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。     

PECAM-1 and gelatinase B coexist in vascular cuffs of multiple sclerosis lesions

In multiple sclerosis (MS), the matrix metalloprotease (MMP) gelatinase B/MMP-9 and platelet endothelial cell adhesion molecule (PECAM)-1 have both been implicated in trans-endothelial infiltration of leucocytes into the brain, but their functional connection has not yet been investigated. We investigated the expression of gelatinase B and PECAM-1 in post mortem brains of MS patients by immunohistochemistry. Because increased soluble PECAM-1 serum levels have been observed in MS patients, we also tested in vitro whether this could be due to cleavage of PECAM-1 by gelatinase B or matrilysin-1/MMP-7. Constitutive expression of PECAM-1 was found on brain endothelial cells, whilst in active MS lesions cell-bound PECAM-1 was highly up-regulated on foamy macrophages in perivascular infiltrates and co-localized with gelatinase B. However, human THP-1 monocyte-bound or soluble recombinant PECAM-1 were both resistant to proteolytic cleavage by gelatinase B or matrilysin-1 in vitro, as demonstrated by Western blot analysis and flow cytometry. These results suggest that PECAM-1 and gelatinase B may complement each other during the transmigration of the blood-brain barrier by mononuclear cells.     

Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in patients with relapsing-remitting multiple sclerosis treated with interferon beta

OBJECTIVES: Matrix metalloproteinases (MMPs), particularly MMP-9, facilitate T-cell migration into the central nervous system. They play a key role in the disruption of the blood-brain barrier (BBB) and thus in the pathogenesis of multiple sclerosis. Interferon beta's (IFNbeta) ability to alter the balance between MMP-9 and MMP-9s natural inhibitor, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), may play a role in stabilizing the BBB. The aim of this study, was to evaluate serum MMP-9 and TIMP-1 and cerebrospinal fluid (CSF) TIMP-1 levels in patients with relapsing-remitting multiple sclerosis (RRMS) treated with IFNbeta-1a. PATIENTS AND METHODS: Blood and CSF samples from 14 patients with RRMS before and 6 months after IFNbeta therapy and 14 age and sex-matched controls were obtained. Levels of MMP-9 and TIMP-1 were measured using ELISA. RESULTS: Before treatment, patients with MS had higher levels of serum MMP-9 and a higher MMP-9/TIMP-1 ratio than the controls. Although serum levels of TIMP-1 were lower in RRMS patients than in the controls, the differences did not reach statistical significance. CSF levels of TIMP-1 were significantly lower in RRMS patients. In the sixth month of IFNbeta therapy serum MMP-9 and the MMP-9/TIMP-1 ratio were significantly decreased, whereas the changes in serum TIMP-1 were not statistically significant. There was a significant increase in CSF TIMP-1 levels in the sixth month of IFNbeta therapy. CONCLUSIONS: Our result shows that RRMS patients have an impaired MMP-9 and TIMP-1 balance, and that 6 months of IFNbeta therapy is beneficial in restoring this balance.     

Immunohistochemistry analysis of bone marrow biopsies in multiple sclerosis patients undergoing autologous haematopoietic stem cells transplantation

Objective

Recently autologous haematopoietic stem cell transplantation (AHSCT) has been introduced for the treatment of severe forms of multiple sclerosis (MS). As little data are available on bone marrow (BM) of MS patients undergoing AHSCT, we investigated the morphological and phenotypic characteristics of MS BM.

Methods

BM biopsies of 14 MS patients screened for AHSCT and 10 control patients were evaluated to assess cellularity, morphology, immunological profile and bone marrow microenvironment. Immunohistochemistry analysis was performed to evaluate the expression of CD3, CD4, CD8, CD20, CD68, CD45, MMP-9.

Results

8 out of 14 MS (57%) patients showed a reduction of age-related bone marrow cellularity, possibly due to previous immunosuppressive therapies. There were no differences in the T CD3+ lymphocyte expression rate amongst MS and the control patients, the CD4/CD8 ratio (2:1) was maintained as was the rate of B lymphocytes. We found an increased, although not significant, MMP-9 expression (9.2%) in the bone marrow of MS patients, when compared to the control patients (6.3%).

