肝豆靈對Wilson病患者腦血流動力學和血管損傷因子及TX小鼠血管損傷病理研究
發(fā)布時間：2018-08-27 14:21
【摘要】：目的探討WD患者是否存腦血流改變和血管損害;觀察肝豆靈對Wilson病患者腦血管損害的影響;觀察肝豆靈對TX小鼠腦血管組織的病理形態(tài)學變化。方法臨床部分:60例WD患者與健康組比較,觀察2組超聲檢測(超聲腦血管功能檢測儀、經(jīng)顱多普勒彩超)、磁共振灌注成像、血管損傷因子(血管性血友病因子(v WF)、血栓調(diào)節(jié)蛋白(TM)、內(nèi)皮細胞蛋白C受體(EPCR)、同型半胱氨酸(HCY))變化,上述60例WD患者隨機分為治療組和對照組,治療組采用肝豆靈聯(lián)合西藥二巰基丙磺酸鈉(DMPS)治療,對照組僅使用DMPS治療,觀察2組治療前后上述指標變化。實驗部分:TX小鼠隨機分為模型組、肝豆靈組、青霉胺組,另DL小鼠設(shè)為對照組,4組經(jīng)不同處理后,檢測上述血管損傷因子變化,觀察光鏡下腦血管病理變化,觀察電鏡下細胞超微結(jié)構(gòu)變化,免疫組化觀察ICAM-1和VCAM-1在腦血管上的表達。結(jié)果臨床部分:(1)超聲腦血管功能檢測結(jié)果:WD組雙側(cè)頸總動脈最大流速、最小流速平均流速、平均流量低于健康組(P0.05);WD組雙側(cè)頸總動脈動態(tài)阻力、雙側(cè)外周阻力、脈搏波速、特性阻抗數(shù)值高于健康組(P0.05)。治療組治療后與治療前比較雙側(cè)頸總動脈最大流速、最小流速、平均流速、平均血流量均提升(P0.05);治療組治療后與治療前比較雙側(cè)外周阻力、動態(tài)阻力、脈搏波速、特性阻抗改變無統(tǒng)計學意義(P0.05)。對照組雙側(cè)頸總動脈各項指標改變均無統(tǒng)計學意義(P0.05)。(2)TCD結(jié)果:WD組LMCA、LACA血管收縮期峰值流速低于健康組(P0.05);RMCA、RACA血管收縮期峰值流速低于健康組(P0.01);RPCA血管舒張末期血流速度低于健康組(P0.05);LMCA、LACA、LPCA、RMCA、RACA、血管舒張末期血流速度低于健康組(P0.01),LMCA、LACA、RMCA、RACA血管平均流速低于健康組(P0.01);LPCA、RPCA管平均流速低于健康組(P0.05);WD組各血管PI值與健康組比較差異無統(tǒng)計學意義(P0.05)。經(jīng)治療后,治療組LMCA、LACA、RMCA、RACA的收縮期峰值速度較治療前升高(P0.01),LPCA、RPCA的收縮期峰值速度較治療前升高(P0.05),LMCA、LACA、RMCA、RACA的舒張末期速度較治療前升高(P0.01),LPCA、RPCA的舒張末期速度較治療前升高(P0.05);LMCA、LACA、RMCA、RACA、LPCA、RPCA的平均血流速度較治療前升高(P0.01);各血管PI值療前療后比較無統(tǒng)計學意義(P0.05)。對照組各血管收縮期峰值速度、舒張末期速度、平均血流速度、PI值療前療后無統(tǒng)計學意義(P0.05)。治療組治療后LACA、RMCA收縮期峰值速度和平均速度與對照組治療后比較(P0.05);治療組治療后RACA收縮期峰值速度和平均速度與對照組治療后比較(P0.01)。(3)磁共振灌注成像結(jié)果:與健康組比較,WD組雙側(cè)丘腦r CBF無統(tǒng)計學意義(P0.05),雙側(cè)尾狀核區(qū)域、雙側(cè)尾狀核頭區(qū)域r CBF數(shù)值降低(P0.01)。治療后治療組雙側(cè)尾狀核頭區(qū)域、雙側(cè)豆狀核區(qū)域r CBF較治療前升高(P0.05);對照組各區(qū)域數(shù)值變化無統(tǒng)計學意義(P0.05)。治療組治療后右側(cè)豆狀核區(qū)域r CBF數(shù)值較對照組治療后明顯升高(P0.01);左側(cè)豆狀核區(qū)域r CBF數(shù)值較對照組治療后升高(P0.05)。(4)血管損傷因子結(jié)果:WD組HCY、v WF、TM、EPCR與健康組比較數(shù)值均升高(P0.01)。經(jīng)治療后,治療組Hcy下降有顯著性差異(P0.05),v WF、TM、EPCR數(shù)值均下降有極顯著性差異(P0.01)。治療組治療后v WF、EPCR數(shù)值均低于于對照組治療后(P0.01);TM數(shù)值低于對照組治療(P0.05)。實驗部分:(1)血管損傷因子測定:與對照組比較,模型組Hcy、v WF、TM、EPCR數(shù)值明顯升高(P0.01)。與模型組比較,肝豆靈組Hcy、v WF、EPCR數(shù)值下降(P0.05),TM數(shù)值明顯下降(P0.01)。與模型組比較,青霉胺組Hcy、v WF、TM、EPCR數(shù)值下降,無統(tǒng)計學意義(P0.05)。與青霉胺組比較,肝豆靈組Hcy、v WF、TM、EPCR數(shù)值下降(P0.05)。(2)腦血管病理學改變:1H-E染色:可見模型組、肝豆靈組、青霉胺組腦血管內(nèi)皮細胞有不同程度水腫變性,神經(jīng)元細胞有不同程度變性及壞死,改變以模型組為著,青霉胺組、肝豆靈組與模型組相比損傷輕。2透射電鏡觀測:腦組織可見腦血管內(nèi)皮細胞和神經(jīng)元不同程度變性及壞死,線粒體空泡化,嵴模糊甚至消失,以模型組損傷最重,治療后青霉胺組、肝豆靈組改善,且肝豆靈組改善較明顯。(3)免疫組化結(jié)果:1ICAM-1免疫染色陽性血管的變化:模型組與對照組比較ICAM-1表達增多(P0.01);肝豆靈組與模型組比較表達減少(P0.01);青霉胺組與模型組比較表達減少(P0.05);肝豆靈組與青霉胺組比較表達較少(P0.05)。2VCAM-1免疫染色陽性血管的變化:模型組與對照組比較ICAM-1表達增多(P0.01);肝豆靈組與模型組比較表達較少(P0.01);青霉胺組與模型組比較表達減少(P0.01);肝豆靈組與青霉胺組比較表達減少(P0.05)。結(jié)論(1)WD患者存在血管損傷;表現(xiàn)為腦中小動脈血流速度下降;豆狀核區(qū)域、尾狀核頭區(qū)域局部腦血流量減低。血管損傷因子(Hcy、v WF、TM、EPCR)異常增高。而大血管頸總動脈血流動力學改變不明顯。(2)肝豆靈能夠提高痰瘀互結(jié)型WD患者中小血管血流,增加豆狀核區(qū)域、尾狀核頭區(qū)域腦血流量;減少血管損害因子(Hcy、v WF、TM、EPCR)水平。(3)WD模型TX小鼠同樣血管存在損傷,血管內(nèi)皮細胞和神經(jīng)元不同程度變性及壞死,導致血管損傷因子(Hcy、v WF、TM、EPCR、ICAM-1、VCAM-1)水平升高。(4)肝豆靈能夠改善TX小鼠血管損傷,減輕內(nèi)皮細胞及神經(jīng)元病理損傷,減少血管損傷因子(Hcy、v WF、TM、EPCR、ICAM-1、VCAM-1)表達,肝豆靈對WD模型TX小鼠的血管具有一定的保護作用。
