基质金属蛋白酶-9与脑缺血

脑缺血后基质金属蛋白酶-9(MMP-9)因其表达细胞众多、作用底物广泛而备受医学界重视。脑缺血后表达的MMP-9能降解基底膜而破坏血脑屏障,导致血管源性脑水肿和出血性转化。MMP-9抑制剂有可能成为治疗脑血管病的一条新途径。     

多发性硬化患者病情演变与血浆和脑脊液趋化因子CXCL10水平的相关性

目的 观察急性期多发性硬化(MS)患者血浆和脑脊液中趋化因子CXCL10水平的动态变化规律及其与临床神经功能障碍的相关性,探讨其对疾病活动性的判定价值.方法 收集急性期MS患者、缓解期MS患者及健康对照各53例,神经系统非炎性疾病(NIND)32例,采用酶联免疫吸附试验法检测血浆和脑脊液中CXCL10水平,并进行扩展残疾状况评分量表(EDSS)评分.结果 (1)与急性期初期相比,急性期MS组患者第2、4周血浆CXCL10水平[(601±365)、(575±297)pg/ml]明显升高(t=-2.898、-2.651,P=0.001、0.003);第4周脑脊液中CXCL10水平[(1807±803)pg/ml]与急性期初期比较差异无统计学意义.(2)急性期初期MS组血浆CXCL10水平明显高于缓解期MS组[(287±118)pg/ml,t=3.555,P=0.001]和健康对照组[(248±130)pg/ml,t=4.895,P=0.000].(3)急性期MS组脑脊液CXCL10水平[(1774±604)pg/ml]明显高于NIND组[(122±114)pg/ml,t=15.192,P=0.000].(4)急性期MS组患者血浆与脑脊液中CXCL10水平间存在相关性(r=0.792,P=0.001);脑脊液CXCL10水平与同期EDSS评分之间存在相关性(r=0.526,P=0.002).结论 (1)MS患者血浆中CXCL10水平对判断疾病活动性有一定的参考价值.(2)急性期MS患者血浆CXCL10水平能在一定程度上反映其在脑脊液中的水平.(3)检测急性期MS患者脑脊液CXCL10水平对判断临床功能障碍程度有一定的参考价值.

Abstract：

Objective To investigate the evolution of CXCL10 in blood plasma and cerebrospinal fluid (CSF) during relapses of multiple sclerosis (MS),and the correlation between these and the clinical neurological dysfunction.Methods Fifty-three patients with definite MS during relapsing state (relapsing MS group) diagnosed by the McDonald criteria;fifty-three patients with definite MS during remitting state ( remitting MS group);thirty-two patients with non-inflammatory neurologic disease ( NIND group) and fiftythree healthy controls (NC group) were enrolled in the study.Each patient clinical status was evaluated with the Expanded Disability Status Scale ( EDSS).Plasma and CSF levels were analyzed by enzyme-linked immunoassay.Results ( 1 ) The CXCL10 level in plasma in relapsing MS group elevated significantly between the 2nd ( (601 ± 365 ) pg/ml,t = - 2.898,P = 0.001) and the 4th ( (575 ± 297 ) pg/ml,t = -2.651,P=0.003) week after relapsing;GXL10 in CSF (n =32) did not changed significantly in the 4th week after relapsing( (1807 ±803) pg/ml).(2) The CXCL10 level in plasma in relapsing MS group were significantly higher than that in the healthy control group ((248±130) pg/ml,(=4.895,P=0.000) and remitting MS group ((287 ±118) pg/ml,t = 3.555,P = 0.001 ).( 3 ) The CXCL10 level in CSF in relapsing MS group (( 1774 ± 604) pg/ml) was significantly higher than that in NIND group ( ( 122 ± 114) pg/ml,t= 15.192,P =0.000).(4) The CXCL10 level in plasma in relapsing MS group had correlation with that in CSF (r=0.792,P=0.001).The CXCL10 level in CSF in relapsing MS group had correlation with EDSS scores (r = 0.526,P = 0.002 ).Conclusions The CXCL10 level in plasma might be implemented as a paraclinical marker of disease activity in MS.The CXCL10 level in plasma of MS may be relevant to that in CSF.The CXCL10 level in CSF of MS may indicate the clinical neurological dysfunction.     