Conclusion

The BM of MS patients showed a reduced cellularity and CD45+ cells content in comparison to the controls. A slightly increased expression of MMP-9 was also shown, possibly confirming an involvement of this compartment in the pathogenesis of the disease.     

基质金属蛋白酶-2、-7、-9在人脑星形细胞瘤中的表达及临床意义

目的 探讨基质金属蛋白酶(matrix metalloproteinase，MMP)在人脑星形细胞瘤侵袭、转移中的作用。方法 用免疫组织化学方法(S-P法)检测了45例人脑星形细胞瘤组织中MMP-2、MMP-7、MMP-9的表达情况。结果 Ⅲ、Ⅳ级中MMP-2、MMP-9蛋白表达要明显高于I、Ⅱ级，而MMP-7在部分Ⅳ级星形细胞瘤中过度表达，而在T、Ⅱ、Ⅲ级中无表达。结论 MMP-2、MMP-7、MMP-9蛋白的表达与星形细胞瘤的恶性程度有关，其高表达可能与星形细胞瘤的侵袭、转移等恶性生物学行为有关，并有可能成为星形细胞瘤恶性程度、侵袭能力的判断指标。     

β-干扰素对多发性硬化患者趋化因子mRNA表达的影响

目的　观察干扰素 β 1b(IFNβ 1b)在体外对多发性硬化 (MS)患者趋化因子mRNA表达的影响。方法　取MS患者外周血 ,分离单个核细胞 (MNC) ,以其他非炎性神经系统疾病 (OND)及健康人 (HC)为对照组。MNC在完全培养基中分别与自身抗原髓鞘碱性蛋白 (MBP)、对照抗原AChR及不加抗原组 ,加或不加药物IFNβ 1b共同培养 ,3d后收集细胞 ,涂片 ,用地高辛标记的寡核苷酸探针进行原位杂交 (ISH) ,检测C C趋化因子单核细胞炎性蛋白 1α/ β(MIP 1α/ β)、单核细胞趋化蛋白 1(MCP 1 )和正常T细胞表达及分泌的调节活化因子 (RANTES)mRNA的表达。结果　MBP刺激的MIP 1α及自发产生的MIP 1αmRNA均受到IFN β 1b的抑制 ,但差异无显著意义 (P >0 0 5)。RANTESmRNA的表达受到IFNβ 1b的抑制 ,在MBP诱导下无药物处理时为 30 2± 1 5 0 (细胞数 / 1 0 5,下同 ) ,有药物处理为 1 1 1± 5 3 ,差异有显著意义 (P <0 0 1 ) ;在无抗原诱导下无药物处理时为 1 8 5± 3 3 ,有药物处理为 5 1± 3 2 ,差异亦有显著意义 (P <0 0 1 )。IFNβ 1b在 1 0U/ml浓度下 ,可对MBP刺激的MCP 1mRNA的表达产生抑制作用 (分别为 1 58 4± 1 0 4 3和 63 2± 36 9,差异有显著性意义 ,P <0 0 1 ) ,而对自发产生的MCP 1mRNA作用不明显 ;对MBP刺激     

Atypical inflammatory demyelinating lesions and atypical multiple sclerosis

Atypical idiopathic inflammatory demyelinating disorders (IIDDs) of the brain have long been known to be disorders closely related to multiple sclerosis (MS), despite having distinctive clinical and radiological characteristics. Originally, they mostly corresponded to acute-onset variants of MS that classically had poor prognoses, such as Baló’s concentric sclerosis, Marburg variant of MS and Schilder's disease, and their relationship with MS was based on their shared pathological findings and the co-occurrence of these variants in patients with typical MS. More recently, other atypical disorders, such as solitary sclerosis, have also been described as belonging to the MS spectrum, raising the question of their links with MS. Meanwhile, multiple MS mimics have been described and need to be considered in the differential diagnosis of MS. In addition, thorough characterization of these atypical entities, including advanced MRI and biological studies, is now warranted to further improve their management.     

