,说明全身短暂低温或损伤局部短暂低温对肢体爆炸伤后肺Nrf2转录调节活性的调控并非发生在基因转录水平。
4.采用不同剂量H2O2或TNFα处理肺微血管内皮细胞后,Nrf2转录调节活性发生不同的改变:中、低剂量H2O2(0.125、0.25、0.5mM)或TNFα(2.5、5、10ng/ml)引起Nrf2转录调节活性呈剂量依赖性升高,而高浓度H2O2(1、2mM)或TNFα(20、40ng/ml)引起Nrf2转录调节活性下降。结合全身短暂低温或损伤局部短暂低温可明显抑制肢体爆炸伤后肺组织氧化损伤和炎症反应的实验结果,我们认为全身短暂低温或损伤局部短暂低温可能通过抑制肢体爆炸伤后肺自由基和炎症因子的产生,从而增强Nrf2的转录调节活性。
5.采用RNAi技术阻断肺微血管内皮细胞Nrf2的表达后,TNFα或H2O2引起肺微血管内皮细胞更为严重的炎症损伤和氧化损伤:与野生对照细胞和转染空质粒的细胞比较,Nrf2表达下降的细胞凋亡率增高,LDH水平升高;MDA含量升高;IL-6水平升高,IL-10水平下降;GSH含量下降;且上述指标的变化幅度与Nrf2表达受抑程度一致,说明Nrf2在细胞抗氧化损伤和炎症损伤过程中具有重要作用,而氧化损伤和炎症反应恰好是引起肢体爆炸伤后肺损伤的重要原因,因此Nrf2转录调节活性增强是全身短暂低温或损伤局部短暂低温减轻肢体爆炸伤后肺损伤的重要机制之一。全身短暂低温或损伤局部短暂低温通过增强肺Nrf2转录调节活性,发挥长时程保护作用,减轻肢体爆炸伤后肺损伤。
Being the main reason for traumatic amputation in war time, limb’s explosion injury frequently occurs in modern wars, causing damages to blood vessel, neurotmesis and extensive soft tissue. Immune system is often excessively activated after limb’s explosion injury, subsequently resulting in remote organ damage. Amongst, incidence rate of acute lung injury is the highest, which often portends multiple organ dysfunction syndrome, so mitigation and prevention of acute lung injury become the very key step to improve prognosis of limb’s explosion injury.
Previous investigations indicate that controlled whole-body hypothermia obviously mitigates lung injury caused by sepsis, endotoxin and ischemic-reperfusion injury etc. while for limb’s explosion injury accompanying with active bleeding, a long-time hypothermia may lead to fateful hemorrhage. Recent studies found that for the therapy of acute lung injury, early and short-time (2h) application of whole-body hypothermia is better than long-time hypothermia (5h). Transient(30min) whole-body hypothermia can significantly increase ischemic tolerance. Moreover, we also found that transient regional hypothermia can mitigate lung injury and intestinal tract barrier damage by inhibiting the systemic inflammatory reaction and oxidative injury in our early investigations. Therefore, the animal model is made for limb’s explosion injury, meanwhile observing effects of transient(30min) whole-body hypothermia or regional hypothermia on lung injury.
Endogenous protective system damage has driven considerable interests recently. NF-E2 related factor (Nrf2) is the key transcription factor in endogenous protective system, playing important roles in reducing oxidative stress, inflammatory damage and accumulation of toxic metabolites which are all involved in secondary lung injury after limb’s explosion injury. Latest study points out that Nrf2 is activated to regulate antioxidant defenses during hibernation. However, relevant reports about hypothermia protection effects of Nrf2 on lung injury after limb’s explosion injury are presently unavailable.
In view of that, this paper is divided into four parts:
Part 1: Animal model was made by detonating 80mg DDNP fixed on left hind limb of SD rats, meanwhile observing effects of transient (30min) whole-body hypothermia or regional hypothermia on secondary lung injury after limb’s explosion injury.
Part 2: Effects of transient (30min) whole-body hypothermia or regional hypothermia on Nrf2 of lung after limb’s explosion injury was observed.
Part 3: Pulmonary micro-vascular endothelial cells (PMVECs) were cultured. In order to investigate changes of Nrf2-transcriptional activity, PMVECs were treated with different doses of hydrogen peroxide (H2O2) or tumor necrosis factorα, expecting to explore the mechanism of Nrf2 transcriptional activity regulated by transient (30min) whole-body hypothermia or regional hypothermia.
