氧化苦参碱对感染性休克大鼠心肺组织的保护作用
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摘要
目的本实验在盲肠节扎穿孔法(cecal ligation and puncture,CLP)复制大鼠感染性休克(septic shock)模型的基础上,给予氧化苦参碱(oxymatrine,OMT)注射液进行干预,旨在:1.观察OMT对肺组织NF-κB通路的影响并分析其可能的作用机制;2.从心肌细胞能量代谢、心肌及线粒体(mitochondrion,Mit)超微结构和钙超载等方面,对感染性休克大鼠心功能、心肌Mit结构和功能的改变及OMT对其保护作用进行较深入的研究。揭示OMT对感染性休克大鼠心、肺功能的保护作用及其机制,为临床上感染性休克的防治及OMT药理作用的研究与临床应用提供基础实验依据。方法采用CLP法复制大鼠感染性休克动物模型,随机将56只雄性、SD大鼠分为假手术组、OMT对照组、模型(CLP)组、CLP + OMT高、中、低剂量组、阳性对照(CLP+地塞米松)组。观察OMT对感染性休克大鼠血气、肺组织W/D比值、肺系数、肺含水量等指标及肺组织病理学改变(大体改变及肺病理组织切片)的影响,并采用免疫组化法检测肺组织NF-κB(p65)及IκB-α的活性,放射免疫分析法测定肺组织匀浆中肿瘤坏死因子-a(tumour necrosis factor-α,TNF-α)及白细胞介素-6(Interleukin-6,IL-6)蛋白含量的改变。同时,观察OMT对感染性休克大鼠各项心功能参数的影响。比色法测定各组大鼠血浆乳酸脱氢酶(lactic dehydrogenase,LDH)的活性和心肌组织琥珀酸脱氢酶(succinic dehydrogenase,SDH)活性以及心肌钙含量。制备心肌组织光镜标本及心肌电镜标本,观察心肌组织病理学及超微结构的改变。结果与假手术组比较:模型组大鼠肺组织NF-κB(p65)及IκB-α的表达明显升高(均P<0.05),并与TNF-a及IL-6含量的上升相一致(TNF-α及IL-6含量分别增加205%和242%)。同时动脉血PaO2及SaO2值分别下降34%和23%(P<0.01);PaCO2增加30%(P<0.05),HCO3-增加31%(P<0.05);肺组织W/D比值、肺系数及肺含水量分别增加36%、34%和11%(均P<0.05),肺组织充血、水肿、中性粒细胞大量浸润及透明膜形成,提示肺组织结构及肺通气/换气功能严重受损。在给予不同剂量的OMT干预后,OMT能显著抑制肺组织NF-κB(p65)及IκB-α的活性(P<0.05),降低肺组织匀浆中TNF-α及IL-6的含量(TNF-αP<0.05;IL-6 P<0.01),提高动脉血PaO2、SaO2含量(均P<0.05),降低PaCO2、HCO3-含量(均P<0.05);降低肺组织W/D比值、肺系数及肺含水量(均P<0.05);并减轻肺组织充血、水肿和中性粒细胞大量浸润及透明膜形成等炎症反应,并且该作用在OMT-高、中剂量组与阳性对照(CLP+地塞米松组)组的结果相一致。
同时,模型组大鼠心肌组织光镜下可见心内膜下广泛的心肌结构紊乱;大范围的炎性细胞浸润,多为单核细胞,间杂有少量淋巴细胞和中性粒细胞,也可见毛细血管扩张、出血;间质水肿及成纤维细胞增殖;不同程度的细胞坏死和组织纤维化。超微结构表现为:线粒体显著肿胀,内膜和外膜的完整性明显受到破坏,嵴模糊紊乱,数量减少,融合破坏,部分嵴消失或空泡化,破裂的膜形成小泡或空泡,线粒体内腔扩大,出现无定型电子致密性颗粒,甚至断裂、溶解或消失,内容物溢出,基质模糊不清,并可见破碎线粒体。同时可见心肌纤维排列紊乱,有溶解和空泡形成;胞核固缩明显,染色质边集;闰盘不连续,有断裂、溶解。同假手术组相比,模型组大鼠HR增加15%(P<0.01)、LVEDP增加47%(P<0.01);MAP降低33%、LVSP减少24%、LVdp/dtmax减少38%、-LVdp/dtmax减少32%(均P<0.01);血浆LDH活性增加35%(P<0.01);心肌组织SDH活性下降28%(P<0.01);钙含量增加34%(P<0.01)。在给予不同剂量的OMT干预后,心肌损伤有不同程度的减轻,表现为心肌结构基本正常,水肿及变性、坏死等改变明显减轻,但仍伴有少量的炎性细胞浸润及渗出等改变。电镜下可见心肌纤维排列正常,胞核损伤有不同程度的减轻等。心肌线粒体损伤程度有不同程度的减轻,多数线粒体结构较完整,嵴致密,排列较整齐,部分嵴模糊,排列尚规则,线粒体肿胀减轻,少数线粒体的损伤尚未完全恢复,以CLP+OMT-低剂量组表现最为明显。同时,OMT+CLP-高剂量组及OMT+CLP-中剂量组HR、LVEDP明显降低;MAP、LVSP、LVdp/dtmax等明显升高;-LVdp/dtmax增加(均P<0.01)。血浆LDH活性降低(P<0.01);心肌组织SDH活性升高(P<0.01);钙含量减少(P<0.01)。OMT+CLP-低剂量组只有MAP、±LVdp/dtmax、血浆LDH活性及心肌组织SDH活性等指标明显改善(P<0.01或P<0.05),而HR、LVEDP、LVSP及心肌组织钙含量等无明显改善(均P>0.05)。OMT+地塞米松组与假手术组比较各指标均无明显差异;与模型组比较上述各指标均有明显改善(均P<0.01);与CLP +OMT-高、中剂量组比较各指标均无明显差异(均P>0.05);与CLP +OMT-低剂量组比较各指标均有明显差异(均P<0.05)。结论1.氧化苦参碱能够抑制NF-κB的活化,减少促炎因子(TNF-α,IL-6)的生成,对感染性休克大鼠肺损伤性病变起到保护作用。该作用可能与氧化苦参碱抑制细菌、病毒、LPS等对NIK的活化有关。2.氧化苦参碱具有保护感染性休克大鼠心肌及其线粒体结构和功能完整性、减轻心功能损害的作用,其机制与氧化苦参碱改善感染性休克过程中心肌细胞能量代谢状况,减少心肌细胞内钙超载有关。3.氧化苦参碱高、中剂量组能够有效地改善感染性休克大鼠心肺功能,该作用与地塞米松对感染性休克大鼠心肺功能的保护作用相一致。