[Abstract]:Objective To investigate whether there are cerebral blood flow changes and vascular damage in patients with WD, to observe the effect of Gandouling on cerebral vascular damage in patients with Wilson disease, and to observe the pathomorphological changes of cerebrovascular tissue in TX mice. Puller color Doppler ultrasound, magnetic resonance perfusion imaging, vascular injury factor (von Willebrand factor (v WF), thrombomodulin (TM), endothelial cell protein C receptor (EPCR), homocysteine (HCY) changes, the above 60 cases of WD patients were randomly divided into treatment group and control group, the treatment group was treated with Gandouling combined with Western medicine sodium dimercaptopropionate (DMPS), on. The experimental part: TX mice were randomly divided into model group, Gandouling group, Penicillin group, and DL mice as control group. After different treatments, the changes of above-mentioned vascular injury factors were detected, the pathological changes of cerebrovascular under light microscope were observed, and the ultrastructural changes of cells under electron microscope were observed. Results: (1) Ultrasound cerebrovascular function test showed that the maximum and minimum common carotid artery flow velocity in WD group were lower than those in healthy group (P 0.05), and the dynamic resistance, peripheral resistance, pulse wave velocity and characteristic impedance of common carotid artery in WD group were lower than those in healthy group (P 0.05). After treatment, the maximum, minimum, average and average blood flow of the bilateral common carotid artery were increased (P 0.05), while the peripheral resistance, dynamic resistance, pulse wave velocity and characteristic impedance of the treatment group were not significantly different from those before treatment (P 0.05). TCD results: The peak systolic velocity of LMCA and LACA in WD group was lower than that of healthy group (P 0.05); the peak systolic velocity of RMCA and RACA was lower than that of healthy group (P 0.01); the late diastolic velocity of RPCA was lower than that of healthy group (P 0.05); LMCA, LACA, LPCA, RMCA, RACA, and the end diastolic velocity of blood vessels were lower than that of healthy group (P 0.05). The mean velocity of LMCA, LACA, RMCA and RACA was lower than that of healthy group (P 0.01), LPCA and RPCA were lower than that of healthy group (P 0.05), and the PI value of each vessel in WD group was not significantly different from that of healthy group (P 0.05). The peak systolic velocity of LMCA, LACA, RMCA, RACA was higher than that before treatment (P 0.05), and the end diastolic velocity of LPCA, RPCA was higher than that before treatment (P 0.01); the mean blood flow velocity of LMCA, LACA, RMCA, RACA, LPCA, RPCA was higher than that before treatment (P 0.01); there was no significant difference between pre-and post-treatment (P 0.01). The peak systolic velocity, end-diastolic velocity, mean blood flow velocity and PI value of the control group had no statistical significance before and after treatment (P 0.05). Comparison after treatment (P 0.01). (3) Magnetic resonance perfusion imaging results: Compared with the healthy group, there was no significant difference in bilateral thalamus R CBF (P 0.05), bilateral caudate nucleus region, bilateral caudate nucleus head region R CBF decreased (P 0.01). There was no significant difference in the domain values (P 0.05). After treatment, the R CBF values in the right lenticular nucleus region in the treatment group were significantly higher than those in the control group (P 0.01); the R CBF