巨噬细胞炎性蛋白-1α在深静脉血栓形成及溶解中作用的实验及临床研究
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摘要
本课题为创伤后深静脉血栓形成(Deep Venous Thrombosis, DVT)系列研究的一部分,在基于课题组前期动物建模方法的探索及基因芯片技术对相关基因筛选工作的基础上,我们发现炎性因素与DVT之间关系密切。结合经典文献关于DVT的研究,本课题就巨噬细胞炎性蛋白-1α (Macrophage Inflammatory Protein-1α, MIP-1α)及其调控的单核/巨噬细胞、基质金属蛋白酶2/9(MatrixMetalloproteinase-2/9, MMP-2/9)在DVT形成及溶解中的作用,对经结扎下腔静脉造模的淤滞型小鼠DVT模型血液、静脉壁和血栓栓子以及人血液中与DVT形成及溶解关系密切的MIP-1α、F4/80、MMP-2、-9的表达变化和其作用作一初步研究。
目的：
1.以结扎下腔静脉法建立淤滞型小鼠DVT模型,参照经典文献的报导,设立不同的时间点,获取相应时间点造模小鼠心脏血液、下腔静脉和血栓组织,HE染色观察造模小鼠建模后DVT形成的具体时间点,RT-PCR、 ELISA法检测其血液中MIP-1α在DVT形成前后的表达变化；
2.应用MIP-1α中和抗体(rh-MIP-1α Ab)腹腔注射建模后DVT形成的小鼠,明确其是否具有促进DVT溶解的作用；同时以RT-PCR、ELISA法检测不同组别造模后小鼠在预设时间点MIP-1α、 MMP-2、-9的表达变化,免疫组化法检测静脉壁和血栓栓子中巨噬细胞表面特异性抗原F4/80的表达,初步明确MIP-1α与DVT形成及溶解的关系,进而初步探讨其与血栓形成及溶解的相关机制；
3.对不同分组的人群血液样本,提取全血中MIP-1α、 F4/80、MMP-2、-9的mRNA,检测其在人血中的表达变化,探讨不同血栓形成状态下所关注的MIP-1α、 F4/80、 MMP-2、-9基因的表达变化及其与DVT的相关性。
方法：
1.96只昆明种小鼠参照随机数字表分为对照组(n=8)和模型组(n=88),模型组采用结扎下腔静脉法建立淤滞型小鼠DVT模型,参照经典文献报道,在建模后设立2h、4h、6h、8h、12h、1d、2d、4d、8d、14d、21d等11个时间点,在每个时间点将8只造模后小鼠麻醉后行心脏采血,同时获取造模段长约1.0cm的下腔静脉组织。将获取的小鼠血液样本以RT-PCR, ELISA法检测MIP-1α的表达,获取的下腔静脉组织以石蜡包埋后行静脉组织冠状面组织切片,观察血栓形成情况。
2.再取152只昆明种小鼠参照随机数字表分为对照组(n=8)和模型组(n=144),模型组采用结扎下腔静脉法建立淤滞型小鼠DVT模型,参照经典文献报道,造模后将模型组小鼠随机分为DVT组(n=72,小鼠不加任何干预措施)及DVT+MIP-1α-Ab组(n=72,小鼠造模后予以MIP-1α中和抗体0.5m1持续腹腔注射7d)；建模后设立2d、4d、8d、12d、14d、21d等6个时间点,在每个时间点将12只造模后小鼠过量麻醉后处死,获取造模段的下腔静脉组织。质量/长度比值评估血栓的溶解程度,应用RT-PCR及ELISA法检测造模段静脉及血栓组织中MIP-1α、MMP-2、-9的表达量；同时免疫组化法检测相应时间点静脉壁及血栓组织中巨噬细胞表面特异抗原F4/80的表达。
3.采集人血并依据诊断(详见附表2)分为血栓组、血栓未形成组和健康对照组,用Paxgene blood RNA kit试剂盒提取mRNA,胶回收测序证实PCR所扩增基因准确,后以real-time PCR定量检测、统计学分析不同组间MIP-1α、F4/80、MMP-2、-9mRNA的表达。对于临床一般资料、血细胞检验、血生化检验、凝血指标和彩色多普勒超声检查等的结果进行搜集、统计,结合mRNA的表达结果进行综合分析。
结果：
1.结扎下腔静脉法建立小鼠淤滞型DVT模型,HE组织染色显示在6h时间点小鼠下腔静脉中有部分血栓形成,8h时间点有完全性血栓形成,与血管壁粘连；血栓主要为均匀分布的红细胞,其间可见纤维素网状结构及散在的血小板及白细胞；在14d时间点可见血栓明显机化缩小。
2.模型组小鼠MIP-1α mRNA、蛋白在血液中的表达呈造模后8h、12h、1d、2d、4d、8d逐渐升高的趋势(P<0.05),8d达到峰值(P<0.01),21d降至正常水平(P>0.05)。
3.DVT组及DVT+MIP-1α-Ab组血栓质量/长度比值随时间的延长呈逐渐缩小的趋势(P<0.05),相同时间点DVT组血栓栓子质量/长度比值减小更为明显(P<0.05)。
4.相同时间点DVT组F4/8、MMP-9的表达明显高于DVT+MIP-1α-Ab组(P<0.05), MMP-2的表达相同时间点组间无差异(P>0.05)。
5.PCR电泳检测半定量分析及Real-time PCR定量检测人血MIP-1α、 F4/80、MMP-2、-9mRNA在血栓组中的表达显著高于血栓未形成组和健康对照组,血栓未形成组的表达量与健康对照组无差别。
结论：
1.结扎下腔静脉法建立淤滞型小鼠DVT模型在8h左右可形成完全性血栓,14d左右血栓可发生明显机化。
2.小鼠DVT模型血液中MIP-1α的表达在建模后8d达到最高值,21d降至正常水平。
3. MIP-1α与深静脉血栓溶解密切相关,其中和抗体可减弱MIP-1α促进血栓溶解的效应。
4. MIP-1α促进血栓溶解的作用与单核/巨噬细胞聚集、MMP-9的表达密切相关,MMP-2与血栓溶解的关系可能是独立于MIP-1α之外存在的。
5. MIP-1α、F4/80、MMP-2、-9mRNA在人群中DVT形成后的血液中呈高表达,结合MIP-1α较强的诱导单核/巨噬细胞向损伤部位聚集、及诱导MMP-9表达的作用,提示MIP-1α可能参与了DVT的形成、溶解过程。