Primary CNS demyelinating diseases in childhood: multiple sclerosis

We report on five children (three female and two male, age span 11–16 years) with laboratory-supported definite multiple sclerosis, or clinically definite multiple sclerosis, diagnosed on the basis of Poser and Paty criteria. All patients were subjected to serial clinical examinations, magnetic resonance investigations, CSF biochemical and immunological studies, and neurophysiological and neuropsychological assessments. Four of the five examined subjects underwent steroid treatment. Over a period of 3 years relapses have been observed in three of them. The first symptoms and signs of multiple sclerosis may be subtle and misleading; careful assessment of them may be crucial for an early diagnosis of the disease.     

阿加曲班对实验性大脑内出血后脑组织 MMP-9表达变化的研究

目的研究大鼠实验性大脑内出血(ICH)后脑组织基质金属蛋白酶-9(matrix metalloproteinases- 9,MMP-9)的表达在阿加曲班(argatroban)注入前后的变化及意义。方法采用立体定向技术将自体不凝血注入大鼠尾状核区制备不同时间段的大脑内出血模型。另设加药组,术后30min及术后每天给予同等量的阿加曲班(3.0 mg/kg)。免疫组化染色法检测注药前后出血脑组织MMP-9的表达。结果未加药组MMP-9表达的阳性细胞数在出血后2d达到最高峰,之后又下降。加药后MMP-9表达的变化趋势消失(P>0.05),同一时相MMP-9阳性表达的细胞数与加药前无显著性差别(P>0.05)。结论进行阿加曲班治疗后MMP-9表达无显著性改变,MMP-9在出血后脑组织可能具有双重作用。     

大鼠脑出血后脑组织MMP-2、MMP-9 表达的实验研究

目的　探讨大鼠脑出血后不同时程脑组织中的基质金属蛋白酶 - 2 ( MMP- 2 )、基质金属蛋白酶 - 9( MMP- 9)的表达及其规律。方法　采用立体定向技术制作大鼠脑出血模型 ,在脑出血后不同时间分别断头取脑 ,免疫组化法测定脑组织 MMP- 2、MMP- 9的表达量。结果　 ( 1)与假手术对照组比较 ,脑出血后 6 h血肿周围可见到微血管内皮表达 MMP- 9( P<0 .0 1) ,48h达高峰 ,至 5～ 7d后下降 ,但仍高于假手术对照组 ( P<0 .0 1) ,2周时降至零表达 ;12～ 2 4h中性粒细胞亦表达 MMP- 9;( 2 ) MMP- 2的表达要迟于 MMP- 9,2 4h可见到少量的 MMP- 2表达 ( P>0 .0 5 ) ,5～ 7d时逐渐达高峰 ( P<0 .0 1) ,主要在巨噬细胞上表达 ,2周时仍保持较高水平 ( P<0 .0 1)。结论　脑出血后出血侧血肿边缘有 MMP- 9、MMP- 2表达 ,推测 MMP- 9在急性期参与了脑水肿的形成 ,而 MMP- 2在脑出血后期可能参与了脑组织的修复.     

