氢气盐溶液在肝脏缺血再灌注损伤中保护作用的机制
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摘要
研究目的：肝脏缺血再灌注损伤(hepatic ischemia-reperfusion injury, HIRI)是肝脏外科常见的问题,可见于肝脏外伤、肝肿瘤切除术,肝移植及休克,感染等。HIRI的发生机理非常复杂,其确切机制目前尚不完全清楚,多数观点认为HIRI的损伤机制主要与氧自由基释放、炎性细胞因子表达、钙离子超载、微循环障碍、线粒体功能受损、能量代谢障碍等因素有关。肝脏作为机体重要的防御屏障,其功能的受损常常造成内毒素血症,后者反过来又加重肝脏功能受损,形成恶性循环,造成严重的脓毒症及多脏器功能衰竭甚至死亡。目前,国内外研究所报道的肝脏缺血再灌注损伤的防护策略主要集中在抗氧化,抗炎等主要方面,因此,寻找特异性强、副反应小、临床应用可能性大的抗氧化抗炎双重效能的药物,具有迫切的研究意义和潜在的临床应用前景。近期,有文献指出氢分子具有选择性抗氧化的生理特性,呼吸氢气能显著缓解肝,脑,肾脏等器官的缺血再灌注损伤。但是通过呼吸的方法不仅在气体混合过程中存在爆炸的危险,而且需要比较特殊的设备,操作比较复杂,在临床上难以推广。经过理论推算发现,将氢气溶解在生理盐水中,经过加压等特殊的处理,使其达到饱和溶解,可制造出氢的生理盐水饱和溶液。本研究旨在研究氢气盐溶液在肝脏缺血再灌注损伤中的保护效应及相关机制。
研究方法：①比较假手术、缺血再灌注、生理盐水+缺血再灌注(对照组)和氢气盐溶液组+缺血再灌注组(治疗组)之间血清中转氨酶以及肝脏组织结构变化的差异,以及各组的MDA含量的差异；②DAB免疫组织化学染色的方法检测氧自由基与细胞内脂质以及DNA反应的产物羟基丙烯醛(HNE)以及8-羟基鸟嘌呤(8-OH-G),比较各组之间阳性细胞数的差异；③检测肝脏缺血再灌注2,6,12,24小时肝组织炎性细胞因子TNF-a和IL-6 mRNA水平；利用Westernblot的方法分析肝内和血清中内源性损伤蛋白HMGB1的含量；检测肝脏缺血再灌注损伤后内源性损伤蛋白HMGB1在肝细胞中的定位,分析其与肝细胞氧化损伤之间的关联。研究结果：
1.动物实验研究：①与对照组组大鼠相比,缺血前腹腔注射氢气盐溶液再灌注后2,6,12,24小时血清丙氨酸氨基转移酶水平明显降低(P<0.05),其中IRhy-2h降低38.0%,IRhy-6h小时降低44.0%,IRhy-12h降低56.5%,IRhy-24h降低74.8%；同时肝脏组织缺血再灌注6小时后HE染色结果显示治疗组无明显细胞坏死以及中性粒细胞浸润；②与对照组比,缺血前腹腔注射氢气盐溶液再灌注后2,6,12,24小时组织MDA含量也显著降低(P<0.05),其中IRhy-2h降低31.2%,IRhy-6h小时降低42.8%, IRhy-12h降低48.3%,IRhy-24h降低70.5%；同时,治疗组HNE和8-OH-G阳性细胞数较对照组显著减少,P<0.05。
2.分子机制研究：①与对照组相比,治疗组再灌注2,6,12,24小时肝组织中细胞因子TNF-a和IL-6 mRNA水平明显降低,其中TNF-a水平在6h,12h,24h分别较对照组降低25.6%,39.6%,54.6%,P<0.05；IL-6水平在2h,6h,12h,24h分别下降44.6%,39.2%,40.2%,36.6%,P<0.05；②氢气盐溶液组肝脏组织中HMGB1表达较对照组降低,P<0.05,同时循环系统中的HMGB1含量也较对照组显著降低,P<0.05；另外,免疫组织化学显示氢气盐溶液能抑制缺血再灌注诱导的HMGB1表达及释放,仅有少量在胞浆及胞核表达HMGB1的阳性细胞。
结论：本研究显示,腹腔注射10ml/kg氢气盐溶液显著改善肝脏缺血再灌注诱导的肝脏损伤,表现为降低术后血清转氨酶ALT水平,较少肝细胞坏死,降低肝脏组织中细胞因子TNF-a和IL-6 mRNA水平,减轻由肝脏缺血再灌注诱导的局部及全身炎症反应,并且这种保护作用与氢气分子在体内清除毒性自由基,抑制内源性损伤蛋白HMGB1的表达及释放有关。
Backgroud:Hepatic ischemia-reperfusion injury is common in liver surgery, particularly in hepatic transplantation, part lobes of liver resection, hemorrhagic shock and trauma. HIRI is a dynamic process, the mechanism of which has not been clear now. Free oxygen radical release, active pro-inflammatory cytokines expression, calcium overload, microcirculation dysfuction, mitochondrial damage as well as energy metabolism disruption were considered to involve the HIRI pathophysiological procedure. As the most important defensive barrier, hepatic injury induced the endotoxemia with high probability, which in turn aggravate the injured liver to nonfunction, with the result of sepsis as well as multiple organ failure or even to death. The current papers reported that the therapeutic strategies on HIRI mainly aimed at anti-inflammation and