This study was one part of the research of post-traumatic deep venous thrombosis(DVT), based on the research of animal model and gene chip technology, we found that the inflammation and DVT had close relationship. Therefore, through experiments on DVT mouse model and human blood, initial research was made about macrophage inflammatory protein-1alpha (MIP-1α) and matrix metalloproteinase2/9(MMP-2/9) who have close relationship with DVT.
Objective:
1. Established DVT mouse model by ligating inferior vena cava, set up different time points with reference to the classical literature reports, harvested the blood and inferior vena cava organization, observed the specific time point of DVT formation by HE dyeing, checked MIP-1α expression of blood before and after the formation of DVT.
2. Application of MIP-1α neutralizing antibody (rhMIP-1α Ab) with the DVT mouse model by intraperitoneal injection, to further clarify the role of promoting DVT resolution; at the same time, to detected MIP-1α and MMP-2,-9expression in different groups by RT-PCR and ELISA methods, immunohistochemical method to detect surface specific antigen F4/80expressio of macrophages in venous wall and thromboembolus, preliminary cleared the relationship of MIP-1α and DVT.
3. Gather blood samples and detect the expression changes of MIP-1, MMP-2,-9and F4/80in DVT group, non-thrombosis group and healthy control, then explor the relationship of gene expression changes and thrombosis states.
Method:
1.100KunMing mice were randemely divided into control group (n=8) and model group (n=92). Model was built by ligating inferior vena cava. After established model, set up2h,4h,6h,8h,12h,1d,2d,4d,8d,14d and21d etc.11time points with reference to the classical literature. Kill model mice in different time, harvested the blood and about1.0cm inferior vena cava organization. detected MIP-1α expression of the blood samples with RT-PCR and ELISA methods, observed thrombosis by paraffining the inferior vena cava organization.
2.200KunMing mice were randemely divided into control group (n=8) and model group (n=192). Model was built by ligating inferior vena cava. Model mice were randomly divided into DVT group (n=96, the mice were without any intervention measures) and DVT+MIP-1α-Ab group (n=96, mice had been intraperitoneal injection MIP-1α neutralizing antibody0.5mL for7days).Set up2d,4d,8d,12d,14d and21d etc. six time points after the model established, and in every time point killed12mice of different groups, harvested about1.0cm long inferior vena cava organization. Evaluated the degree of thrombus resolution by quality/length ratio; detected MIP-1α, MMP-2, and-9expression of thrombi and vein wall by RT-PCR and ELISA method; immunohistochemical method to detect the F4/80expression of vein wall and thrombi organization in corresponding time points.