values in the left lenticular nucleus region were significantly higher than those in the control group (P 0.05). (4) Vascular injury factor results: HCY, V WF, TM, EPCR values in WD group were higher than those in the healthy group (P 0.01). After treatment, the values of VWF, TM and EPCR in the treatment group were lower than those in the control group (P 0.01), and the values of TM were lower than those in the control group (P 0.05). Compared with the model group, the values of Hcy, V WF, EPCR decreased (P 0.05), TM decreased significantly (P 0.01). Compared with the model group, the values of Hcy, V WF, TM and EPCR in the penicillamine group decreased, with no statistical significance (P 0.05). Compared with the penicillamine group, the values of Hcy, V WF, TM and EPCR in the Gandouling group decreased (P 0.05). Changes: 1H-E staining: It was observed that the cerebral vascular endothelial cells of model group, Gandouling group and Penicillin group had edema and degeneration in different degrees, and neurons had degeneration and necrosis in different degrees. Mitochondrial vacuolation, cristae blurred and even disappeared in different degrees of degeneration and necrosis. Injury in model group was the most serious. After treatment, penicillamine group and Gandouling group were improved, and Gandouling group was improved significantly. (3) Immunohistochemical results: 1 ICAM-1 immunostaining positive vascular changes: The expression of ICAM-1 increased in model group compared with control group (P 0.01); Gandouling group and Gandouling group were improved significantly. (3) Immunohistochemical results: 1 ICAM-1 The expression of ICAM-1 was decreased in model group (P 0.01), decreased in penicillamine group and model group (P 0.05), less in Gandouling group and penicillamine group (P 0.05). The expression of ICAM-1 was increased in model group and control group (P 0.01), less in Gandouling group and model group (P 0.01), less in Penicillamine group and penicillamine group (P 0.05). CONCLUSION (1) Vascular injury exists in WD patients, which is manifested by decreased blood flow velocity of small and medium cerebral arteries, decreased regional cerebral blood flow in the lentiform nucleus region and caudate nucleus region, abnormal increase of vascular injury factors (Hcy, V WF, TM, EPCR), and abnormal increase of common carotid artery in large vessels. (2) Gandouling could increase the blood flow of small and medium vessels, increase the cerebral blood flow in the area of lenticular nucleus and caudate nucleus, and decrease the levels of vascular damage factors (Hcy, V WF, TM, EPCR). (3) TX mice of WD model also had vascular damage, vascular endothelial cells and neurons degenerated and deteriorated in different degrees. (4) Gandouling can improve the vascular injury of TX mice, alleviate the pathological injury of endothelial cells and neurons, reduce the expression of vascular injury factors (Hcy, V WF, TM, EPCR, ICAM-1, VCAM-1). Gandouling has a protective effect on the blood vessels of WD model TX mice.
【學位授予單位】：安徽中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R742.4
本文編號：2207547
