七氟醚吸入对急性肺损伤大鼠肺组织HO-1表达的影响及机制初探
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摘要
研究背景
急性肺损伤(acute lung injury,ALI)是临床常见的难治性并发症之一,是由严重感染、各种休克、创伤及外科手术等多种病因所致的肺实质弥漫性损伤,是现代危重病医学的一大难题,其预后差,若不能得到及时有效的治疗,往往会发展成急性呼吸窘迫综合症(ARDS),严重危及患者生命,并耗费大量的医疗资源。ALI致病因素很多,其共同的病理生理改变是肺泡毛细血管内皮细胞、肺泡上皮细胞和肺间质的急性弥漫性损害。ALI的发病机制也错综复杂,至今尚未完全明了。目前大部分观点认为中性粒细胞的活化;炎症因子和炎症介质的大量释放;氧化应激反应;细胞凋亡等在内毒素性肺损伤的发病机制中起了重要的作用,而肺内过度的失控的炎症反应是导致ALI的根本原因。
目前对于ALI,临床上除了在积极去除病因和控制原发病的基础上之外,主要依赖于支持性治疗。呼吸支持治疗已经得到广泛公认,而药物治疗的研究也取得了很多新的进展,其中吸入麻醉药在近几年来已成为一个研究热点。七氟醚由于其具有对气道无刺激性、血中溶解度低、麻醉诱导及苏醒快速平顺的药理特点,已是临床常用的吸入麻醉药之一。有研究认为七氟醚预处理对缺血/再灌注所致ALI具有保护作用,能抑制氧化应激反应,而七氟醚后处理能提高内毒素所致ALI肺组织SOD活性,降低MDA、NO及iNOSmRNA及其蛋白表达,降低肺组织病理损害,这一启动机体内源性保护的作用已初见端倪,但其详细作用机制仍有待进一步探讨。
作为机体重要的内源性保护蛋白血红素氧合酶-1(HO-1)及其催化产物参与多种疾病的病理过程,HO-1活性或基因表达上调进而通过抗氧化、抗炎、抗凋亡等多重机制发挥组织器官保护作用,而抑制HO-1的表达则加重组织器官的损害。在有关HO-1对ALI的影响方面已有诸多探讨,如热应激、缺血预处理、药物预处理以及基因转染等,但这些研究都是模拟出现ALI前采取各种方法诱导肺组织上调HO-1表达来显示保护效应,因此这些保护作用多属于预防性的。如果在ALI发生之后诱导或增加HO-1的表达,是否具有保护作用,或者产生相反的作用?目前有关这方面的研究很少。七氟醚后处理内毒素性ALI是否通过上调HO-1表达,从而抑制炎症介质过度释放和PMN浸润,发挥肺保护作用,目前还不清楚。为此我们设计了本实验,通过内毒素急性肺损伤大鼠模型,探讨应用七氟醚后处理对急性肺损伤的作用以期明确七氟醚治疗ALI的分子生物学机制,为临床治疗性应用提供理论依据。
目的
建立内毒素性ALI大鼠模型,研究大鼠急性肺损伤时,不同浓度七氟醚吸入后处理对肺组织形态学、氧合以及肺组织氧化应激和炎症介质的影响,明确七氟醚具有保护效应的适宜吸入浓度;研究HO-1在七氟醚后处理内毒素诱导大鼠急性肺损伤中的变化及其意义,初步探讨HO-1发挥保护作用的调控机制。
方法
1.选取健康雄性SD大鼠,依文献复制内毒素性ALI大鼠模型:20%乌拉坦1g/kg腹腔注射麻醉后,气管切开,插入导管行机械通气,股静脉缓慢注射LPS 5 mg/kg,对照组注入等量生理盐水,各组于注射后6h行动脉血气分析,放血处死大鼠,取肺组织行组织病理学检查,判断模型是否成功。
2.48只健康雄性SD大鼠行气管切开机械通气,随机分为6组:生理盐水对照组(A组)股静脉注射1ml/kg生理盐水后持续机械通气6h;单纯1.5MAC七氟醚组(B组)股静脉注射1ml/kg生理盐水2h后吸入1.5MAC七氟醚并维持机械通气4h;C、D、E、F四组分别股静脉注射LPS5mg/kg制作ALI模型。C、D、E三组在注射LPS2h后分别吸入1.5MAC、1.0MAC、0.5MAC七氟醚并维持机械通气4h;F组注射LPS后维持机械通气6h。分别记录并监测注射LPS或生理盐水前即刻(T0)、2h后(T1)、6h后(T2)三个时间点MAP、动脉血气。6组大鼠皆于注射LPS或生理盐水6h后取肺组织检测肺组织匀浆SOD、MPO活性和MDA含量;HE染色行肺组织病理学检查;免疫印迹(Western blotting)法检测肺组织ICAM-1、CINC-1蛋白的表达,RT-PCR法检测CINC-1、ICAM-1mRNA的表达。
3.48只健康雄性SD大鼠行气管切开机械通气,随机分为6组:A、C、D、F组分别提前10min股静脉注入生理盐水1ml/kg;生理盐水对照组(A组)股静脉注射1ml/kg生理盐水后持续机械通气6h;ZnPP预处理组(B组)提前10min股静脉注入ZnPP(10 mg/kg,10g·L~(-1)),余同A组;单纯1.0MAC七氟醚吸入组(C组)股静脉注射1ml/kg生理盐水2h后吸入1.0MAC七氟醚并维持机械通气4h;LPS+1.0MAC七氟醚后处理组(D组)股静脉注射LPS5mg/kg2h后吸入1.0MAC七氟醚4h;ZnPP预处理+LPS+1.0MAC七氟醚后处理组(E组)提前10min股静脉注入ZnPP(10 mg/kg,10g·L~(-1)),余同D组;LPS组(F组)股静脉注射LPS5mg/kg后维持机械通气6h。6组大鼠皆于注射LPS或第二次注射生理盐水6h后取肺组织检测肺组织匀浆SOD、MPO活性和MDA含量;HE染色行肺组织病理学检查;Western blotting法检测肺组织ICAM-1、CINC-1、HO-1蛋白的表达,RT-PCR法检测CINC-1、ICAM-1、HO-1mRNA的表达。
4.48只健康雄性SD大鼠行气管切开机械通气,随机分为6组:除B、E两组以PI3K拮抗剂LY294002(1.5mg/kg,1.5g·L~(-1))代替ZnPP预处理外,其余实验步骤以及A、C、D、F组的实验步骤均同第三部分。6组大鼠取肺组织和检测指标除另western blotting法检测PI3K、磷酸化PI3K(iPI3K)、Akt、磷酸化Akt(iAkt)蛋白表达外,余同第三部分。
结果
1.LPS5mg/kg股静脉注射后2h、6h,与基础值和生理盐水对照组比较MAP、PaO2以及氧合指数明显下降(p＜0.05);6h肺组织切片病理形态学改变符合ALI,证明ALI模型复制成功。
2.ALI大鼠肺组织SOD活性明显下降,MDA含量、MPO活性以及ICAM-1、CINC-1mRNA及其蛋白表达明显增高,与盐水对照组比较,差异有统计学意义(p＜0.05);0.5MAC、1.0MAC、1.5MAC七氟醚吸入4h后处理,肺组织病理损害减轻,病理形态学积分下降,SOD活性上升,MDA含量、MPO活性以及ICAM-1、CINC-1mRNA及其蛋白表达降低,以1.0MAC和1.5MAC七氟醚吸入组更明显,与未吸入七氟醚的ALI组比较,差异有统计学意义(p＜0.05);1.5MAC七氟醚吸入组在T2时点MAP下降比1.0MAC七氟醚吸入组更明显(p＜0.05),但在病理形态学积分、SOD、MDA、MPO、ICAM-1、CINC-1mRNA及其蛋白表达等指标方面没有明显差异(p＞0.05);单纯1.5MAC七氟醚吸入除MAP下降外,与盐水对照组比较上述指标没有明显差异。