antioxidation were proved to be available. Therefore, seeking for an agent with the characteristic of high specificity, mild side reaction, potential clinical application prospect and effective anti-inflammatory and antioxidative action is requisite and significant. Recent papers point out that hydrogen molecule act as an oxygen free radical scavenger to neutralize the cytotoxic hydroxyl radical selectively and hydrogen gas inhalation was demonstrated to protect liver, brain, kindey against ischemia reperfusion injury. Otherwise, for explosion danger of mixed gas, special equipment for inhalation, complex operating sequence, inhalation hydrogen gas is difficult to generalize in clinical. Thus, the suitable therapeutic method need to be further studied. It is calculated theoretically that hydrogen gas could be dissolved to saturation in saline under 0.4 KPa, which is named as hydrogen-enrich saline. The current study was designed to evaluate the protection of this novel agent in hepatic ischemia reperfusion injury and probe the underlying mechanism.
Methods:①Serum alanine aminotransferase level as well as morphological change was detected in rats treated with sham, hepatic ischemia reperfusion only, saline before hepatic IR and hydrogen-enrich saline before hepatic IR respectively to determine the protection of this novel agent in HIRI.②Malondialdehyde level in hepatic tissue was also detedcted to estimate the antioxidation of hydrogen-enrich saline. To further determine the underlying mechanism of cytoprotection of novel fluid, the HNE and 8-OH-G location was detected through immunohistochemistry and the positive percentage was compared among sham, control and therapeutic groups.③Pro-inflammative cytokines levels including TNF-a and IL-6 mRNA levels in hepatic tissue after 2,6,12,24 h reperfusion between control and therpeutic groups was measured. HMGB1 protein expression in hepatic tissue and plasma were detected through westernblot analysis between two groups. Immunohistochemistry was performed to determine HMGB1 location in hepatic tissue.
Results:
1. Study of animal models:Significantly lower serum alanine aminotransferase as well as tissue malondialdehyde level were observed in hydrogen-enrich saline treated animals than controls. Moreover, morphological detetion results showed little necrosis in hydrogen-enrich saline treated animals than controls. Furthermore, HNE and 8-OH-G positive cells were lower in therpeutic animals than controls. Accordingly, the results suggested this that protection is asscoiated with low oxidation result from hydrogen molecule.