[Abstract]:Objective To investigate whether there are cerebral blood flow changes and vascular damage in patients with WD, to observe the effect of Gandouling on cerebral vascular damage in patients with Wilson disease, and to observe the pathomorphological changes of cerebrovascular tissue in TX mice. Puller color Doppler ultrasound, magnetic resonance perfusion imaging, vascular injury factor (von Willebrand factor (v WF), thrombomodulin (TM), endothelial cell protein C receptor (EPCR), homocysteine (HCY) changes, the above 60 cases of WD patients were randomly divided into treatment group and control group, the treatment group was treated with Gandouling combined with Western medicine sodium dimercaptopropionate (DMPS), on. The experimental part: TX mice were randomly divided into model group, Gandouling group, Penicillin group, and DL mice as control group. After different treatments, the changes of above-mentioned vascular injury factors were detected, the pathological changes of cerebrovascular under light microscope were observed, and the ultrastructural changes of cells under electron microscope were observed. Results: (1) Ultrasound cerebrovascular function test showed that the maximum and minimum common carotid artery flow velocity in WD group were lower than those in healthy group (P 0.05), and the dynamic resistance, peripheral resistance, pulse wave velocity and characteristic impedance of common carotid artery in WD group were lower than those in healthy group (P 0.05). After treatment, the maximum, minimum, average and average blood flow of the bilateral common carotid artery were increased (P 0.05), while the peripheral resistance, dynamic resistance, pulse wave velocity and characteristic impedance of the treatment group were not significantly different from those before treatment (P 0.05). TCD results: The peak systolic velocity of LMCA and LACA in WD group was lower than that of healthy group (P 0.05); the peak systolic velocity of RMCA and RACA was lower than that of healthy group (P 0.01); the late diastolic velocity of RPCA was lower than that of healthy group (P 0.05); LMCA, LACA, LPCA, RMCA, RACA, and the end diastolic velocity of blood vessels were lower than that of healthy group (P 0.05). The mean velocity of LMCA, LACA, RMCA and RACA was lower than that of healthy group (P 0.01), LPCA and RPCA were lower than that of healthy group (P 0.05), and the PI value of each vessel in WD group was not significantly different from that of healthy group (P 0.05). The peak systolic velocity of LMCA, LACA, RMCA, RACA was higher than that before treatment (P 0.05), and the end diastolic velocity of LPCA, RPCA was higher than that before treatment (P 0.01); the mean blood flow velocity of LMCA, LACA, RMCA, RACA, LPCA, RPCA was higher than that before treatment (P 0.01); there was no significant difference between pre-and post-treatment (P 0.01). The peak systolic velocity, end-diastolic velocity, mean blood flow velocity and PI value of the control group had no statistical significance before and after treatment (P 0.05). Comparison after treatment (P 0.01). (3) Magnetic resonance perfusion imaging results: Compared with the healthy group, there was no significant difference in bilateral thalamus R CBF (P 0.05), bilateral caudate nucleus region, bilateral caudate nucleus head region R CBF decreased (P 0.01). There was no significant difference in the domain values (P 0.05). After treatment, the R CBF values in the right