3.与盐水对照组比较,ALI组肺组织HO-1mRNA及其蛋白表达上调(p＜0.05);与ALI组比较,1.0MAC七氟醚吸入后处理组HO-1mRNA及其蛋白表达进一步上调(p＜0.05);HO-1拮抗剂ZnPP预处理后七氟醚吸入HO-1mRNA及其蛋白表达下调,肺组织病理损害加重,病理形态学积分增加,SOD活性明显下降,MDA含量、MPO活性以及ICAM-1、CINC-1mRNA及其蛋白表达明显增高,与1.0MAC七氟醚吸入后处理组比较,差异有统计学意义(p＜0.05);单纯七氟醚吸入组和单纯ZnPP处理组肺组织HO-1mRNA及其蛋白表达与盐水对照组比较无差异(p＞0.05)。
4.与盐水对照组比较,ALI组肺组织PI3K、Akt无差异(p＞0.05),但iPI3K、iAkt蛋白表达上调(p＜0.05);1.0MAC七氟醚吸入后处理后iPI3K、iAkt蛋白表达进一步上调(p＜0.05);PI3K拮抗剂LY294002预处理的七氟醚吸入后处理组与未用拮抗剂的七氟醚吸入后处理组比较,iPI3K、iAkt蛋白、HO-1mRNA及其蛋白表达下调(p＜0.05),但在肺组织病理形态学积分、SOD、MDA、MPO以及ICAM-1、CINC-1mRNA及其蛋白表达指标方面,无明显差异(p＞0.05)。
结论
1.5mg/kgLPS股静脉注射可诱导SD大鼠产生ALI,氧化应激和炎症反应是ALI的发病机制之一;
2.不同浓度七氟醚吸入后处理能减轻LPS所致ALI氧化应激和炎症反应,其中以1.0MAC七氟醚吸入后处理为较适宜的药物浓度;
3.对已发生的LPS诱导ALI七氟醚后处理可通过上调HO-1mRNA及其蛋白表达起保护作用;
4.内毒素性ALI可引起肺组织PI3K/Akt磷酸化水平提高,同时HO-1mRNA及其蛋白表达上调;
5.PI3K/Akt细胞信号传导通路部分参与了七氟醚对HO-1mRNA及其蛋白表达的调控。
本实验课题的创新点和不足之处
1.创新点
(1)目前临床上导致急性肺损伤最常见原因是脓毒症,本实验采用LPS诱导,2h后再进行药物处理,利用这种最接近临床实际且已经发生ALI的大鼠模型作为研究对象,更具有现实指导意义。
(2)七氟醚作为一种新型麻醉药,其非麻醉方面的器官保护作用已倍受关注,七氟醚预处理在缺血再灌注损伤方面的保护作用已得到证实;而七氟醚的后处理方式以及其对炎症反应所致肺损伤的作用都鲜有研究,本实验证实了七氟醚吸入对脂多糖所致的急性肺损伤具有治疗作用。
(3)热应激、缺血预处理及基因转染等研究都是在诱发ALI前采取各种方法诱导肺组织内源性保护蛋白的表达,如HO-1的表达,因此其保护作用属于预防性的。如果在ALI发生之后诱导或增加HO-1的表达,是否具有保护作用目前尚不明确。本实验研究证实在ALI发生之后诱导或增加HO-1的表达对肺组织亦具保护作用。
(4)本实验通过一条比较完整的信号通路链观察了七氟醚对LPS诱导ALI的作用,并首次探讨了PI3K/Akt信号转导通路对肺组织HO-1的影响。
2.不足之处
(1)由于经费、时间等原因未能完成急性肺损伤有关细胞凋亡及其它可能的机制方面的研究;
(2)组织器官的损伤和保护作用机制涉及众多的信号通路,由于同样的原因,本实验没能对其它可能起作用的信号通路进行研究。
(3)临床部分尚未进行进一步研究和验证。
Background
Acute lung injury(ALI) is one of the refractory complications which is associated with several clinical disorders,including severe sepsis,all kinds of shock,trauma,surgery and so on.Acute lung injury and its more severe form,the acute respiratory distress syndrome(ARDS),are generally refractory to clinical control and have a continuing high morbidity in critical ill patients.Pathogenic factors of ALI is many,but the common pathophysiology disorders are the diffuse injury of the alveolar epithelial cells,endothelial cells and pulmonary interstitial substance.The pathogenesis of ALI is complicated,activated neutrophils accumulated, inflammatory factor and media released,oxidative stress and apoptosis play a key role in lung tissue injury.SIRS is the root cause.
So far,the therapeutic methods for ALI have not been improved. Respiratory support is still one of major methods for treating ALI which based on the treatment of primary disease.Pharmacological treatment especially inhaled anesthetic become a hot research topic at present. Sevoflurane is an inhaled anesthetic agent.Many researches have indicated that sevoflurane has a benefical protective function on lung tissue suffered from ALI.However,the mechanisms of action of sevoflurane on ALI have been not yet clarified.
