Peripheral levels of matrix metalloproteinase-9, interleukin-6, and C-reactive protein are elevated in patients with acute coronary syndromes: correlations with serum troponin I

BACKGROUND: Acute coronary syndromes (ACS) are characterized by activation of systemic and local inflammatory mediators. The interrelation between these soluble inflammatory markers and their association with markers of myocardial necrosis have not been extensively studied. HYPOTHESIS: The study was undertaken to evaluate the association of the systemic levels of matrix metalloproteinase-9 (MMP-9) and the tissue inhibitor of metalloproteinase-1 (TIMP-1), with C-reactive protein (CRP), interleukin-6 (IL-6), and serum troponin-I in patients admitted with ACS. METHODS: Analysis of serum concentrations of the above inflammatory markers was performed in 53 patients with unstable angina (UA) and in 15 with non-ST-segment elevation myocardial infarction (NSTEMI) within 48 h of admission, and 34 patients with stable coronary artery disease. RESULTS: Compared with patients with stable angina, those with ACS had elevated admission levels of MMP-9 (p = 0.04), CRP (p < 0.001), and IL-6 (p = 0.001), but not TIMP-1 (p = 0.55). Compared with patients with UA, those with NSTEMI also had higher levels of IL-6 (p < 0.001), CRP (p = 0.002), and MMP-9 (p = 0.05). CONCLUSIONS: In patients with ACS, the admission levels of inflammatory mediators, including MMP-9, CRP, and IL-6 are significantly elevated, specifically in association with serum troponin I. Systemic and local markers of inflammatory activity may be directly associated with myocardial injury.     

Elevated circulating levels of matrix metalloproteinase-9 and -2 in patients with symptomatic coronary artery disease

BACKGROUND: Matrix metalloproteinases (MMP-9 and MMP-2) have been implicated in development of atherosclerosis and plaque rupture in acute coronary syndromes (ACS). AIM: To determine the relationship between circulating MMPs and symptomatic coronary artery disease. METHODS: Plasma levels of MMP-9 and MMP-2 were measured in patients with ACS, stable angina (SA) and in controls, using a quantitative gelatin zymography. These measurements were correlated with markers of systemic inflammation (hs-CRP) in all subjects and myocardial injury (troponin T) in patients with ACS. RESULTS: Plasma MMP-9 in ACS was greater than in SA, and was greater in SA than in controls (P < 0.01 ACS vs SA and controls, P < 0.01 SA vs control). Plasma MMP-2 was significantly greater in ACS than SA or controls (P < 0.01 vs SA and controls). There was strong overall relationship between hs-CRP and MMP-9 (r = 0.65, P < 0.0001) driven by a significant relationship in ACS patients (r = 0.58, P = 0.02), as there was no significant association in SA or controls. A weaker overall correlation was found between hs-CRP and MMP-2 (r = 0.39, P = 0.02), but no significant relationship was present for either of the two patient subgroups or controls. There was no correlation between levels of troponin T and MMP-9, MMP-2 or hs-CRP in ACS patients. CONCLUSION: Quantitative gelatin zymography identifies increased circulating levels of MMP-9 and MMP-2 in patients with symptomatic coronary disease. MMP-9 and MMP-2 are higher in ACS than SA patients and might have use as markers of plaque rupture or instability. The strong relationship between MMP-9 and hs-CRP in ACS patients suggests MMP-9 might be an additional marker and/or consequence of the inflammatory component in ACS.     

Prognostic significance of p53 and matrix metalloproteinase-9 expression in follicular lymphoma

Objectives: p53 mutations and high protein expression are associated with adverse prognosis in several lymphoma subtypes. Matrix metalloproteinase‐9 (MMP‐9) has also been found to correlate with poor survival in all lymphomas studied. The data concerning the clinical role of protein expression of p53 or gelatinases and their inhibitors in follicular lymphoma are rare. The purpose of this study was to evaluate the prognostic and clinical implications of the immunoreactive proteins p53, MMP‐2, MMP‐9, tissue inhibitor of matrix metalloproteinase‐1 (TIMP‐1) and TIMP‐2 in follicular lymphoma. Methods: The material consisted of 67 patients with primarily non‐transformed follicular lymphoma. Diagnostic lymph node tissue sections of patients were stained by immunohistochemical method using specific monoclonal antibodies. Results: p53 over‐expression was detected in 8 (12%) out of 67 cases. p53 over‐expression correlated with high grade (P = 0.011), bulky tumour (P = 0.031) and forthcoming transformation (P = 0.001). It also correlated with poor overall (P = 0.001) and cause‐specific survival (P = 0.010) in multivariate analysis and had a strong inverse correlation with time to transformation (P < 0.001). MMP‐2, MMP‐9 and TIMP‐2 expression correlated with high grade. MMP‐9 positivity in centroblasts correlated with good chemotherapy response (P = 0.019), but it was not prognostic for survival. MMP‐2, TIMP‐1 or TIMP‐2 did not associate with survival, either. Conclusions: In this study, p53 over‐expression predicted both transformation to diffuse large B‐cell lymphoma and poorer overall and cause‐specific survival of patients with follicular lymphoma. Expression of gelatinases or their inhibitors did not have any significant correlations with prognosis, although MMP‐9 predicted a good response to first‐line chemotherapy.     