3. Gather human blood samples and divided into DVT group, non-thrombosis group and healthy control group according to diagnosis. Extracte mRNA with Paxgene blood RNA kit, detected MIP-1a, MMP-2,-9and F4/80expression in human blood by RT-PCR, then verify PCR result by sequencing, and quantitatively detected by real-time PCR, then analyze the differences among the groups. Gather clinical data including the results of complete blood count, blood biochemistry, blood coagulation, color Doppler ultrasonography and etc, and then make statistical analysis.
Result:
1. The method to establish the stasis DVT mouse by ligating inferior vena cava, HE tissue staining displayed that at6h after modeling the inferior vena cava had partial thrombi intravascular filling and at8h it had complete thrombi; Thrombus mainly had uniform distribution of red blood cells, which visible cellulose reticular structure and scattered platelet and leukocyte; At14d the thrombi obviously reduce and organization.
2. MIP-1α mRNA and protein expression in the blood of the model mice showed rising trend from2h,4h,6h,8h,12h,1d,2d,4d to8d, and at8d reached peak, then at21d drop to normal levels.
3. The quality/length ratio of thrombi showed that was diminishing trend with the extension of time (P<0.05) in both DVT group and DVT+MIP-1α-Ab group; at the same time point, DVT group thromboembolus quality/length ratio is more obvious decrease (P<0.05).
4. AT the same time point, F4/80and MMP-9expression in DVT group is obviously higher than that of the DVT+MIP-1α-Ab group (P<0.05), MMP-2expression between the two groups had no difference (P>0.05).
5. Gene expression changes of MIP-1a, MMP-2,-9and F4/80were detected by PCR amplificate and electrophoresis, as well as real-time PCR. The gene expressions in DVT group were higher than non-thrombosis group and control group, and there is no difference between non-thrombosis and control group.
Conclusion:
1. By ligating inferior vena cava method to establish stasis DVT mouse model, at8h there were complete thrombosis in vein, and at14d the thrombi can occur obvious organization.
2. MIP-1α expression in model group showed that it rised to the peak after8days, and at21d it droped to the normal levels.
3. MIP-1α and deep vein thrombosis, which is closely related to the resolution, and its antibody could weaken the effect of thrombolysis.
4. The effect of MIP-1a promoting thrombi resolution were related with monocyte/macrophage gathered and MMP-9expression; the relationship between MMP-2and thrombi resolution may be independent of the MIP-1 a effect.
5. MIP-1α, MMP-2,-9and F4/80may play important role in recruit inflammatory cells and thrombosis recanalization.
目的：
1.以结扎下腔静脉法建立淤滞型小鼠DVT模型,参照经典文献的报导,设立不同的时间点,获取相应时间点造模小鼠心脏血液、下腔静脉和血栓组织,HE染色观察造模小鼠建模后DVT形成的具体时间点,RT-PCR、 ELISA法检测其血液中MIP-1α在DVT形成前后的表达变化；