Heme oxygenase 1(HO-1) represents the inducible isoform of the microsomal HO family.HO-1 gene expression is up-regulated in response to a variety of stimuli and catalyzes the oxidation of heme to biliverdin-IXa,iron,and carbon monoxide.The HO system exerts major antioxidative,antiinflammatory,antiapoptotic,and vasodilatory characteristics.Many efforts have been made to modulate or preinduce HO-1 and to optimize its protective potency against subsequent noxious stimuli.However,most inducers of HO-1(e.g.,oxidative stress,hypoxia, hemin,cobalt chloride,radiation) have numerous side effects and therefore cannot be used in patients.Therefore,it is essential to identify substances or conditions that induce HO-1 without endangering the patient.We recently want to know that the volatile anesthetic sevoflurane is able to specifically up-regulate HO-1 gene expression or not.In the current study,we investigated the actions and mechanisms of sevoflurane post-treatment in ALI induced by LPS.
Objective
The present study was undertaken to assess the protective effects of sevoflurane on LPS-induced acute lung injury(ALI),investigate the influence of sevoflurane with different concentrations on tectology, oxygenation,inflammatory media and oxidative stress of the lung,then determine the conformable concentration.Determine whether the protective effects of sevoflurane on ALI is associated with HO-1.
Methods
1.A rat model of ALI was established according to document, healthy male SD rats anesthetized by intraperitoneal injection of 20%urethane 1g/kg which were tracheotomized and mechanically ventilated,then femoral vein injection of LPS at a dose of 5mg/kg.All groups were sacrificed respectively after 6 hours,lung biopsies were obtained to determine if the model of ALI successed.
2.Forty-eight male SD rats anesthetized by intraperitoneal injection of 20%urethane 1g/kg which were tracheotomized and mechanically ventilated for 30 min were randomly divided into six groups,eight of each,group A(control group) were vena femoralis injected with 1ml/kg saline and continuous ventilated for 6 hours,group B(1.5MACSevo group) were vena femoralis injected 1ml/kg saline,2 hours later inhalated 1.5 MAC and continuous ventilated for 4 hours,group C (LPS+1.5MACSevo group) were vena femoralis injected LPS 5mg/kg,2 hours later inhalated 1.5 MAC and continuous ventilated for 4 hours,group D(LPS+1.0MACSevo group) were vena femoralis injected LPS 5mg/kg,2 hours later inhalated 1.0 MAC and continuous ventilated for 4 hours,group E(LPS+0.5MACSevo group) were vena femoralis injected LPS 5mg/kg,2 hours later inhalated 0.5 MAC and continuous ventilated for 4 hours,group F(LPS group) were vena femoralis injected with LPS 5mg/kg and continuous ventilated for 6 hours.Blood pressure was measured directly from artery during above processes mentioned, mean arterial pressure and arterial blood gas were both measured and recorded at three time points T0(LPS or saline injection rightly before), T1(2 hours after injection),T2(6hours after injection).All groups were sacrificed respectively by losing blood at T2 time point.The dry/wet (D/W) ratio,the activity of superoxide dismutase(SOD) myeloperoxidase (MPO),and malondialdehyde MDA contents in lung tissues were determined and lung biopsies were also obtained.The expression of ICAM-1,CINC-1 mRNA and protein were detected in lung tissue.