2. Study of underlying mechanism:①Compared with controls, animals treated with hydrogen-enrich saline showed the low proinflammatory cytokines mRNA levels in tissue including TNF-a和IL-6.②HMGB1 protein expression both in tissue and blood decreased significantly in compared with controls. Moreover, only a little of HMGB1 was detected inside cells, while abundant positive cells with brown precipitation both in cytoplasm as well as nucleus were detected in controls.
Conclusion:Intraperitoneal injection of hydrogen-enriched saline attenuates hepatic ischemia reperfusion injury, with the characteristic of low serum ALT and little necrotic hepatic cells. Hydrogen-enriched saline play an antioxidative role in hepatic ischemia reperfusion injury, characterized by little peroxdiative hepatocytes and low level of tissue MDA. Moreover, hydrogen-enrich saline prevent HMGB1 and cytokines from expressing as well as releaseing during the period of ischemia reperfusion, with the subsequent of inhibiting inflammatory response.
研究方法：①比较假手术、缺血再灌注、生理盐水+缺血再灌注(对照组)和氢气盐溶液组+缺血再灌注组(治疗组)之间血清中转氨酶以及肝脏组织结构变化的差异,以及各组的MDA含量的差异；②DAB免疫组织化学染色的方法检测氧自由基与细胞内脂质以及DNA反应的产物羟基丙烯醛(HNE)以及8-羟基鸟嘌呤(8-OH-G),比较各组之间阳性细胞数的差异；③检测肝脏缺血再灌注2,6,12,24小时肝组织炎性细胞因子TNF-a和IL-6 mRNA水平；利用Westernblot的方法分析肝内和血清中内源性损伤蛋白HMGB1的含量；检测肝脏缺血再灌注损伤后内源性损伤蛋白HMGB1在肝细胞中的定位,分析其与肝细胞氧化损伤之间的关联。研究结果：
1.动物实验研究：①与对照组组大鼠相比,缺血前腹腔注射氢气盐溶液再灌注后2,6,12,24小时血清丙氨酸氨基转移酶水平明显降低(P<0.05),其中IRhy-2h降低38.0%,IRhy-6h小时降低44.0%,IRhy-12h降低56.5%,IRhy-24h降低74.8%；同时肝脏组织缺血再灌注6小时后HE染色结果显示治疗组无明显细胞坏死以及中性粒细胞浸润；②与对照组比,缺血前腹腔注射氢气盐溶液再灌注后2,6,12,24小时组织MDA含量也显著降低(P<0.05),其中IRhy-2h降低31.2%,IRhy-6h小时降低42.8%, IRhy-12h降低48.3%,IRhy-24h降低70.5%；同时,治疗组HNE和8-OH-G阳性细胞数较对照组显著减少,P<0.05。
2.分子机制研究：①与对照组相比,治疗组再灌注2,6,12,24小时肝组织中细胞因子TNF-a和IL-6 mRNA水平明显降低,其中TNF-a水平在6h,12h,24h分别较对照组降低25.6%,39.6%,54.6%,P<0.05；IL-6水平在2h,6h,12h,24h分别下降44.6%,39.2%,40.2%,36.6%,P<0.05；②氢气盐溶液组肝脏组织中HMGB1表达较对照组降低,P<0.05,同时循环系统中的HMGB1含量也较对照组显著降低,P<0.05；另外,免疫组织化学显示氢气盐溶液能抑制缺血再灌注诱导的HMGB1表达及释放,仅有少量在胞浆及胞核表达HMGB1的阳性细胞。
结论：本研究显示,腹腔注射10ml/kg氢气盐溶液显著改善肝脏缺血再灌注诱导的肝脏损伤,表现为降低术后血清转氨酶ALT水平,较少肝细胞坏死,降低肝脏组织中细胞因子TNF-a和IL-6 mRNA水平,减轻由肝脏缺血再灌注诱导的局部及全身炎症反应,并且这种保护作用与氢气分子在体内清除毒性自由基,抑制内源性损伤蛋白HMGB1的表达及释放有关。
Backgroud:Hepatic ischemia-reperfusion injury is common in liver surgery, particularly in hepatic transplantation, part lobes of liver resection, hemorrhagic shock and trauma. HIRI is a dynamic process, the mechanism of which has not been clear now. Free oxygen radical release, active pro-inflammatory cytokines expression, calcium overload, microcirculation dysfuction, mitochondrial damage as well as energy metabolism disruption were considered to involve the HIRI pathophysiological procedure. As the most important defensive barrier, hepatic injury induced the endotoxemia with high probability, which in turn aggravate the injured liver to nonfunction, with the result of sepsis as well as multiple organ failure or even to death. The current papers reported that the therapeutic strategies on HIRI mainly aimed at anti-inflammation and antioxidation were proved to be available. Therefore, seeking for an agent with the characteristic of high specificity, mild side reaction, potential clinical application prospect and effective anti-inflammatory and antioxidative action is requisite and significant. Recent papers point out that hydrogen molecule act as an oxygen free radical