Objective The septic shock model was produced by cecal ligation and puncture(CLP), the purpose of this study was explored the protective effect of oxymatrine(omt) against NF-κB pathway in lung tissue and performed to investigate the protective mechanism of oxymatrine on myocardium mitochondrial energy metabolism, cardiac function, myocardial mitochondria ultrastructure changes and calcium overload in rats with septic shock. Revealing the protective effect and mechanism of oxymatrine on the heart and lung tissues in rats with septic shock. Therefore to provide reliable strategies for researching the pharmacologic action, clinical application to this praeparatum and the prevention and therapy of septic shock in the clinic. Methods Using a septic shock model produced by CLP, fifty-six male SD rats were randomly divided into 7 groups: sham operation group, OMT control group, model (CLP)group, CLP+OMT high, middle, low-dose group, positive control (CLP+ Dexamethasone) group. Then to observe the effect of oxymatrine on blood gas, the ratio between wet weight of the lung and dry weight of the lung(W/D), pulmonary coefficient and pulmonary moisture capacity, gross changes and pathological changes examined with lightmicroscope in the pulmonary tissue. Changes in NF-κB(p65) and IkB-αactivity in the pulmonary tissue were determined by immunohistochemical method,tumour necrosis factor-a(TNF-α) and interleukin-6(IL-6) levels in pulmonary tissue were determined by radioimmunoassay. Meanwhile, to observe the changes of pathological and ultrastructural organization with lightmicroscope and electron microscope in the cardiac muscle tissue.and to observe the effect of oxymatrine on heart function. Changes in plasma lactic dehydrogenase(LDH) , succinic dehydrogenase(SDH) and calcium content in the cardiac muscle tissue activity were determined by colorimetric method. Results In model group, The NF-κB(p65) and IkB-αactivity in the pulmonary tissue were advanced obviously(all P<0.05), and that results equal pace with the changes of the TNF-αand IL-6(the content of TNF-αand IL-6 increased respectively 205% and 242%). Meanwhile, PaO2 and SaO2 decreased respectivel 34% and 23% (all P<0.01). PaCO2 increased 30%(P<0.05). HCO3- increased 31%(P<0.05). W/D, pulmonary coefficient and pulmonary moisture capacity increased respectively 36%, 34% and 11%(all P<0.05). And observed that pulmonary hyperemia, edema, infiltrate of heterophil granulocyte and emerge of asphyxial membrane, this explain that pulmonary structure, lung ventilation/ gas exchange function were damaged Severity. After interfered in OMT, OMT could decrease significantly the NF-κB(p65) and IkB-αactivity in the pulmonary tissue(all P<0.05), TNF-αand IL-6 levels in pulmonary tissue homogenate decreased markedly(TNF-αP<0.05, IL-6 P<0.01). OMT could elevate the content of PaO2, SaO2(P<0.05), decrease the content of PaCO2, HCO3-(P<0.05) and decrease the W/D and the pulmonary coefficient and pulmonary moisture capacity(all P<0.05). improve the condition of pulmonary hyperemia, edema, infiltrate of heterophil granulocyte and emerge of asphyxial membrane, alleviate the inflammatory reaction. and that results equal pace with the positive control(CLP+Dexamethasone) group.