3.Forty-eight male SD rats anesthetized by intraperitoneal injection of 20%urethane 1g/kg which were tracheotomized and mechanically ventilated for 20 min were randomly divided into six groups,eight of each,group A(control group),group B(ZnPP group),group C(1.0MACSevo group),group D(LPS+1.0MACSevo group),group E(ZnPP+LPS+1.0MACSevo group),group F(LPS group).rats in group B、E were vena femoralis injected 10mg/kg ZnPP,while 1mg/kg saline in other groups.Ten minutes later,rats in group D、E、F were vena femoralis injected LPS 5mg/kg,while 1mg/kg saline in other groups.Two hours later,1.0 MAC sevoflurane was inhalated for 4 hours continuously in group C、D、E.All groups were sacrificed respectively by losing blood. The dry/wet(D/W) ratio,the activity of superoxide dismutase(SOD) myeloperoxidase(MPO),HO-1 and the contents of malondialdehyde MDA in lung tissues were determined and lung biopsies were also obtained.The expression of ICAM-1,CINC-1,and HO-1 protein was detected by western-blotting while the expression of ICAM-1,CINC-1, and HO-1 mRNA was detected by RT-PCR in lung tissues.
4.Forty-eight male SD rats anesthetized by intraperitoneal injection of 20%urethane 1g/kg which were tracheotomized and mechanically ventilated for 20 min were randomly divided into six groups,eight of each,group A(control group),group B(1.0MACSevo group),group C(LY294002 group),group D(LPS+1.0MACSevo group),group E(LY294002+LPS+1.0MACSevo group),group F(LPS group).Rats in group C、E were vena femoralis injected 10mg/kg LY294002,while 1mg/kg saline in other groups.Ten minutes later,rats in group D、E、F were vena femoralis injected LPS 5mg/kg,while 1mg/kg saline in other groups.Two hours later,1.0 MAC sevoflurane was inhalated for 4 hours continuously in group B、D、E,but not in group A、C、F.All groups were sacrificed respectively by losing blood.The dry/wet(D/W) ratio,the activity of superoxide dismutase(SOD) myeloperoxidase(MPO),HO-1 and the contents of malondialdehyde MDA in lung tissues were determined and lung biopsies were also obtained.The expression of ICAM-1,CINC-1,HO-1,PI3K,piPA3K,Akt,piAkt protein was detected by western-blotting while the expression of ICAM-1,CINC-1,and HO-1 mRNA was detected by RT-PCR in lung tissues.
Results
1.Compared with control group,PaO2、MAP and oxygenation index decreased in group LPS despite at 2 or 6 h,the lung biopsies at 6h prove the model of ALI is successed.
2.Compare to group A(control group),SOD activity was obvious decreased,while MPO activity and MDA content were increased in lung homogenates of group C(LPS+1.5MACSevo group)、D(LPS+1.0MACSevo group)、E(LPS+0.5MACSevo group)、F(LPS group)(p＜0.05),moreover the expression of ICAM-1,CINC-1 mRNA and protein were increased in lung tissues of group C、D、E、F too(p＜0.05).Compared to group F,SOD activity was increased while MPO activity,MDA content and the expression of ICAM-1,CINC-1 mRNA and protein were decreased in group C、D、E(p＜0.05),especially in group C and D,the difference between group C and group D was not significant except MAP in T2.Group B(1.5MACSevo group) were not obvious different from group A except MAP.
3.The activity of HO-1,expression of HO-1 mRNA and protein in group F(LPS group) were higher than group A(control group)(p＜0.05), while these in group D(LPS+1.0MACSevo group) were higher than group F(p＜0.05),the activity of HO-1,expression of HO-1 mRNA and protein in group E(ZnPP +LPS+1.0MACSevo group) were lower than group D(p＜0.05).HO-1 mRNA and protein in group B(ZnPP group),and group C(1.0MACSevo group) were not obvious different from group A (p＞0.05).
4.The activity of HO-1,expression of HO-1 mRNA and protein, piPA3K、piAkt protein in group F(LPS group) were higher than group A(control group)(p＜0.05),while these in group D(LPS+1.0MACSevo group) were higher than group F(p＜0.05),the activity of HO-1, expression of HO-1 mRNA and protein piPA3K、piAkt protein in group E(LY294002+LPS+1.0MACSevo group) were lower than group D (p＜0.05),but the differences of pathologic change,SOD,MDA,MPO,the expression of ICAM-1 and CINC-1 were not statically significant(p＞0.05).
Conclusion
1.Vena femoralis injected LPS 5mg/kg could induce ALI in rats. Oxidative stress and inflammatory reaction involved in pathogenesis of ALI.
2.Sevoflurane post-treatment with different concentrations, especially 1.0MAC sevoflurane post-treatment could decrease oxidative stress and inflammatory reaction in ALI induced by LPS.
3.The protective effect of sevoflurane post-treatment on LPS-induced ALI were produced by uptaking of HO-1 activity,HO-1 mRNA and protein expression.
4.The phosphorylation of PI3K/AKT signal transduction pathway, the increase of HO-1 activity,expression of HO-1 mRNA and protein involved in acute lung injury induced by endotoxin.
5.Effect of sevoflurane on protection of HO-1 on LPS-induced ALI was partly mediated by PI3K/AKT signal transduction pathway.