lenticular nucleus region in the treatment group were significantly higher than those in the control group (P 0.01); the R CBF values in the left lenticular nucleus region were significantly higher than those in the control group (P 0.05). (4) Vascular injury factor results: HCY, V WF, TM, EPCR values in WD group were higher than those in the healthy group (P 0.01). After treatment, the values of VWF, TM and EPCR in the treatment group were lower than those in the control group (P 0.01), and the values of TM were lower than those in the control group (P 0.05). Compared with the model group, the values of Hcy, V WF, EPCR decreased (P 0.05), TM decreased significantly (P 0.01). Compared with the model group, the values of Hcy, V WF, TM and EPCR in the penicillamine group decreased, with no statistical significance (P 0.05). Compared with the penicillamine group, the values of Hcy, V WF, TM and EPCR in the Gandouling group decreased (P 0.05). Changes: 1H-E staining: It was observed that the cerebral vascular endothelial cells of model group, Gandouling group and Penicillin group had edema and degeneration in different degrees, and neurons had degeneration and necrosis in different degrees. Mitochondrial vacuolation, cristae blurred and even disappeared in different degrees of degeneration and necrosis. Injury in model group was the most serious. After treatment, penicillamine group and Gandouling group were improved, and Gandouling group was improved significantly. (3) Immunohistochemical results: 1 ICAM-1 immunostaining positive vascular changes: The expression of ICAM-1 increased in model group compared with control group (P 0.01); Gandouling group and Gandouling group were improved significantly. (3) Immunohistochemical results: 1 ICAM-1 The expression of ICAM-1 was decreased in model group (P 0.01), decreased in penicillamine group and model group (P 0.05), less in Gandouling group and penicillamine group (P 0.05). The expression of ICAM-1 was increased in model group and control group (P 0.01), less in Gandouling group and model group (P 0.01), less in Penicillamine group and penicillamine group (P 0.05). CONCLUSION (1) Vascular injury exists in WD patients, which is manifested by decreased blood flow velocity of small and medium cerebral arteries, decreased regional cerebral blood flow in the lentiform nucleus region and caudate nucleus region, abnormal increase of vascular injury factors (Hcy, V WF, TM, EPCR), and abnormal increase of common carotid artery in large vessels. (2) Gandouling could increase the blood flow of small and medium vessels, increase the cerebral blood flow in the area of lenticular nucleus and caudate nucleus, and decrease the levels of vascular damage factors (Hcy, V WF, TM, EPCR). (3) TX mice of WD model also had vascular damage, vascular endothelial cells and neurons degenerated and deteriorated in different degrees. (4) Gandouling can improve the vascular injury of TX mice, alleviate the pathological injury of endothelial cells and neurons, reduce the expression of vascular injury factors (Hcy, V WF, TM, EPCR, ICAM-1, VCAM-1). Gandouling has a protective effect on the blood vessels of WD model TX mice.
【學位授予單位】：安徽中醫(yī)藥大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R742.4
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