The pathological histology showed severe cardiac muscle derangement, inflammatory cell infiltrate wide-ranging, much of them is mononuclear cell and a few is lymphocyte or neutrophil in model group. That also showed telangiectasis and hemorrhage, interstitial edema, fibroblast proliferation, cell necrosis and tissue fibrosis. The ultrastructure showed that mitochondrion intumesced, intimal and adventitial integrity were demolished obviously, some crista confused and amount were reduced, the other were vanished or vacuolization. Inner mitochondrial space enlarged, showed up some electron-dense particles, and breaking mitochondria. Meanwhile, cardiac muscle fiber aligned confused, dissolved and formed some vacuoles, pyknosis obviously, chromatin margination, intercalated disk asynechiaed or dissolved. Compared with the normal control, HR increased 15%(P<0.01), LVEDP increased 47%(P<0.01), MAP decreased 33%, LVSP decreased 24%, LVdp/dtmax decreased 38%, - LVdp/dtmax negative value decreased 32%(all P<0.01). LDH activity in blood plasma increased 35%(P<0.01), SDH activity in cardiac muscle decreased 28%(P<0.01), calcium contents in cardiac muscle increased 34%(P<0.01). iv. OMT 52、26、13mg·kg-1, myocardial damage was ameliorated with different degree, it was showed that most of cardiac muscle structures was normal, and changes of edema, degeneration, necrosis were ameliorated obviously, but still have slight inflammatory cell infiltrate and exudation. From the electron microscope, it is thus clear that cardiac muscle fiber was aligned normal, nucleus and the cardiac muscle’s mitochondria damages were relieved with different degree, most of the mitochondria structures was normal and crista was aligned regularity, a few of crista was vagued. Mitochondrion’s engorgement was relieved. A few of mitochondrion’s damage were not full recovery, it was showed obviousily in the CLP+OMT low-dose group. Meanwhile, in the CLP+OMT high and middle group, HR and LVEDP were decreased(P<0.01), MAP, LVSP and LVdp/dtmax were increased(all P<0.01), -LVdp/dtmax’s negative value increased(P<0.01), LDH activity in blood plasma decreased(P<0.01), SDH activity in cardiac muscle increased(P<0.01), calcium contents in cardiac muscle decreased (P<0.01). In the CLP+OMT low-dose group, LVEDP,±LVdp/dtmax and calcium contents were not improved obviousily(all P>0.05). Above-mentioned