基质金属蛋白酶9在实验性自身免疫性脑脊髓炎大鼠发病过程中的动态表达

目的通过检测基质金属蛋白酶-9(MMP-9)在EAE大鼠发病过程中不同阶段外周血和中枢神经系统中的表达水平及动态变化,以探讨其在多发性硬化发病过程中的作用及机制。方法 Wistar雌性大鼠80只,分为模型组(EAE组)、完全福氏佐剂组(CFA组),分别于免疫后6天、8天、10天、12天、14天、16天、18天及20天取视交叉处脑组织和脊髓腰膨大段行HE染色观察炎性细胞的浸润状况;免疫组化法检测脑和脊髓组织中MMP-9的表达,酶联免疫吸附实验测定血清中MMP-9的含量。结果 EAE组大鼠脊髓和脑组织中MMP-9阳性细胞数及血清中MMP-9水平均显著高于同期CFA组(P<0.05);EAE 10天组与EAE 6天、14天、18天及20天组比较,大鼠脊髓腰膨大处MMP-9阳性细胞数较多(P<0.05);EAE 12天组与EAE 6天组、8天组、14天组、16天组、18天组及20天组比较,大鼠脑组织视交叉处MMP-9阳性细胞数较多(P<0.05);EAE 12天组与EAE 6天组、8天组、10天组、14天组、16天组、18天组及20天组相比较,大鼠血清中MMP-9含量较高(P<0.05)。结论在EAE大鼠发病前期即有中枢组织内MMP-9的高表达,且EAE大鼠脊髓中MMP-9的高表达要早于脑组织和外周血,但MMP-9表达的高峰在第12天与病理变化和疾病进展是同步的。     

Chemokine expression by astrocytes plays a role in microglia/macrophage activation and subsequent neurodegeneration in secondary progressive multiple sclerosis

The pathological hallmarks of secondary progressive (SP) multiple sclerosis (MS) include slowly expanding demyelination and axonal damage with less inflammation. To elucidate the pathomechanisms of secondary progressive (SP) multiple sclerosis (MS), we have investigated the expression of chemokines, chemokine receptors, matrix metalloproteinase-9 (MMP-9) and immunoglobulins in the demyelinating plaques. Immunohistochemical analysis revealed that numerous hypertrophic astrocytes were observed at the rim, but not in the center, of the chronic active lesions. Microglia/macrophages phagocytosing myelin debris were also found at the lesion border. In contrast, T cell infiltration was minimal in these plaques. Characteristically, at the rim of the lesions, there were abundant immunoreactivities for monocyte chemoattractant protein-1 (MCP-1)/CCL2 and interferon-γ inducible protein-10 (IP-10)/CXCL10 and their receptors, CCR2 and CXCR3, while these immunoreactivities were weak in the center, thus forming a chemokine gradient. Double immunofluorescense staining demonstrated that cellular sources of MCP-1/CCL2 and IP-10/CXCL10 were hypertrophic astrocytes and that both astrocytes and microglia/macrophages expressed CCR2 and CXCR3. MMP-9 was also present at the rim of the lesions. These results suggest that MCP-1/CCL2 and IP-10/CXCL10 produced by astrocytes may activate astrocytes in an autocrine or paracrine manner and direct reactive gliosis followed by migration and activation of microglia/macrophages as effector cells in demyelinating lesions. Targeting chemokines in SPMS may therefore be a powerful therapeutic approach to inhibit lesional expansion.     

MMP-2、MMP-9在人脑胶质瘤及其浸润组织中的表达和临床意义

目的 阐述MMP-2、MMP-9与胶质瘤的浸润机制.方法 应用免疫组化方法 和原位杂交方法 检测胶质瘤和胶质瘤浸润组织中的MMP-2、MMP-9蛋白及MMP-2 mRNA、MMP-9 mRNA的表达.结果 MMP-2 mRNA和MMP-9 mRNA表达在Ⅰ、Ⅱ、Ⅲ和Ⅳ级胶质瘤的阳性表达分别为5.26±1.47、9.51±0.96、14.58±1.42、20.56 4±1.56和7.90±0.50、14.46±0.75、23.54±1.32、28.07±0.81.MMP-2 mRNA和MMP-9 mRNA在Ⅰ～Ⅱ级胶质瘤浸润组织与Ⅲ～Ⅳ级胶质瘤浸润组织中的阳性表达分别为5.70±0.95、8.20±0.43和2.30±0.14、10.32±0.65.两者之间有显著差异(P<0.01).结论 胶质瘤的恶性程度与MMP-2、MMP-9表达呈正相关,随着胶质瘤的恶性程度的增高而增加.恶性程度高的胶质瘤,分泌基质金属蛋白酶能力越强,肿瘤的浸润性也越强.在胶质瘤治疗的过程中,即使肿瘤组织自身被切除,浸润组织则是胶质瘤复发的根源.     