2.应用MIP-1α中和抗体(rh-MIP-1α Ab)腹腔注射建模后DVT形成的小鼠,明确其是否具有促进DVT溶解的作用；同时以RT-PCR、ELISA法检测不同组别造模后小鼠在预设时间点MIP-1α、 MMP-2、-9的表达变化,免疫组化法检测静脉壁和血栓栓子中巨噬细胞表面特异性抗原F4/80的表达,初步明确MIP-1α与DVT形成及溶解的关系,进而初步探讨其与血栓形成及溶解的相关机制；
3.对不同分组的人群血液样本,提取全血中MIP-1α、 F4/80、MMP-2、-9的mRNA,检测其在人血中的表达变化,探讨不同血栓形成状态下所关注的MIP-1α、 F4/80、 MMP-2、-9基因的表达变化及其与DVT的相关性。
方法：
1.96只昆明种小鼠参照随机数字表分为对照组(n=8)和模型组(n=88),模型组采用结扎下腔静脉法建立淤滞型小鼠DVT模型,参照经典文献报道,在建模后设立2h、4h、6h、8h、12h、1d、2d、4d、8d、14d、21d等11个时间点,在每个时间点将8只造模后小鼠麻醉后行心脏采血,同时获取造模段长约1.0cm的下腔静脉组织。将获取的小鼠血液样本以RT-PCR, ELISA法检测MIP-1α的表达,获取的下腔静脉组织以石蜡包埋后行静脉组织冠状面组织切片,观察血栓形成情况。
2.再取152只昆明种小鼠参照随机数字表分为对照组(n=8)和模型组(n=144),模型组采用结扎下腔静脉法建立淤滞型小鼠DVT模型,参照经典文献报道,造模后将模型组小鼠随机分为DVT组(n=72,小鼠不加任何干预措施)及DVT+MIP-1α-Ab组(n=72,小鼠造模后予以MIP-1α中和抗体0.5m1持续腹腔注射7d)；建模后设立2d、4d、8d、12d、14d、21d等6个时间点,在每个时间点将12只造模后小鼠过量麻醉后处死,获取造模段的下腔静脉组织。质量/长度比值评估血栓的溶解程度,应用RT-PCR及ELISA法检测造模段静脉及血栓组织中MIP-1α、MMP-2、-9的表达量；同时免疫组化法检测相应时间点静脉壁及血栓组织中巨噬细胞表面特异抗原F4/80的表达。
3.采集人血并依据诊断(详见附表2)分为血栓组、血栓未形成组和健康对照组,用Paxgene blood RNA kit试剂盒提取mRNA,胶回收测序证实PCR所扩增基因准确,后以real-time PCR定量检测、统计学分析不同组间MIP-1α、F4/80、MMP-2、-9mRNA的表达。对于临床一般资料、血细胞检验、血生化检验、凝血指标和彩色多普勒超声检查等的结果进行搜集、统计,结合mRNA的表达结果进行综合分析。
结果：
1.结扎下腔静脉法建立小鼠淤滞型DVT模型,HE组织染色显示在6h时间点小鼠下腔静脉中有部分血栓形成,8h时间点有完全性血栓形成,与血管壁粘连；血栓主要为均匀分布的红细胞,其间可见纤维素网状结构及散在的血小板及白细胞；在14d时间点可见血栓明显机化缩小。
2.模型组小鼠MIP-1α mRNA、蛋白在血液中的表达呈造模后8h、12h、1d、2d、4d、8d逐渐升高的趋势(P<0.05),8d达到峰值(P<0.01),21d降至正常水平(P>0.05)。
3.DVT组及DVT+MIP-1α-Ab组血栓质量/长度比值随时间的延长呈逐渐缩小的趋势(P<0.05),相同时间点DVT组血栓栓子质量/长度比值减小更为明显(P<0.05)。
4.相同时间点DVT组F4/8、MMP-9的表达明显高于DVT+MIP-1α-Ab组(P<0.05), MMP-2的表达相同时间点组间无差异(P>0.05)。
5.PCR电泳检测半定量分析及Real-time PCR定量检测人血MIP-1α、 F4/80、MMP-2、-9mRNA在血栓组中的表达显著高于血栓未形成组和健康对照组,血栓未形成组的表达量与健康对照组无差别。
结论：
1.结扎下腔静脉法建立淤滞型小鼠DVT模型在8h左右可形成完全性血栓,14d左右血栓可发生明显机化。
2.小鼠DVT模型血液中MIP-1α的表达在建模后8d达到最高值,21d降至正常水平。
3. MIP-1α与深静脉血栓溶解密切相关,其中和抗体可减弱MIP-1α促进血栓溶解的效应。
4. MIP-1α促进血栓溶解的作用与单核/巨噬细胞聚集、MMP-9的表达密切相关,MMP-2与血栓溶解的关系可能是独立于MIP-1α之外存在的。
5. MIP-1α、F4/80、MMP-2、-9mRNA在人群中DVT形成后的血液中呈高表达,结合MIP-1α较强的诱导单核/巨噬细胞向损伤部位聚集、及诱导MMP-9表达的作用,提示MIP-1α可能参与了DVT的形成、溶解过程。
This study was one part of the research of post-traumatic deep venous thrombosis(DVT), based on the research of animal model and gene chip technology, we found that the inflammation and DVT had close relationship. Therefore, through experiments on DVT mouse model and human blood, initial research was made about macrophage inflammatory protein-1alpha (MIP-1α) and matrix metalloproteinase2/9(MMP-2/9) who have close relationship with DVT.
Objective:
1. Established DVT mouse model by ligating inferior vena cava, set up different time points with reference to the classical literature reports, harvested the blood and inferior vena cava organization, observed the specific time point of DVT formation by HE dyeing, checked MIP-1α expression of blood before and after the formation of DVT.