环孢素A对链脲佐菌素诱导的糖尿病大鼠肾脏基质金属蛋白酶-2和基质金属蛋白酶-9表达的影响

目的 观察免疫抑制剂环孢素A(CsA)对糖尿病大鼠肾脏基质金属蛋白酶(MMP)表达的影响.方法 健康雄性SD大鼠74只,平均体重250 g,采用数字表法随机分为正常对照组(n=10)、单纯糖尿病组(n=8)、胰岛素治疗组(n=9)、造模前低剂量CsA治疗组(n=9;造模前1周皮下注射1μg·g-1·d-1 CsA)、造模前中剂量CsA治疗组(n=8;造模前1周皮下注射4μg·g-1·d-1CsA)、造模前高剂量CsA治疗组(n=8;造模前1周皮下注射8μg·g-1·d-1CsA)、造模后低剂量CsA治疗组(n=8;造模后1周皮下注射1μg·g-1·d-1CsA)、造模后中剂量CsA治疗组(n=7;造模后1周皮下注射4μg·g-1·d-1 CsA)和造模后高剂量CsA治疗组(n=7;造模后1周皮下注射8μg·g-1·d-1 CsA).8周后处死动物,采用免疫组织化学法、逆转录-聚合酶链反应和Western blot检测肾脏MMP-2、MMP-9 mRNA和蛋白表达水平.采用单因素方差分析和直线相关分析进行统计学分析.结果 8周时,单纯糖尿病组24 h尿微量蛋白显著高于正常对照组[分别为(5.80±3.23)、(1.24±0.21)mg/24 h,F=4.229,P＜0.01];各CsA治疗组24 h尿微量蛋白不同程度降低,与正常对照组比较差异无统计学意义.单纯糖尿病组肾小管上皮细胞和肾小球系膜基质MMP-2、MMP-9mRNA(分别为2.22±0.08、2.55±1.10)和蛋白表达(分别为3.1±1.5、2.8±1.0)显著高于正常对照组(MMP-2 mRNA:0.70±0.26,F=6.031;MMP-9 mRNA:0.37±0.24,F=5.193;MMP-2蛋白:1.0±0.0,F=7.532;MMP-9蛋白:1.0±0.0,F=6.100;均P＜0.01).胰岛素治疗对其表达无影响,但CsA干预可下调MMP-2、MMP-9 mRNA和蛋白的异常表达.MMP-2 mRNA与蛋白表达呈显著正相关(r=0.618,P＜0.01),而MMP-9 mRNA与蛋白表达未见相关性(r=0.420,P＞0.05).结论 CsA可减少糖尿病大鼠肾脏MMP-2和MMP-9基因转录和蛋白表达,改善细胞外基质代谢紊乱,可能具有延缓糖尿病肾病发生的作用.     

Steroid therapy and renal dysfunction are independently associated with serum levels of matrix metalloproteinase-3 in patients with rheumatoid arthritis

Objective: This study aimed to evaluate whether the level of serum matrix metalloproteinase-3 (MMP-3), a marker of synovium inflammation, is affected by clinical characteristics of patients in rheumatoid arthritis (RA) patients.

Methods: We analyzed data from 1087 female patients with RA. Pearson’s correlation coefficients were calculated to explore associations between variables. Stepwise multiple linear regression analysis was performed to evaluate patient background variables that could potentially affect serum MMP-3 levels.

Results: Serum MMP-3 was moderately correlated with C-reactive protein (CRP) (r: 0.478). Factors that independently influenced serum MMP-3 levels were CRP (β: 0.450), prednisolone (PSL) use (β: 0.100), estimated glomerular filtration rate (eGFR) (β: ?0.085), swollen joint count assessed on 28 joints (β: 0.072), and body mass index (β: ?0.061) in female patients with RA. In RA patients with PSL use, factors that independently influenced serum MMP-3 levels were CRP (β: 0.480), eGFR (β: ?0.175), and PSL dose (β: 0.171).

Conclusions: Our findings suggest that steroid therapy and renal dysfunction affect serum MMP-3 levels in patients with RA.     