scavenger to neutralize the cytotoxic hydroxyl radical selectively and hydrogen gas inhalation was demonstrated to protect liver, brain, kindey against ischemia reperfusion injury. Otherwise, for explosion danger of mixed gas, special equipment for inhalation, complex operating sequence, inhalation hydrogen gas is difficult to generalize in clinical. Thus, the suitable therapeutic method need to be further studied. It is calculated theoretically that hydrogen gas could be dissolved to saturation in saline under 0.4 KPa, which is named as hydrogen-enrich saline. The current study was designed to evaluate the protection of this novel agent in hepatic ischemia reperfusion injury and probe the underlying mechanism.
Methods:①Serum alanine aminotransferase level as well as morphological change was detected in rats treated with sham, hepatic ischemia reperfusion only, saline before hepatic IR and hydrogen-enrich saline before hepatic IR respectively to determine the protection of this novel agent in HIRI.②Malondialdehyde level in hepatic tissue was also detedcted to estimate the antioxidation of hydrogen-enrich saline. To further determine the underlying mechanism of cytoprotection of novel fluid, the HNE and 8-OH-G location was detected through immunohistochemistry and the positive percentage was compared among sham, control and therapeutic groups.③Pro-inflammative cytokines levels including TNF-a and IL-6 mRNA levels in hepatic tissue after 2,6,12,24 h reperfusion between control and therpeutic groups was measured. HMGB1 protein expression in hepatic tissue and plasma were detected through westernblot analysis between two groups. Immunohistochemistry was performed to determine HMGB1 location in hepatic tissue.
Results:
1. Study of animal models:Significantly lower serum alanine aminotransferase as well as tissue malondialdehyde level were observed in hydrogen-enrich saline treated animals than controls. Moreover, morphological detetion results showed little necrosis in hydrogen-enrich saline treated animals than controls. Furthermore, HNE and 8-OH-G positive cells were lower in therpeutic animals than controls. Accordingly, the results suggested this that protection is asscoiated with low oxidation result from hydrogen molecule.
2. Study of underlying mechanism:①Compared with controls, animals treated with hydrogen-enrich saline showed the low proinflammatory cytokines mRNA levels in tissue including TNF-a和IL-6.②HMGB1 protein expression both in tissue and blood decreased significantly in compared with controls. Moreover, only a little of HMGB1 was detected inside cells, while abundant positive cells with brown precipitation both in cytoplasm as well as nucleus were detected in controls.
Conclusion:Intraperitoneal injection of hydrogen-enriched saline attenuates hepatic ischemia reperfusion injury, with the characteristic of low serum ALT and little necrotic hepatic cells. Hydrogen-enriched saline play an antioxidative role in hepatic ischemia reperfusion injury, characterized by little peroxdiative hepatocytes and low level of tissue MDA. Moreover, hydrogen-enrich saline prevent HMGB1 and cytokines from expressing as well as releaseing during the period of ischemia reperfusion, with the subsequent of inhibiting inflammatory response.
引文
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