2. Application of MIP-1α neutralizing antibody (rhMIP-1α Ab) with the DVT mouse model by intraperitoneal injection, to further clarify the role of promoting DVT resolution; at the same time, to detected MIP-1α and MMP-2,-9expression in different groups by RT-PCR and ELISA methods, immunohistochemical method to detect surface specific antigen F4/80expressio of macrophages in venous wall and thromboembolus, preliminary cleared the relationship of MIP-1α and DVT.
3. Gather blood samples and detect the expression changes of MIP-1, MMP-2,-9and F4/80in DVT group, non-thrombosis group and healthy control, then explor the relationship of gene expression changes and thrombosis states.
Method:
1.100KunMing mice were randemely divided into control group (n=8) and model group (n=92). Model was built by ligating inferior vena cava. After established model, set up2h,4h,6h,8h,12h,1d,2d,4d,8d,14d and21d etc.11time points with reference to the classical literature. Kill model mice in different time, harvested the blood and about1.0cm inferior vena cava organization. detected MIP-1α expression of the blood samples with RT-PCR and ELISA methods, observed thrombosis by paraffining the inferior vena cava organization.
2.200KunMing mice were randemely divided into control group (n=8) and model group (n=192). Model was built by ligating inferior vena cava. Model mice were randomly divided into DVT group (n=96, the mice were without any intervention measures) and DVT+MIP-1α-Ab group (n=96, mice had been intraperitoneal injection MIP-1α neutralizing antibody0.5mL for7days).Set up2d,4d,8d,12d,14d and21d etc. six time points after the model established, and in every time point killed12mice of different groups, harvested about1.0cm long inferior vena cava organization. Evaluated the degree of thrombus resolution by quality/length ratio; detected MIP-1α, MMP-2, and-9expression of thrombi and vein wall by RT-PCR and ELISA method; immunohistochemical method to detect the F4/80expression of vein wall and thrombi organization in corresponding time points.
3. Gather human blood samples and divided into DVT group, non-thrombosis group and healthy control group according to diagnosis. Extracte mRNA with Paxgene blood RNA kit, detected MIP-1a, MMP-2,-9and F4/80expression in human blood by RT-PCR, then verify PCR result by sequencing, and quantitatively detected by real-time PCR, then analyze the differences among the groups. Gather clinical data including the results of complete blood count, blood biochemistry, blood coagulation, color Doppler ultrasonography and etc, and then make statistical analysis.
Result:
1. The method to establish the stasis DVT mouse by ligating inferior vena cava, HE tissue staining displayed that at6h after modeling the inferior vena cava had partial thrombi intravascular filling and at8h it had complete thrombi; Thrombus mainly had uniform distribution of red blood cells, which visible cellulose reticular structure and scattered platelet and leukocyte; At14d the thrombi obviously reduce and organization.
2. MIP-1α mRNA and protein expression in the blood of the model mice showed rising trend from2h,4h,6h,8h,12h,1d,2d,4d to8d, and at8d reached peak, then at21d drop to normal levels.
3. The quality/length ratio of thrombi showed that was diminishing trend with the extension of time (P<0.05) in both DVT group and DVT+MIP-1α-Ab group; at the same time point, DVT group thromboembolus quality/length ratio is more obvious decrease (P<0.05).
4. AT the same time point, F4/80and MMP-9expression in DVT group is obviously higher than that of the DVT+MIP-1α-Ab group (P<0.05), MMP-2expression between the two groups had no difference (P>0.05).
5. Gene expression changes of MIP-1a, MMP-2,-9and F4/80were detected by PCR amplificate and electrophoresis, as well as real-time PCR. The gene expressions in DVT group were higher than non-thrombosis group and control group, and there is no difference between non-thrombosis and control group.
Conclusion:
1. By ligating inferior vena cava method to establish stasis DVT mouse model, at8h there were complete thrombosis in vein, and at14d the thrombi can occur obvious organization.
2. MIP-1α expression in model group showed that it rised to the peak after8days, and at21d it droped to the normal levels.
3. MIP-1α and deep vein thrombosis, which is closely related to the resolution, and its antibody could weaken the effect of thrombolysis.
4. The effect of MIP-1a promoting thrombi resolution were related with monocyte/macrophage gathered and MMP-9expression; the relationship between MMP-2and thrombi resolution may be independent of the MIP-1 a effect.
5. MIP-1α, MMP-2,-9and F4/80may play important role in recruit inflammatory cells and thrombosis recanalization.
引文
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