急性脑出血患者血浆基质金属蛋白酶-9的动态变化与预后的相关性研究

血浆基质金属蛋白酶(MMPs)在正常人的脑组织中及血浆中表达较低,其异常的表达与血脑屏障被破坏直接相关,本文从临床的角度研究关于MMP-9的动态变化与血肿周围缺血的关系,现将结果报道如下。1研究对象入组脑出血患者25例,男17例,女8例,在发病24小时确诊,均为单侧出血,无意识障碍     

颈动脉粥样硬化患者血清基质金属蛋白酶-9水平、颈动脉斑块及其与人巨细胞病毒感染的关系

目的 探讨颈动脉粥样硬化(CAS)患者基质金属蛋白酶(MMP)-9水平、颈动脉斑块及其与人巨细胞病毒(HCMV)感染的相关性.方法 对90例CAS患者的HCMV-PP65抗原、血清MMP-9水平和颈动脉彩色多普勒超声检测结果进行分析和比较.结果 (1)HCMV阳性(A组)、HCMV阴性(B组)及正常对照者(C组)血清MMP-9含量分别为(260.25±89.03)pg/ml、(157.47±78.28)pg/ml、(138.65±80.73)pg/ml,A组显著高于B组与C组(均P＜0.01);B组及C组间差异无统计学意义.(2)A组颈动脉不稳定斑块检出率为81.25%(39/48),软斑积分为(2.905±0.768)分,显著高于B组[59.52%(25/42),(1.750±0.463)分](均P＜0.05);A组硬斑积分[(2.273±0.647)分]与B组[(2.364±0.658)分]比较差异无统计学意义.结论 CAS伴HCMV-PP65抗原阳性患者血清MMP-9水平明显增高,CAS斑块检出率高,且更具不稳定性.     

基质金属蛋白酶-3(MMP-3)5A/6A基因多态性与多发性硬化相关性研究

目的对河南省汉族人群中多发性硬化(MS)患者基质金属蛋白酶-3(MMP-3)5A/6A基因作基因分型,探讨MMP-3启动子5A/6A基因遗传多态性与河南汉族人群中MS遗传易感性的可能关系。方法采用聚合酶链式反应-连接酶检测反应(LDR)的基因分型技术对51例无亲缘关系的MS患者和55例无血缘关系的河南籍健康汉族人作MMP-3启动子5A/6A基因分型。结果 MMP-3启动子5A/6A基因各等位基因和基因型频率在MS组和正常人组间无显著差异(P>0.05)。结论从目前调查的例数分析,河南省人群中MS遗传易感性与MMP-3启动子5A/6A基因无明显关联。     

基质金属蛋白酶-2、9与脑梗死初发及复发相关性研究

目的研究脑梗死初发及复发患者血清基质金属蛋白酶-2、9(matrix metalloproteinase-2,-9)的水平,探讨其临床意义。方法选取初发脑梗死组343例,复发组307例,320例健康体检者作为对照组,检测3组血清MMP-2、MMP-9水平。结果复发组MMP-2、MMP-9表达显著高于初发组,初发组高于对照组(P0.05);初发组及复发组中MMP-2与MMP-9表达无相关性(P0.05)。结论 MMP-2、MMP-9在脑梗死发生发展中起重要作用,可作为检查脑梗死复发分子标记物。     

糖皮质激素对多发性硬化患者血清MMP-9、TIMP-1水平的调控作用

目的观察糖皮质激素(GC)治疗多发性硬化(MS)患者过程中血清MMP-9和TIMP-1水平的动态变化,探讨GC治疗MS的作用机制。方法收集80例MS患者不同时间点外周血;急性初期进行EDSS评分,根据EDSS评分将MS患者分为2组,其中GC治疗组(EDSS≧5分)急性期50例、追踪至缓解期46例,空白对照组(EDSS<5分)急性期30例、缓解期26例;健康对照组50例。采用酶联免疫吸附试验法检测血清MMP-9与TIMP-1水平。结果 (1)急性期MS血清MMP-9水平高于缓解期和健康对照组,而TIMP-1水平降低(P<0.05),缓解期和健康对照组间差异无统计学意义(P>0.05)。(2)MMP-9在MS血清中呈先升后降的趋势;GC治疗组不同时间点间差异有统计学意义(F=16.35,P<0.01),治疗1w时MMP-9水平达高峰,治疗4w时较治疗前降低(P<0.05);而空白对照组发病2w时MMP-9水平达高峰,且高于GC治疗组高峰(P<0.05)。(3)GC治疗组TIMP-1水平呈缓慢增高趋势,不同时间点间差异有统计学意义(F=4.27,P<0.05),与治疗前相比,治疗4w时TIMP-1水平升高(P<0.05);而空白对照组TIMP-1水平随病情波动变化不大。结论 MMP-9在MS急性期血清中表达增强,TIMP-1表达降低,MMP-9、MMP-9/TIMP-1水平反应了MS疾病活动性,监测其水平具有一定的诊断价值;MMP-9在MS血清中呈先升后降趋势,GC治疗可降低MMP-9上升的幅度,缩短MMP-9升高的时间,降低MMP-9的表达,并诱导TIMP-1的表达,这可能是GC治疗MS、加速MS病情缓解、缩短其病程的机制之一。     