Part 4: Nrf2 expression in PMVECs was inhibited by RNA interference. Simultaneously, that whether Nrf2 exerts effects on anti-oxidative injury and anti-inflammation was investigated, exploring Nrf2’role in hypothermia protection.
The main results and conclusions are as follows:
1. Secondary lung injury resulted from limb’s explosion injury are characterized of inflammatory reaction, oxidative injury and PMN infiltration. MDA contents and MPO activity in lung tissue are significantly increased (p<0.05), SOD activity decreased, TNFα、IL-6 and IL-10 concentration are remarkably increased (p<0.01).
2. Transient whole-body hypothermia or regional hypothermia obviously inhibits inflammatory cells infiltration, mitigates pulmonary edema, decreases MDA content and MPO activity (p<0.01), increases SOD activity and decrease the level of TNFα, IL-6 and IL-10 (p<0.01) in lung tissue. All these show that transient whole-body hypothermia and regional hypothermia can mitigate lung injury after limb’s explosion injury by inhibiting oxidative stress and inflammatory reaction.
3. Transcriptional activity of Nrf2 in lung tissue is increased after limb’s explosion injury, and further increased by early application of transient whole-body or regional hypothermia. However, Nrf2 mRNA levels are not changed, indicating that regulation of Nrf2 transcriptional activity does not occur at gene transcriptional level.
4. Nrf2-ARE binding activity is increased after PMVECs exposed to 0.125mM, 0.25mM and 0.5mM hydrogen peroxide (H2O2) or 2.5 ng/ml, 5 ng/ml and 10ng/ml TNFαsolution, showing concentration-dependent. Nrf2-ARE binding activity is decreased after PMVECs exposed to 1mM or 2mM hydrogen peroxide and 20 or 40ng/ml TNF-αsolution compared with 0.5mM hydrogen peroxide or 10ng/ml TNF-αsolution. In consideration that transient whole-body or regional hypothermia can significantly inhibit oxidative injury and inflammatory reaction in lung after limb’explosion injury, it is concluded that Nrf2 transcriptional activity and endogenous protective competent can be increased due to inflammatory cytokines and free radicals are reduced by early application of transient whole-body or regional hypothermia, which is helpful to mitigate lung injury after limb’s explosion injury.
5. Hydrogen peroxide (H2O2) or tumor necrosis factorαcan lead to more severe injury of PMVECs after Nrf2 gene expression is inhibited by RNA interfere, indicating Nrf2 play important role in the process of anti-oxidative injury and anti-inflammatory reaction. It is suggested transient whole-body or regional hypothermia alleviates lung injury via enhancing transcriptional activity of Nrf2 in the lung tissue.