急性肺损伤(acute lung injury,ALI)是临床常见的难治性并发症之一,是由严重感染、各种休克、创伤及外科手术等多种病因所致的肺实质弥漫性损伤,是现代危重病医学的一大难题,其预后差,若不能得到及时有效的治疗,往往会发展成急性呼吸窘迫综合症(ARDS),严重危及患者生命,并耗费大量的医疗资源。ALI致病因素很多,其共同的病理生理改变是肺泡毛细血管内皮细胞、肺泡上皮细胞和肺间质的急性弥漫性损害。ALI的发病机制也错综复杂,至今尚未完全明了。目前大部分观点认为中性粒细胞的活化;炎症因子和炎症介质的大量释放;氧化应激反应;细胞凋亡等在内毒素性肺损伤的发病机制中起了重要的作用,而肺内过度的失控的炎症反应是导致ALI的根本原因。
目前对于ALI,临床上除了在积极去除病因和控制原发病的基础上之外,主要依赖于支持性治疗。呼吸支持治疗已经得到广泛公认,而药物治疗的研究也取得了很多新的进展,其中吸入麻醉药在近几年来已成为一个研究热点。七氟醚由于其具有对气道无刺激性、血中溶解度低、麻醉诱导及苏醒快速平顺的药理特点,已是临床常用的吸入麻醉药之一。有研究认为七氟醚预处理对缺血/再灌注所致ALI具有保护作用,能抑制氧化应激反应,而七氟醚后处理能提高内毒素所致ALI肺组织SOD活性,降低MDA、NO及iNOSmRNA及其蛋白表达,降低肺组织病理损害,这一启动机体内源性保护的作用已初见端倪,但其详细作用机制仍有待进一步探讨。
作为机体重要的内源性保护蛋白血红素氧合酶-1(HO-1)及其催化产物参与多种疾病的病理过程,HO-1活性或基因表达上调进而通过抗氧化、抗炎、抗凋亡等多重机制发挥组织器官保护作用,而抑制HO-1的表达则加重组织器官的损害。在有关HO-1对ALI的影响方面已有诸多探讨,如热应激、缺血预处理、药物预处理以及基因转染等,但这些研究都是模拟出现ALI前采取各种方法诱导肺组织上调HO-1表达来显示保护效应,因此这些保护作用多属于预防性的。如果在ALI发生之后诱导或增加HO-1的表达,是否具有保护作用,或者产生相反的作用?目前有关这方面的研究很少。七氟醚后处理内毒素性ALI是否通过上调HO-1表达,从而抑制炎症介质过度释放和PMN浸润,发挥肺保护作用,目前还不清楚。为此我们设计了本实验,通过内毒素急性肺损伤大鼠模型,探讨应用七氟醚后处理对急性肺损伤的作用以期明确七氟醚治疗ALI的分子生物学机制,为临床治疗性应用提供理论依据。
目的
建立内毒素性ALI大鼠模型,研究大鼠急性肺损伤时,不同浓度七氟醚吸入后处理对肺组织形态学、氧合以及肺组织氧化应激和炎症介质的影响,明确七氟醚具有保护效应的适宜吸入浓度;研究HO-1在七氟醚后处理内毒素诱导大鼠急性肺损伤中的变化及其意义,初步探讨HO-1发挥保护作用的调控机制。
方法
1.选取健康雄性SD大鼠,依文献复制内毒素性ALI大鼠模型:20%乌拉坦1g/kg腹腔注射麻醉后,气管切开,插入导管行机械通气,股静脉缓慢注射LPS 5 mg/kg,对照组注入等量生理盐水,各组于注射后6h行动脉血气分析,放血处死大鼠,取肺组织行组织病理学检查,判断模型是否成功。
2.48只健康雄性SD大鼠行气管切开机械通气,随机分为6组:生理盐水对照组(A组)股静脉注射1ml/kg生理盐水后持续机械通气6h;单纯1.5MAC七氟醚组(B组)股静脉注射1ml/kg生理盐水2h后吸入1.5MAC七氟醚并维持机械通气4h;C、D、E、F四组分别股静脉注射LPS5mg/kg制作ALI模型。C、D、E三组在注射LPS2h后分别吸入1.5MAC、1.0MAC、0.5MAC七氟醚并维持机械通气4h;F组注射LPS后维持机械通气6h。分别记录并监测注射LPS或生理盐水前即刻(T0)、2h后(T1)、6h后(T2)三个时间点MAP、动脉血气。6组大鼠皆于注射LPS或生理盐水6h后取肺组织检测肺组织匀浆SOD、MPO活性和MDA含量;HE染色行肺组织病理学检查;免疫印迹(Western blotting)法检测肺组织ICAM-1、CINC-1蛋白的表达,RT-PCR法检测CINC-1、ICAM-1mRNA的表达。
3.48只健康雄性SD大鼠行气管切开机械通气,随机分为6组:A、C、D、F组分别提前10min股静脉注入生理盐水1ml/kg;生理盐水对照组(A组)股静脉注射1ml/kg生理盐水后持续机械通气6h;ZnPP预处理组(B组)提前10min股静脉注入ZnPP(10 mg/kg,10g·L~(-1)),余同A组;单纯1.0MAC七氟醚吸入组(C组)股静脉注射1ml/kg生理盐水2h后吸入1.0MAC七氟醚并维持机械通气4h;LPS+1.0MAC七氟醚后处理组(D组)股静脉注射LPS5mg/kg2h后吸入1.0MAC七氟醚4h;ZnPP预处理+LPS+1.0MAC七氟醚后处理组(E组)提前10min股静脉注入ZnPP(10 mg/kg,10g·L~(-1)),余同D组;LPS组(F组)股静脉注射LPS5mg/kg后维持机械通气6h。6组大鼠皆于注射LPS或第二次注射生理盐水6h后取肺组织检测肺组织匀浆SOD、MPO活性和MDA含量;HE染色行肺组织病理学检查;Western blotting法检测肺组织ICAM-1、CINC-1、HO-1蛋白的表达,RT-PCR法检测CINC-1、ICAM-1、HO-1mRNA的表达。
4.48只健康雄性SD大鼠行气管切开机械通气,随机分为6组:除B、E两组以PI3K拮抗剂LY294002(1.5mg/kg,1.5g·L~(-1))代替ZnPP预处理外,其余实验步骤以及A、C、D、F组的实验步骤均同第三部分。6组大鼠取肺组织和检测指标除另western blotting法检测PI3K、磷酸化PI3K(iPI3K)、Akt、磷酸化Akt(iAkt)蛋白表达外,余同第三部分。
结果
1.LPS5mg/kg股静脉注射后2h、6h,与基础值和生理盐水对照组比较MAP、PaO2以及氧合指数明显下降(p＜0.05);6h肺组织切片病理形态学改变符合ALI,证明ALI模型复制成功。
2.ALI大鼠肺组织SOD活性明显下降,MDA含量、MPO活性以及ICAM-1、CINC-1mRNA及其蛋白表达明显增高,与盐水对照组比较,差异有统计学意义(p＜0.05);0.5MAC、1.0MAC、1.5MAC七氟醚吸入4h后处理,肺组织病理损害减轻,病理形态学积分下降,SOD活性上升,MDA含量、MPO活性以及ICAM-1、CINC-1mRNA及其蛋白表达降低,以1.0MAC和1.5MAC七氟醚吸入组更明显,与未吸入七氟醚的ALI组比较,差异有统计学意义(p＜0.05);1.5MAC七氟醚吸入组在T2时点MAP下降比1.0MAC七氟醚吸入组更明显(p＜0.05),但在病理形态学积分、SOD、MDA、MPO、ICAM-1、CINC-1mRNA及其蛋白表达等指标方面没有明显差异(p＞0.05);单纯1.5MAC七氟醚吸入除MAP下降外,与盐水对照组比较上述指标没有明显差异。