Gene expression profiling in multiple sclerosis brain

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and the leading cause of non-traumatic neurological disability in young adults in the United States and Europe. The clinical disease course is variable and starts with reversible episodes of neurological disability in the third or fourth decade of life. Microarray-based comparative gene profiling provides a snapshot of genes underlying a particular condition. Several large scale microarray studies have been conducted using brain tissue from MS patients. In this review, we summarize existing data from different gene expression profiling studies and how they relate to understand the pathogenesis of MS.     

Age-related gadolinium-enhancement of MRI brain lesions in multiple sclerosis

There is evidence that inflammatory processes in multiple sclerosis (MS) are age-dependent. In this study we evaluated the impact of aging on gadolinium (Gd) enhancement of brain magnetic resonance imaging (MRI) lesions in MS patients. Pre- and post-contrast MRI scans, acquired using a standardized procedure by the same MRI scanner, at least 1 month far from clinical relapse or steroid treatment, were examined in 200 disease-modifying treatment free MS patients. Seventy-three patients (36.5%) showed at least one enhancing lesion. Age at MRI examination (p=0.0001), disease duration (p=0.002) and EDSS score were significantly (p=0.02) lower, whereas relapse rate in the preceding 2 years was higher (p=0.003) in patients with enhancing lesions than in patients with unenhancing scans. Multivariate logistic analysis showed that current age was the variable better predicting Gd enhancement (p=0.004). The odds ratios were 0.95 (CI: 0.92-0.98) for each year of patient's age and 0.64 (CI: 0.48-0.87) for each age decade. The main changes in enhancement risk occurred after 35 years of age. Multivariate Poisson regression model showed that relapse rate in the preceding 2 years (p<0.0001) and current age (p=0.0003) were the best predictors of the number of enhancing lesions. This information can be used to increase the statistical power of clinical trials using Gd-enhancing lesions as an outcome measure.     

CDlb is expressed in multiple sclerosis lesions

Recent observations have shown that CD1 molecules act as restriction elements in the presentation of antigens to specialized subsets of T cells. To examine the expression of CD1 molecules in multiple sclerosis (MS) lesions, frozen sections of central nervous system (CNS) tissues from nine MS and three other neurological disease (OND) patients, one patient with Wilson's disease, and one non-neurological control were stained by immunocytochemistry. In chronic-active MS lesions, CDlb immunoreactivity was prominent on perivascular inflammatory cells whereas macrophages within the lesion showed little reactivity. At the lesion edge, intense immunoreactivity for CDlb was found on hypertrophie astrocytes. High level expression of CDlb in MS lesions was found to colocalize with the presence of GM-CSF in astrocytes. In chronic-silent lesions, CDlb expression was found on only a few perivascular astrocytic foot processes and the occasional perivascular macrophage. CDlb was not found in the tissues studied for control purposes. In contrast, MHC class II expression was detected on microglia in all tissues examined. The relatively low level expression of CDlb in normal-appearing tissues, chronic-silent lesions and in the OND controls supports the conclusion that the expression of CDlb in active MS lesions is significantly upregulated and could contribute to lesion development.     