parameters all have improved in the OMT+DEX group(all P<0.01), and each parameters compared with CON group were not discrepancy obviousily. Conclusions 1.Oxymatrine can inhibit NF-κB pathway’s activation and reduce proinflammatory factor’s expression for instance TNF-αa or IL-6 etc in lung tissue with septic shock.Thus,Oxymatrine can produce protective effects on pulmonary functionl injury in rats with septic shock and this protective effects maybe related with that Oxymatrine inhibited NF-κB-inducing Kinase’s activation by bacilli, virus and LPS etc. 2.Oxymatrine can produce protective effects on cardiac function in myocardial injury rats with septic shock. Its mechanism associated with improving energy metabolism and reducing calcium overload in cardiac muscle cell and protecting both the ultrastructure and the function of myocardial mitochondria.3.That protective effects in the CLP+OMT high and middle group as well as in the OMT+DEX group.
同时,模型组大鼠心肌组织光镜下可见心内膜下广泛的心肌结构紊乱;大范围的炎性细胞浸润,多为单核细胞,间杂有少量淋巴细胞和中性粒细胞,也可见毛细血管扩张、出血;间质水肿及成纤维细胞增殖;不同程度的细胞坏死和组织纤维化。超微结构表现为:线粒体显著肿胀,内膜和外膜的完整性明显受到破坏,嵴模糊紊乱,数量减少,融合破坏,部分嵴消失或空泡化,破裂的膜形成小泡或空泡,线粒体内腔扩大,出现无定型电子致密性颗粒,甚至断裂、溶解或消失,内容物溢出,基质模糊不清,并可见破碎线粒体。同时可见心肌纤维排列紊乱,有溶解和空泡形成;胞核固缩明显,染色质边集;闰盘不连续,有断裂、溶解。同假手术组相比,模型组大鼠HR增加15%(P<0.01)、LVEDP增加47%(P<0.01);MAP降低33%、LVSP减少24%、LVdp/dtmax减少38%、-LVdp/dtmax减少32%(均P<0.01);血浆LDH活性增加35%(P<0.01);心肌组织SDH活性下降28%(P<0.01);钙含量增加34%(P<0.01)。在给予不同剂量的OMT干预后,心肌损伤有不同程度的减轻,表现为心肌结构基本正常,水肿及变性、坏死等改变明显减轻,但仍伴有少量的炎性细胞浸润及渗出等改变。电镜下可见心肌纤维排列正常,胞核损伤有不同程度的减轻等。心肌线粒体损伤程度有不同程度的减轻,多数线粒体结构较完整,嵴致密,排列较整齐,部分嵴模糊,排列尚规则,线粒体肿胀减轻,少数线粒体的损伤尚未完全恢复,以CLP+OMT-低剂量组表现最为明显。同时,OMT+CLP-高剂量组及OMT+CLP-中剂量组HR、LVEDP明显降低;MAP、LVSP、LVdp/dtmax等明显升高;-LVdp/dtmax增加(均P<0.01)。血浆LDH活性降低(P<0.01);心肌组织SDH活性升高(P<0.01);钙含量减少(P<0.01)。OMT+CLP-低剂量组只有MAP、±LVdp/dtmax、血浆LDH活性及心肌组织SDH活性等指标明显改善(P<0.01或P<0.05),而HR、LVEDP、LVSP及心肌组织钙含量等无明显改善(均P>0.05)。OMT+地塞米松组与假手术组比较各指标均无明显差异;与模型组比较上述各指标均有明显改善(均P<0.01);与CLP +OMT-高、中剂量组比较各指标均无明显差异(均P>0.05);与CLP +OMT-低剂量组比较各指标均有明显差异(均P<0.05)。结论1.氧化苦参碱能够抑制NF-κB的活化,减少促炎因子(TNF-α,IL-6)的生成,对感染性休克大鼠肺损伤性病变起到保护作用。该作用可能与氧化苦参碱抑制细菌、病毒、LPS等对NIK的活化有关。2.氧化苦参碱具有保护感染性休克大鼠心肌及其线粒体结构和功能完整性、减轻心功能损害的作用,其机制与氧化苦参碱改善感染性休克过程中心肌细胞能量代谢状况,减少心肌细胞内钙超载有关。3.氧化苦参碱高、中剂量组能够有效地改善感染性休克大鼠心肺功能,该作用与地塞米松对感染性休克大鼠心肺功能的保护作用相一致。
Objective The septic shock model was produced by cecal ligation and puncture(CLP), the purpose of this study was explored the protective effect of oxymatrine(omt) against NF-κB pathway in lung tissue and performed to investigate the protective mechanism of oxymatrine on myocardium mitochondrial energy metabolism, cardiac function, myocardial mitochondria ultrastructure changes and calcium overload in rats with septic shock. Revealing the protective effect and mechanism of oxymatrine on the heart and lung