3.与盐水对照组比较,ALI组肺组织HO-1mRNA及其蛋白表达上调(p＜0.05);与ALI组比较,1.0MAC七氟醚吸入后处理组HO-1mRNA及其蛋白表达进一步上调(p＜0.05);HO-1拮抗剂ZnPP预处理后七氟醚吸入HO-1mRNA及其蛋白表达下调,肺组织病理损害加重,病理形态学积分增加,SOD活性明显下降,MDA含量、MPO活性以及ICAM-1、CINC-1mRNA及其蛋白表达明显增高,与1.0MAC七氟醚吸入后处理组比较,差异有统计学意义(p＜0.05);单纯七氟醚吸入组和单纯ZnPP处理组肺组织HO-1mRNA及其蛋白表达与盐水对照组比较无差异(p＞0.05)。
4.与盐水对照组比较,ALI组肺组织PI3K、Akt无差异(p＞0.05),但iPI3K、iAkt蛋白表达上调(p＜0.05);1.0MAC七氟醚吸入后处理后iPI3K、iAkt蛋白表达进一步上调(p＜0.05);PI3K拮抗剂LY294002预处理的七氟醚吸入后处理组与未用拮抗剂的七氟醚吸入后处理组比较,iPI3K、iAkt蛋白、HO-1mRNA及其蛋白表达下调(p＜0.05),但在肺组织病理形态学积分、SOD、MDA、MPO以及ICAM-1、CINC-1mRNA及其蛋白表达指标方面,无明显差异(p＞0.05)。
结论
1.5mg/kgLPS股静脉注射可诱导SD大鼠产生ALI,氧化应激和炎症反应是ALI的发病机制之一;
2.不同浓度七氟醚吸入后处理能减轻LPS所致ALI氧化应激和炎症反应,其中以1.0MAC七氟醚吸入后处理为较适宜的药物浓度;
3.对已发生的LPS诱导ALI七氟醚后处理可通过上调HO-1mRNA及其蛋白表达起保护作用;
4.内毒素性ALI可引起肺组织PI3K/Akt磷酸化水平提高,同时HO-1mRNA及其蛋白表达上调;
5.PI3K/Akt细胞信号传导通路部分参与了七氟醚对HO-1mRNA及其蛋白表达的调控。
本实验课题的创新点和不足之处
1.创新点
(1)目前临床上导致急性肺损伤最常见原因是脓毒症,本实验采用LPS诱导,2h后再进行药物处理,利用这种最接近临床实际且已经发生ALI的大鼠模型作为研究对象,更具有现实指导意义。
(2)七氟醚作为一种新型麻醉药,其非麻醉方面的器官保护作用已倍受关注,七氟醚预处理在缺血再灌注损伤方面的保护作用已得到证实;而七氟醚的后处理方式以及其对炎症反应所致肺损伤的作用都鲜有研究,本实验证实了七氟醚吸入对脂多糖所致的急性肺损伤具有治疗作用。
(3)热应激、缺血预处理及基因转染等研究都是在诱发ALI前采取各种方法诱导肺组织内源性保护蛋白的表达,如HO-1的表达,因此其保护作用属于预防性的。如果在ALI发生之后诱导或增加HO-1的表达,是否具有保护作用目前尚不明确。本实验研究证实在ALI发生之后诱导或增加HO-1的表达对肺组织亦具保护作用。
(4)本实验通过一条比较完整的信号通路链观察了七氟醚对LPS诱导ALI的作用,并首次探讨了PI3K/Akt信号转导通路对肺组织HO-1的影响。
2.不足之处
(1)由于经费、时间等原因未能完成急性肺损伤有关细胞凋亡及其它可能的机制方面的研究;
(2)组织器官的损伤和保护作用机制涉及众多的信号通路,由于同样的原因,本实验没能对其它可能起作用的信号通路进行研究。
(3)临床部分尚未进行进一步研究和验证。
Background
Acute lung injury(ALI) is one of the refractory complications which is associated with several clinical disorders,including severe sepsis,all kinds of shock,trauma,surgery and so on.Acute lung injury and its more severe form,the acute respiratory distress syndrome(ARDS),are generally refractory to clinical control and have a continuing high morbidity in critical ill patients.Pathogenic factors of ALI is many,but the common pathophysiology disorders are the diffuse injury of the alveolar epithelial cells,endothelial cells and pulmonary interstitial substance.The pathogenesis of ALI is complicated,activated neutrophils accumulated, inflammatory factor and media released,oxidative stress and apoptosis play a key role in lung tissue injury.SIRS is the root cause.
So far,the therapeutic methods for ALI have not been improved. Respiratory support is still one of major methods for treating ALI which based on the treatment of primary disease.Pharmacological treatment especially inhaled anesthetic become a hot research topic at present. Sevoflurane is an inhaled anesthetic agent.Many researches have indicated that sevoflurane has a benefical protective function on lung tissue suffered from ALI.However,the mechanisms of action of sevoflurane on ALI have been not yet clarified.