既往研究表明,控制性全身低温可明显减轻脓毒症、内毒素和缺血—再灌注等引起的肺损伤,但对于有活动性出血的肢体爆炸伤而言,长时间低温可能导致致命性出血。近期研究发现对于急性肺损伤的救治,低温维持时间并非越长越好,相反短时间全身低温(2h)肺保护作用优于长时间全身低温(5h)。全身降温30min也可明显增强组织对缺血的耐受。另外,前期研究提示损伤局部短暂低温可通过抑制全身失控性炎症反应和氧化损伤减轻肺和肠道屏障功能损害。因此,本研究拟通过制作肢体远端爆炸伤动物模型,观察全身短暂低温和损伤局部短暂低温对肺损伤的作用,并初步探讨其机制。
内源性保护机制受损在创伤后脏器功能损害中的作用日益受到人们的关注。NF-E2相关因子(Nrf2)是决定细胞内源性抗损伤能力的关键转录因子,具有抗氧化、抗炎等作用。最新研究发现Nrf2转录调节活性增强在动物冬眠时缺血缺氧的耐受过程中具有重要作用,提示控制性低温可能是通过增强Nrf2转录调节活性,进而发挥保护效应。但Nrf2在肢体爆炸伤后肺损伤及低温脏器保护作用中的相关研究目前尚未见报道。
针对上述问题,本研究分为四个部分:①采用80mg DDNP纸质点爆源紧贴大鼠左后肢下段引爆制作肢体爆炸伤动物模型,观察全身短暂低温(30min)或损伤局部短暂低温(30min)对肢体爆炸伤后肺损伤的作用。②全身短暂低温或损伤局部短暂低温对肢体爆炸伤后肺Nrf2转录调节活性的影响。③培养肺微血管内皮细胞,通过给予肺微血管内皮细胞不同剂量的H2O2或TNFα,观察Nrf2转录调节活性的变化,初步探讨全身短暂低温和损伤局部短暂低温是否通过减少肺自由基和炎症因子的产生,进而参与Nrf2转录调节活性的调控。④采用RNAi技术阻断肺微血管内皮细胞Nrf2表达,研究Nrf2在抗炎症损伤和抗氧化损伤中的作用;探讨Nrf2在低温肺保护中的作用。
主要结果结论如下:
1.大鼠肢体爆炸伤后早期可引起肺组织出现以炎症损伤、氧化损伤、炎症细胞浸润和肺水肿为主要表现的继发肺损伤早期改变;肺组织MDA含量和MPO活性明显升高(p<0.05),SOD活性明显下降;肺组织TNFα、IL-6和IL-10水平均明显升高(p<0.01)。
2.全身短暂低温或损伤局部短暂低温可明显减轻肢体爆炸伤后肺组织炎症细胞浸润,肺水肿;降低肺组织MDA含量和MPO活性(p<0.01),增高SOD活性;降低肺组织TNFα、IL-6和IL-10水平(p<0.01)。说明全身短暂低温或损伤局部短暂低温可通过抑制氧化应激和炎症反应,减轻肢体爆炸伤后肺损伤。
3.肢体爆炸伤后肺Nrf2转录调节活性增强,全身短暂低温或损伤局部短暂低温可进一步增强肺Nrf2的转录调节活性,但对肺Nrf2 mRNA表达水平没有明显影响,说明全身短暂低温或损伤局部短暂低温对肢体爆炸伤后肺Nrf2转录调节活性的调控并非发生在基因转录水平。
4.采用不同剂量H2O2或TNFα处理肺微血管内皮细胞后,Nrf2转录调节活性发生不同的改变:中、低剂量H2O2(0.125、0.25、0.5mM)或TNFα(2.5、5、10ng/ml)引起Nrf2转录调节活性呈剂量依赖性升高,而高浓度H2O2(1、2mM)或TNFα(20、40ng/ml)引起Nrf2转录调节活性下降。结合全身短暂低温或损伤局部短暂低温可明显抑制肢体爆炸伤后肺组织氧化损伤和炎症反应的实验结果,我们认为全身短暂低温或损伤局部短暂低温可能通过抑制肢体爆炸伤后肺自由基和炎症因子的产生,从而增强Nrf2的转录调节活性。
5.采用RNAi技术阻断肺微血管内皮细胞Nrf2的表达后,TNFα或H2O2引起肺微血管内皮细胞更为严重的炎症损伤和氧化损伤:与野生对照细胞和转染空质粒的细胞比较,Nrf2表达下降的细胞凋亡率增高,LDH水平升高;MDA含量升高;IL-6水平升高,IL-10水平下降;GSH含量下降;且上述指标的变化幅度与Nrf2表达受抑程度一致,说明Nrf2在细胞抗氧化损伤和炎症损伤过程中具有重要作用,而氧化损伤和炎症反应恰好是引起肢体爆炸伤后肺损伤的重要原因,因此Nrf2转录调节活性增强是全身短暂低温或损伤局部短暂低温减轻肢体爆炸伤后肺损伤的重要机制之一。全身短暂低温或损伤局部短暂低温通过增强肺Nrf2转录调节活性,发挥长时程保护作用,减轻肢体爆炸伤后肺损伤。
Being the main reason for traumatic amputation in war time, limb’s explosion injury frequently occurs in modern wars, causing damages to blood vessel, neurotmesis and extensive soft tissue. Immune system is often excessively activated after limb’s explosion injury, subsequently resulting in remote organ damage. Amongst, incidence rate of acute lung injury is the highest, which often portends multiple organ dysfunction syndrome, so mitigation and prevention of acute lung injury become the very key step to improve prognosis of limb’s explosion injury.