tissues in rats with septic shock. Therefore to provide reliable strategies for researching the pharmacologic action, clinical application to this praeparatum and the prevention and therapy of septic shock in the clinic. Methods Using a septic shock model produced by CLP, fifty-six male SD rats were randomly divided into 7 groups: sham operation group, OMT control group, model (CLP)group, CLP+OMT high, middle, low-dose group, positive control (CLP+ Dexamethasone) group. Then to observe the effect of oxymatrine on blood gas, the ratio between wet weight of the lung and dry weight of the lung(W/D), pulmonary coefficient and pulmonary moisture capacity, gross changes and pathological changes examined with lightmicroscope in the pulmonary tissue. Changes in NF-κB(p65) and IkB-αactivity in the pulmonary tissue were determined by immunohistochemical method,tumour necrosis factor-a(TNF-α) and interleukin-6(IL-6) levels in pulmonary tissue were determined by radioimmunoassay. Meanwhile, to observe the changes of pathological and ultrastructural organization with lightmicroscope and electron microscope in the cardiac muscle tissue.and to observe the effect of oxymatrine on heart function. Changes in plasma lactic dehydrogenase(LDH) , succinic dehydrogenase(SDH) and calcium content in the cardiac muscle tissue activity were determined by colorimetric method. Results In model group, The NF-κB(p65) and IkB-αactivity in the pulmonary tissue were advanced obviously(all P<0.05), and that results equal pace with the changes of the TNF-αand IL-6(the content of TNF-αand IL-6 increased respectively 205% and 242%). Meanwhile, PaO2 and SaO2 decreased respectivel 34% and 23% (all P<0.01). PaCO2 increased 30%(P<0.05). HCO3- increased 31%(P<0.05). W/D, pulmonary coefficient and pulmonary moisture capacity increased respectively 36%, 34% and 11%(all P<0.05). And observed that pulmonary hyperemia, edema, infiltrate of heterophil granulocyte and emerge of asphyxial membrane, this explain that pulmonary structure, lung ventilation/ gas exchange function were damaged Severity. After interfered in OMT, OMT could decrease significantly the NF-κB(p65) and IkB-αactivity in the pulmonary tissue(all P<0.05), TNF-αand IL-6 levels in pulmonary tissue homogenate decreased markedly(TNF-αP<0.05, IL-6 P<0.01). OMT could elevate the content of PaO2, SaO2(P<0.05), decrease the content of PaCO2, HCO3-(P<0.05) and decrease the W/D and the pulmonary coefficient and pulmonary moisture capacity(all P<0.05). improve the condition of pulmonary hyperemia, edema, infiltrate of heterophil granulocyte and emerge of asphyxial membrane, alleviate the inflammatory reaction. and that results equal pace with the positive control(CLP+Dexamethasone) group.