Heme oxygenase 1(HO-1) represents the inducible isoform of the microsomal HO family.HO-1 gene expression is up-regulated in response to a variety of stimuli and catalyzes the oxidation of heme to biliverdin-IXa,iron,and carbon monoxide.The HO system exerts major antioxidative,antiinflammatory,antiapoptotic,and vasodilatory characteristics.Many efforts have been made to modulate or preinduce HO-1 and to optimize its protective potency against subsequent noxious stimuli.However,most inducers of HO-1(e.g.,oxidative stress,hypoxia, hemin,cobalt chloride,radiation) have numerous side effects and therefore cannot be used in patients.Therefore,it is essential to identify substances or conditions that induce HO-1 without endangering the patient.We recently want to know that the volatile anesthetic sevoflurane is able to specifically up-regulate HO-1 gene expression or not.In the current study,we investigated the actions and mechanisms of sevoflurane post-treatment in ALI induced by LPS.
Objective
The present study was undertaken to assess the protective effects of sevoflurane on LPS-induced acute lung injury(ALI),investigate the influence of sevoflurane with different concentrations on tectology, oxygenation,inflammatory media and oxidative stress of the lung,then determine the conformable concentration.Determine whether the protective effects of sevoflurane on ALI is associated with HO-1.
Methods
1.A rat model of ALI was established according to document, healthy male SD rats anesthetized by intraperitoneal injection of 20%urethane 1g/kg which were tracheotomized and mechanically ventilated,then femoral vein injection of LPS at a dose of 5mg/kg.All groups were sacrificed respectively after 6 hours,lung biopsies were obtained to determine if the model of ALI successed.
2.Forty-eight male SD rats anesthetized by intraperitoneal injection of 20%urethane 1g/kg which were tracheotomized and mechanically ventilated for 30 min were randomly divided into six groups,eight of each,group A(control group) were vena femoralis injected with 1ml/kg saline and continuous ventilated for 6 hours,group B(1.5MACSevo group) were vena femoralis injected 1ml/kg saline,2 hours later inhalated 1.5 MAC and continuous ventilated for 4 hours,group C (LPS+1.5MACSevo group) were vena femoralis injected LPS 5mg/kg,2 hours later inhalated 1.5 MAC and continuous ventilated for 4 hours,group D(LPS+1.0MACSevo group) were vena femoralis injected LPS 5mg/kg,2 hours later inhalated 1.0 MAC and continuous ventilated for 4 hours,group E(LPS+0.5MACSevo group) were vena femoralis injected LPS 5mg/kg,2 hours later inhalated 0.5 MAC and continuous ventilated for 4 hours,group F(LPS group) were vena femoralis injected with LPS 5mg/kg and continuous ventilated for 6 hours.Blood pressure was measured directly from artery during above processes mentioned, mean arterial pressure and arterial blood gas were both measured and recorded at three time points T0(LPS or saline injection rightly before), T1(2 hours after injection),T2(6hours after injection).All groups were sacrificed respectively by losing blood at T2 time point.The dry/wet (D/W) ratio,the activity of superoxide dismutase(SOD) myeloperoxidase (MPO),and malondialdehyde MDA contents in lung tissues were determined and lung biopsies were also obtained.The expression of ICAM-1,CINC-1 mRNA and protein were detected in lung tissue.