多发性硬化患者产后复发并发吉兰-巴雷综合征的诊治

目的探讨多发性硬化(MS)患者产后复发并发吉兰-巴雷综合征的临床特点,以期为临床医生提供诊断、鉴别诊断及治疗线索。方法报道本院1例MS患者产后复发并发吉兰-巴雷综合征的临床表现、血液、脑脊液、影像学、电生理检查和治疗,评价治疗前后EDSS评分。分析临床资料特点并随访4个月。结果患者为27岁女性,主要表现为产后四肢无力(下肢重于上肢)、麻木、呼吸困难伴尿便障碍,EDSS评分:9.0分。血液检查正常,腰穿压力测不到,压颈试验不升,脑脊液白细胞数6×106·L,蛋白285mg·d L-1,颈段增强MRI示颈段脊髓肿胀,存在颈段梗阻;肌电图(EMG)示上下肢周围神经源性损害,下肢重于上肢。给予患者甲强龙、丙种球蛋白治疗。出院时EDSS评分:6.0分,随访6月时EDSS评分:4.0分。结论 MS患者产后复发率高,并发吉兰-巴雷综合征病情重,应注意鉴别诊断,可应用丙种球蛋白预防治疗。     

MMP7 cleaves remyelination‐impairing fibronectin aggregates and its expression is reduced in chronic multiple sclerosis lesions

Upon demyelination, transient expression of fibronectin precedes successful remyelination. However, in chronic demyelination observed in multiple sclerosis (MS), aggregates of fibronectin persist and contribute to remyelination failure. Accordingly, removing fibronectin (aggregates) would constitute an effective strategy for promoting remyelination. Matrix metalloproteinases (MMPs) are enzymes known to remodel extracellular matrix components, including fibronectin. Here, we examined the ability of MMPs to degrade fibronectin aggregates. Our findings reveal that MMP7 cleaved fibronectin aggregates resulting into a prominent 13 kDa EIIIA (16 kDa EDA)‐containing fragment. MMP7 was upregulated during lysolecithin‐induced demyelination, indicating its potential for endogenous fibronectin clearance. In contrast, the expression of proMMP7 was substantially decreased in chronic active and inactive MS lesions compared with control white matter and remyelinated MS lesions. Microglia and macrophages were major cellular sources of proMMP7 and IL‐4‐activated, but not IFNγ+LPS‐activated, microglia and macrophages secreted significant levels of proMMP7. Also, conditioned medium of IL‐4‐activated macrophages most efficiently cleaved fibronectin aggregates upon MMP‐activating conditions. Yet, coatings of MMP7‐cleaved fibronectin aggregate fragments inhibited oligodendrocyte maturation, indicating that further degradation and/or clearance by phagocytosis is essential. These findings suggest that MMP7 cleaves fibronectin aggregates, while reduced (pro)MMP7 levels in MS lesions contribute to their persistent presence. Therefore, upregulating MMP7 levels may be key to remove remyelination‐impairing fibronectin aggregates in MS lesions.     

Serial magnetisation transfer ratios in gadolinium-enhancing lesions in multiple sclerosis

The magnetisation transfer (MT) ratio of eight multiple sclerosis lesions has been studied serially. Initially, when the lesions showed gadolinium enhancement, there was a marked reduction in their MT ratio compared with normal white matter. Follow-up a mean of 11 months later (range 3–23 months), when the lesions no longer enhanced, revealed a consistent and usually marked recovery of the MT ratios towards normal. The MT ratio is thought to reflect the structural integrity of tissues with an important contribution from myelin and axons. MT imaging is a promising tool for elucidating pathophysiology and monitoring treatment in multiple sclerosis. Received: 12 February 1996 Received in revised form: 14 November 1996 Accepted: 16 December 1996     

实验性脑出血后脑水肿的动态变化及其与MMP-9的关系

目的探讨脑出血后脑水肿和MMP-9表达的动态变化,并初步探讨其关系。方法健康雄性Wistar大鼠56只,将动物随机分成假手术组和脑出血组,大鼠尾壳核区注入自体非肝素抗凝动脉血建立脑出血模型,采用干湿重法测量脑组织水含量;免疫组织化学方法观察术后不同时间点MMP-9的动态变化。结果血肿形成后脑水肿产生迅速,从脑出血后3h开始增加,48~72h达高峰;脑出血后12h时,血肿周围组织中开始出现大量的深棕黄色阳性染色细胞,术后72h达高峰,以后逐渐下降,至120h时仍维持在较高水平。结论脑出血后脑水肿可能与MMP-9的活化有关。