The pathological histology showed severe cardiac muscle derangement, inflammatory cell infiltrate wide-ranging, much of them is mononuclear cell and a few is lymphocyte or neutrophil in model group. That also showed telangiectasis and hemorrhage, interstitial edema, fibroblast proliferation, cell necrosis and tissue fibrosis. The ultrastructure showed that mitochondrion intumesced, intimal and adventitial integrity were demolished obviously, some crista confused and amount were reduced, the other were vanished or vacuolization. Inner mitochondrial space enlarged, showed up some electron-dense particles, and breaking mitochondria. Meanwhile, cardiac muscle fiber aligned confused, dissolved and formed some vacuoles, pyknosis obviously, chromatin margination, intercalated disk asynechiaed or dissolved. Compared with the normal control, HR increased 15%(P<0.01), LVEDP increased 47%(P<0.01), MAP decreased 33%, LVSP decreased 24%, LVdp/dtmax decreased 38%, - LVdp/dtmax negative value decreased 32%(all P<0.01). LDH activity in blood plasma increased 35%(P<0.01), SDH activity in cardiac muscle decreased 28%(P<0.01), calcium contents in cardiac muscle increased 34%(P<0.01). iv. OMT 52、26、13mg·kg-1, myocardial damage was ameliorated with different degree, it was showed that most of cardiac muscle structures was normal, and changes of edema, degeneration, necrosis were ameliorated obviously, but still have slight inflammatory cell infiltrate and exudation. From the electron microscope, it is thus clear that cardiac muscle fiber was aligned normal, nucleus and the cardiac muscle’s mitochondria damages were relieved with different degree, most of the mitochondria structures was normal and crista was aligned regularity, a few of crista was vagued. Mitochondrion’s engorgement was relieved. A few of mitochondrion’s damage were not full recovery, it was showed obviousily in the CLP+OMT low-dose group. Meanwhile, in the CLP+OMT high and middle group, HR and LVEDP were decreased(P<0.01), MAP, LVSP and LVdp/dtmax were increased(all P<0.01), -LVdp/dtmax’s negative value increased(P<0.01), LDH activity in blood plasma decreased(P<0.01), SDH activity in cardiac muscle increased(P<0.01), calcium contents in cardiac muscle decreased (P<0.01). In the CLP+OMT low-dose group, LVEDP,±LVdp/dtmax and calcium contents were not improved obviousily(all P>0.05). Above-mentioned parameters all have improved in the OMT+DEX group(all P<0.01), and each parameters compared with CON group were not discrepancy obviousily. Conclusions 1.Oxymatrine can inhibit NF-κB pathway’s activation and reduce proinflammatory factor’s expression for instance TNF-αa or IL-6 etc in lung tissue with septic shock.Thus,Oxymatrine can produce protective effects on pulmonary functionl injury in rats with septic shock and this protective effects maybe related with that Oxymatrine inhibited NF-κB-inducing Kinase’s activation by bacilli, virus and LPS etc. 2.Oxymatrine can produce protective effects on cardiac function in myocardial injury rats with septic shock. Its mechanism associated with improving energy metabolism and reducing calcium overload in cardiac muscle cell and protecting both the ultrastructure and the function of myocardial mitochondria.3.That protective effects in the CLP+OMT high and middle group as well as in the OMT+DEX group.
引文
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