基质金属蛋白酶-9与脑梗死的关系

近年研究发现炎症在动脉粥样硬化及脑梗死中发挥重要作用，炎性标志物基质金属蛋白酶-9（MMP-9）可降解细胞外基质，削弱纤维帽的结构，增加动脉粥样硬化斑块的不稳定性，加速斑块裂解，促进斑块破裂和血栓形成。脑梗死时MMP-9过度表达可破坏血-脑脊液屏障并形成脑水肿，在继发性脑出血和脑损伤过程中发挥了关键性作用。     

中青年脑梗死患者颈动脉粥样硬化及其血清基质金属蛋白酶-9、组织基质金属蛋白酶抑制剂-1、超敏C反应蛋白水平的改变

目的研究中青年脑梗死患者颈动脉粥样硬化及其血清基质金属蛋白酶-9(MMP-9)、组织基质金属蛋白酶抑制剂-1(TIMP-1)、超敏C反应蛋白(hs-CRP)水平的改变。方法应用彩色多普勒超声仪探测42例急性脑梗死患者(ACI组)、29例无症状颈动脉硬化患者(ACA组)及17名健康体检者(NC组)的双侧颈动脉粥样硬化的情况。采用酶联免疫吸附法检测各组血清MMP-9和TIMP-1水平,免疫散射比浊法检测血清hs-CRP水平。结果 NC组均未检出颈动脉粥样硬化斑块。ACI组易损斑块的比例(69.2%)及检出率(47.6%)均明显高于ACA组(46.4%,20.7%)(均P<0.05)。ACI组血清MMP-9、TIMP-1、hs-CRP水平及MMP-9/TIMP-1比值均明显高于ACA组(均P<0.05);ACA组血清MMP-9、TIMP-1、hs-CRP水平均明显高于NC组(均P<0.05)。ACI组中,易损斑块亚组血清MMP-9、TIMP-1、hs-CRP水平及MMP-9/TIMP-1比值均明显高于稳定斑块亚组(均P<0.05);稳定斑块亚组血清MMP-9、TIMP-1、hs-CRP水平均明显高于无斑块亚组(均P<0.05)。结论血清MMP-9、TIMP-1、hs-CRP可作为反映颈动脉粥样硬化及斑块稳定性的血清学指标。MMP-9/TIMP-1比值增高及颈动脉易损斑块可能提示中青年脑梗死的风险。     

脑出血患者血清基质金属蛋白酶-9的动态变化研究

目的观察脑出血患者血清基质金属蛋白酶-9(MMP-9)水平的动态变化,并探讨其与水肿体积的关系。方法应用ELISA法对46例脑出血患者血清MMP-9水平进行动态检测,同时与头部CT扫描所显示的血肿周围水肿(PHE)体积作相关性分析。结果脑出血组血清MMP-9水平在发病24小时、3天及7天与对照组比较显著升高(P<0.05),MMP-9含量在不同血肿体积中具有显著性差异(P<0.05),发病3天及7天的MMP-9水平与血肿周围水肿体积呈正相关(P<0.05)。结论脑出血后血清MMP-9表达水平增高,血清MMP-9水平是早期反映脑出血患者血肿周围水肿严重程度和预后的敏感指标。     

Functional MMP-9 polymorphisms modulate plasma MMP-9 levels in multiple sclerosis patients

We have described that MMP-9 C(-1562)T and (CA)(n) polymorphisms contribute to multiple sclerosis (MS). Here, we evaluate whether plasma MMP-9 levels are related to disease severity, drug therapy resistance and polymorphisms. For sub-study 1, 36 patients with MS and 35 controls were recruited. For sub-study 2, 88 individuals (53 patients and 35 controls) were included in a cross-sectional analysis. MS patients presented higher MMP-9 activity (1.4±0.18 versus 0.93±0.18A.U. for control, P<0.05). Drug-therapy resistant individuals exhibited increased MMP-9 activity (1.96±0.25 versus 1.21±0.09A.U. for non-resistant patients). EDSS score was also related to MMP-9 levels. The CT+TT and HH genotypes had higher MMP-9 levels as compared to patients carrying the CC and LL. Drug therapy resistance, disease severity, MMP-9 plasma activity and polymorphisms are associated with MS.     