3.Forty-eight male SD rats anesthetized by intraperitoneal injection of 20%urethane 1g/kg which were tracheotomized and mechanically ventilated for 20 min were randomly divided into six groups,eight of each,group A(control group),group B(ZnPP group),group C(1.0MACSevo group),group D(LPS+1.0MACSevo group),group E(ZnPP+LPS+1.0MACSevo group),group F(LPS group).rats in group B、E were vena femoralis injected 10mg/kg ZnPP,while 1mg/kg saline in other groups.Ten minutes later,rats in group D、E、F were vena femoralis injected LPS 5mg/kg,while 1mg/kg saline in other groups.Two hours later,1.0 MAC sevoflurane was inhalated for 4 hours continuously in group C、D、E.All groups were sacrificed respectively by losing blood. The dry/wet(D/W) ratio,the activity of superoxide dismutase(SOD) myeloperoxidase(MPO),HO-1 and the contents of malondialdehyde MDA in lung tissues were determined and lung biopsies were also obtained.The expression of ICAM-1,CINC-1,and HO-1 protein was detected by western-blotting while the expression of ICAM-1,CINC-1, and HO-1 mRNA was detected by RT-PCR in lung tissues.
4.Forty-eight male SD rats anesthetized by intraperitoneal injection of 20%urethane 1g/kg which were tracheotomized and mechanically ventilated for 20 min were randomly divided into six groups,eight of each,group A(control group),group B(1.0MACSevo group),group C(LY294002 group),group D(LPS+1.0MACSevo group),group E(LY294002+LPS+1.0MACSevo group),group F(LPS group).Rats in group C、E were vena femoralis injected 10mg/kg LY294002,while 1mg/kg saline in other groups.Ten minutes later,rats in group D、E、F were vena femoralis injected LPS 5mg/kg,while 1mg/kg saline in other groups.Two hours later,1.0 MAC sevoflurane was inhalated for 4 hours continuously in group B、D、E,but not in group A、C、F.All groups were sacrificed respectively by losing blood.The dry/wet(D/W) ratio,the activity of superoxide dismutase(SOD) myeloperoxidase(MPO),HO-1 and the contents of malondialdehyde MDA in lung tissues were determined and lung biopsies were also obtained.The expression of ICAM-1,CINC-1,HO-1,PI3K,piPA3K,Akt,piAkt protein was detected by western-blotting while the expression of ICAM-1,CINC-1,and HO-1 mRNA was detected by RT-PCR in lung tissues.
Results
1.Compared with control group,PaO2、MAP and oxygenation index decreased in group LPS despite at 2 or 6 h,the lung biopsies at 6h prove the model of ALI is successed.
2.Compare to group A(control group),SOD activity was obvious decreased,while MPO activity and MDA content were increased in lung homogenates of group C(LPS+1.5MACSevo group)、D(LPS+1.0MACSevo group)、E(LPS+0.5MACSevo group)、F(LPS group)(p＜0.05),moreover the expression of ICAM-1,CINC-1 mRNA and protein were increased in lung tissues of group C、D、E、F too(p＜0.05).Compared to group F,SOD activity was increased while MPO activity,MDA content and the expression of ICAM-1,CINC-1 mRNA and protein were decreased in group C、D、E(p＜0.05),especially in group C and D,the difference between group C and group D was not significant except MAP in T2.Group B(1.5MACSevo group) were not obvious different from group A except MAP.
3.The activity of HO-1,expression of HO-1 mRNA and protein in group F(LPS group) were higher than group A(control group)(p＜0.05), while these in group D(LPS+1.0MACSevo group) were higher than group F(p＜0.05),the activity of HO-1,expression of HO-1 mRNA and protein in group E(ZnPP +LPS+1.0MACSevo group) were lower than group D(p＜0.05).HO-1 mRNA and protein in group B(ZnPP group),and group C(1.0MACSevo group) were not obvious different from group A (p＞0.05).
4.The activity of HO-1,expression of HO-1 mRNA and protein, piPA3K、piAkt protein in group F(LPS group) were higher than group A(control group)(p＜0.05),while these in group D(LPS+1.0MACSevo group) were higher than group F(p＜0.05),the activity of HO-1, expression of HO-1 mRNA and protein piPA3K、piAkt protein in group E(LY294002+LPS+1.0MACSevo group) were lower than group D (p＜0.05),but the differences of pathologic change,SOD,MDA,MPO,the expression of ICAM-1 and CINC-1 were not statically significant(p＞0.05).
Conclusion
1.Vena femoralis injected LPS 5mg/kg could induce ALI in rats. Oxidative stress and inflammatory reaction involved in pathogenesis of ALI.
2.Sevoflurane post-treatment with different concentrations, especially 1.0MAC sevoflurane post-treatment could decrease oxidative stress and inflammatory reaction in ALI induced by LPS.
3.The protective effect of sevoflurane post-treatment on LPS-induced ALI were produced by uptaking of HO-1 activity,HO-1 mRNA and protein expression.
4.The phosphorylation of PI3K/AKT signal transduction pathway, the increase of HO-1 activity,expression of HO-1 mRNA and protein involved in acute lung injury induced by endotoxin.
5.Effect of sevoflurane on protection of HO-1 on LPS-induced ALI was partly mediated by PI3K/AKT signal transduction pathway.
引文
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