Previous investigations indicate that controlled whole-body hypothermia obviously mitigates lung injury caused by sepsis, endotoxin and ischemic-reperfusion injury etc. while for limb’s explosion injury accompanying with active bleeding, a long-time hypothermia may lead to fateful hemorrhage. Recent studies found that for the therapy of acute lung injury, early and short-time (2h) application of whole-body hypothermia is better than long-time hypothermia (5h). Transient(30min) whole-body hypothermia can significantly increase ischemic tolerance. Moreover, we also found that transient regional hypothermia can mitigate lung injury and intestinal tract barrier damage by inhibiting the systemic inflammatory reaction and oxidative injury in our early investigations. Therefore, the animal model is made for limb’s explosion injury, meanwhile observing effects of transient(30min) whole-body hypothermia or regional hypothermia on lung injury.
Endogenous protective system damage has driven considerable interests recently. NF-E2 related factor (Nrf2) is the key transcription factor in endogenous protective system, playing important roles in reducing oxidative stress, inflammatory damage and accumulation of toxic metabolites which are all involved in secondary lung injury after limb’s explosion injury. Latest study points out that Nrf2 is activated to regulate antioxidant defenses during hibernation. However, relevant reports about hypothermia protection effects of Nrf2 on lung injury after limb’s explosion injury are presently unavailable.
In view of that, this paper is divided into four parts:
Part 1: Animal model was made by detonating 80mg DDNP fixed on left hind limb of SD rats, meanwhile observing effects of transient (30min) whole-body hypothermia or regional hypothermia on secondary lung injury after limb’s explosion injury.
Part 2: Effects of transient (30min) whole-body hypothermia or regional hypothermia on Nrf2 of lung after limb’s explosion injury was observed.
Part 3: Pulmonary micro-vascular endothelial cells (PMVECs) were cultured. In order to investigate changes of Nrf2-transcriptional activity, PMVECs were treated with different doses of hydrogen peroxide (H2O2) or tumor necrosis factorα, expecting to explore the mechanism of Nrf2 transcriptional activity regulated by transient (30min) whole-body hypothermia or regional hypothermia.
Part 4: Nrf2 expression in PMVECs was inhibited by RNA interference. Simultaneously, that whether Nrf2 exerts effects on anti-oxidative injury and anti-inflammation was investigated, exploring Nrf2’role in hypothermia protection.
The main results and conclusions are as follows:
1. Secondary lung injury resulted from limb’s explosion injury are characterized of inflammatory reaction, oxidative injury and PMN infiltration. MDA contents and MPO activity in lung tissue are significantly increased (p<0.05), SOD activity decreased, TNFα、IL-6 and IL-10 concentration are remarkably increased (p<0.01).
2. Transient whole-body hypothermia or regional hypothermia obviously inhibits inflammatory cells infiltration, mitigates pulmonary edema, decreases MDA content and MPO activity (p<0.01), increases SOD activity and decrease the level of TNFα, IL-6 and IL-10 (p<0.01) in lung tissue. All these show that transient whole-body hypothermia and regional hypothermia can mitigate lung injury after limb’s explosion injury by inhibiting oxidative stress and inflammatory reaction.
3. Transcriptional activity of Nrf2 in lung tissue is increased after limb’s explosion injury, and further increased by early application of transient whole-body or regional hypothermia. However, Nrf2 mRNA levels are not changed, indicating that regulation of Nrf2 transcriptional activity does not occur at gene transcriptional level.
4. Nrf2-ARE binding activity is increased after PMVECs exposed to 0.125mM, 0.25mM and 0.5mM hydrogen peroxide (H2O2) or 2.5 ng/ml, 5 ng/ml and 10ng/ml TNFαsolution, showing concentration-dependent. Nrf2-ARE binding activity is decreased after PMVECs exposed to 1mM or 2mM hydrogen peroxide and 20 or 40ng/ml TNF-αsolution compared with 0.5mM hydrogen peroxide or 10ng/ml TNF-αsolution. In consideration that transient whole-body or regional hypothermia can significantly inhibit oxidative injury and inflammatory reaction in lung after limb’explosion injury, it is concluded that Nrf2 transcriptional activity and endogenous protective competent can be increased due to inflammatory cytokines and free radicals are reduced by early application of transient whole-body or regional hypothermia, which is helpful to mitigate lung injury after limb’s explosion injury.
5. Hydrogen peroxide (H2O2) or tumor necrosis factorαcan lead to more severe injury of PMVECs after Nrf2 gene expression is inhibited by RNA interfere, indicating Nrf2 play important role in the process of anti-oxidative injury and anti-inflammatory reaction. It is suggested transient whole-body or regional hypothermia alleviates lung injury via enhancing transcriptional activity of Nrf2 in the lung tissue.
引文
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