Monosymptomatic sensory symptoms and cerebrospinal fluid immunoglobulin levels in relation to multiple sclerosis

Of 53 patients with monosymptomatic paresthesiae, 55% had oligoclonal bands and 28% an elevated cerebrospinal fluid (CSF) IgG index. Over a mean observation period of 64 months, nine patients developed clinically definite multiple sclerosis (MS); all of these patients had IgG bands, illustrating the prognostic importance of this CSF aberration. Two lumbar punctures more than one year apart were performed in 31 of the patients, of whom 20 had oligoclonal bands. This abnormality was constant between the time of punctures in all subjects except one, thus behaving as in MS. Similarly, the CSF findings in the 11 patients without oligoclonal bands remained normal over the observation period. The majority of patients with oligoclonal bands had cells in their CSF producing immunoglobulin of one or more of the three main classes, while none of those without oligoclonal bands displayed immunoglobulin-producing cells in CSF. Occurrence of oligoclonal bands in CSF is common in patients with paresthesiae and increases the risk for future development of MS.     

Growth hormone and insulin growth factor-I levels in plasma and cerebrospinal fluid of patients with multiple sclerosis

Multiple sclerosis (MS) has several clinically different forms. Whereas the illness progresses slowly in most of the patients, 10% have an aggressively progressive course with fatal outcome without signs of remyelination capability. The process of remyelination depends on numerous interactive factors, including the presence of various growth factors, the most important of which in the adult is insulin growth factor-I (IGF-I). On the other hand, the most powerful postnatal regulator of IGF-I is growth hormone (GH), which also acts as a neuroprotective and an antiapoptotic agent, and has direct influence on myelination. Levels of these growth factors have never been examined in the cerebrospinal fluid (CSF) of patients with MS. The levels of IGF-I and GH were measured in serum and CSF of 46 MS patients and compared with those of 49 patients with no evidence of demyelinating disease. The only positive finding was a deficiency of GH in the CSF of MS patients. The possible implications of those findings in the etiopathogenesis of MS will be discussed.     

Interleukin-2 levels in serum and cerebrospinal fluid of multiple sclerosis patients

A sensitive enzyme-linked immunosorbent assay method was employed to measure interleukin-2 (IL-2) levels in cerebrospinal fluid (CSF) and sera from 30 patients with multiple sclerosis (MS) and 8 patients with other neurological diseases. Detectable levels of IL-2 were found in 6 sera and 9 CSF samples of 21 patients with acute relapse of MS. However, only 3 patients showed measurable IL-2 both in CSF and in serum. IL-2 was not detected in specimens from 9 patients with chronic-progressive MS, whereas high levels were found in 2 CSF samples from patients with aseptic meningitis. Our data suggest that systemic activation of a T-cell population is present in some MS patients; moreover, an active immune mechanism involving IL-2 production takes place within the central nervous system.     

ACTH in the plasma and cerebrospinal fluid in patients with multiple sclerosis

In 1984 and at the beginning of 1985 the authors carried out radioimmunoassays (SORIN-CIS kit) the plasma levels of ACTH in 116 multiple sclerosis patients (m-52, f-64) and in 10 cases this radioimmunoassay was done in the cerebrospinal fluid (m-5, f-5). The control group comprised 90 patients with ischialgia and neuroses. The normal value in the plasma was from 0 to 80.86 pg/ml, and in the fluid it was from 0 to 77.08 pg/ml. In multiple sclerosis patients the plasma ACTH level was from 0 to 286.9 pg/ml, in the cerebrospinal fluid from 0 to 89 pg/ml. The values of ACTH were significantly higher in multiple sclerosis patients, mainly in males. In the fluid the level of ACTH was significantly higher in the studied patients. No significant differences in ACTH levels were found between males and females with multiple sclerosis, and in the control group this level was higher in females. Raised ACTH level was found mainly in multiple sclerosis with lung duration of the disease (10 years) at the time of exacerbations. The authors continue studies on the axis hypothalamus-hypophysis-adrenals, on various hormones, prostaglandins, beta-endorphin, biochemical markers, cAMP, cCMP, arylosulphatase A and B MBC etc.     

The relationship between levels of cerebrospinal fluid myelin basic protein and IgG measurements in patients with multiple sclerosis

Cerebrospinal fluid (CSF) myelin basic protein (MBP) levels, CSF/serum albumin ratio (CSF/S alb), and 4 CSF IgG measurements--absolute CSF IgG level (CSF IgG), CSF IgG/albumin ratio, the Tibbling-Link IgG index, and the daily rate of intrathecal IgG synthesis--were measured in patients with multiple sclerosis and control subjects. In four clinical subgroups of patients, including 22 with polysymptomatic exacerbations, 22 with monosymptomatic exacerbations, 41 with chronic progressive disease, and 21 in remission, there was no correlation between CSF MBP and either CSF/S alb or the CSF IgG measurements. This finding was also observed in longitudinal studies of patients. CSF MBP levels, as determined in a cross-sectional study of 325 patients with multiple sclerosis, are an excellent indicator of disease activity.