Role of melatonin in regulating matrix metalloproteinase-9 via tissue inhibitors of metalloproteinase-1 during protection against endometriosis

Abstract:  Endometriosis is a gynecological disease of women and plausibly regulated by matrix metalloproteinases (MMPs). However, mechanisms of alterations in MMPs during endometriosis remain unclear. Human endometriotic tissues possessing varying degrees of severity were examined for expression of MMPs and tissue inhibitors of metalloproteinase (TIMP)-1. In addition, endometriosis was generated in mice and endometriotic tissues were tested for MMP-9 activity. Results show significant upregulation of secreted and synthesized proMMP-9 activity with duration and severity of endometriosis. Along with upregulation of activity, the expression of proMMP-9 was found increased while TIMP-1 expression followed an inverse trend. The effect of melatonin, a major secretory product of the pineal gland, on endometriosis was examined in preventive and therapeutic models in mice. The results show that melatonin arrested lipid peroxidation and protein oxidation and downregulated proMMP-9 activity and expression in a time and dose-dependent manner while protecting and regressing peritoneal endometriosis. Moreover, the attenuated activity and expression of proMMP-9 were associated with subsequent elevation in the expression of TIMP-1. Our study reveals for the first time the role of melatonin in arresting peritoneal endometriosis in mice and a novel marker, expression ratio of proMMP-9 versus TIMP-1, was identified for assessing severity and progression of endometriosis.     

舒血宁对不稳定型心绞痛患者CRP和MMP-9的影响

目的观察经舒血宁治疗后,不稳定型心绞痛（unstable angina pectoris,UAP）患者体内高敏C-反应蛋白（highsensitivity C．reactive protein,hs-CRP）和基质金属蛋白酶-9（matrix metalloproteinase-9,MMP-9）水平的变化。方法：100例UAP患者随机分为试药组和对照组,各50例。对照组给于常规治疗,试药组在此基础上加用舒血宁30mm溶于250 ml 50 s／L葡萄糖注射液中静脉滴注,1次／d,连续治疗两周。在人院时、入院后12 h、24 h、48 h、7 d及14d抽取外周血,检测各组患者hs-CRP和MMP-9表达水平变化。结果：两组UAP患者外周血hs-CRP水平在入院后均开始升高,于24 h达高峰,24 h后逐渐下降;两组MMP-9水平入院后12 h达高峰,后逐渐下降;与对照组相比,试药组hs-CRP和MMP-9水平在入院后12 h、24 h、48 h、7 d及14 d均显著降低。结论：舒血宁可显著降低UAP患者体内hs-CRP和MMP-9表达水平。     

Induced sputum matrix metalloproteinase-9 correlates with lung function and airway inflammation in children with cystic fibrosis

Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in causing airway damage in chronic inflammatory lung diseases, including cystic fibrosis (CF). Our primary objective was to examine the relationship between matrix metalloproteinase-9 (MMP-9) and pulmonary function, as measured by forced expiratory volume in 1 sec (FEV1), in children with CF. We measured MMP-9 and its natural tissue inhibitor of metalloproteinase-1 (TIMP-1) in induced sputum from 18 clinically stable CF children with normal to mildly abnormal lung function and 7 healthy control children. Measures of airway inflammation from induced sputum included cell counts and differentials, interleukin-8 (IL-8), neutrophil elastase, MMP-9, and TIMP-1. Infection was assessed through quantitative bacterial counts. Induced sputum levels of MMP-9 and TIMP-1 were significantly increased in children with CF compared with healthy controls. Also, the MMP-9/TIMP-1 molar ratio was higher in the CF group. Among CF children, there was a significant inverse relationship between MMP-9 and FEV1. In addition, sputum MMP-9 and TIMP-1 concentrations significantly correlated with total white cells and neutrophils, IL-8, and neutrophil elastase. Neither MMP-9 nor TIMP-1 correlated with airway infection. We conclude that clinically stable CF children with normal to mildly abnormal lung function have an increased burden of MMP-9 in their airways. The observed relationships of MMP-9 with lung function and other measures of airway inflammation suggest that this enzyme may be a useful marker of airway injury and airflow obstruction in persons with CF.     

尤瑞克林注射液对脑梗死患者血清基质金属蛋白酶9及预后的影响

目的研究尤瑞克林注射液对脑梗死患者血清基质金属蛋白酶9(matrix metalloproteinase-9,MMP-9)及预后的影响,探讨尤瑞克林注射液治疗脑梗死的作用机制。方法采用随机、双盲的方法,将发病48 h内入院的大面积脑梗死患者50例分为对照组和尤瑞克林组(尤瑞克林注射液0.15 PNA/d),每组25例,连续用药14 d。治疗前后检测血清MMP-9水平,应用美国国立卫生研究院脑卒中量表(NIHSS)及日常生活活动量表Barthel指数(BI)记分法对入院后当天及3个月时神经功能缺损程度进行评分。结果除尤瑞克林组1例患者用药后血压下降,无其他不良反应。对照组和尤瑞克林组治疗后14 d血清MMP-9水平明显降低,且尤瑞克林组较对照组明显降低,差异有统计学意义(P<0.01);对照组和尤瑞克林组治疗后3个月神经功能缺损程度评分较治疗前明显改善,且尤瑞克林组神经功能缺损程度评分改善明显优于对照组(P<0.01)。结论短期应用尤瑞克林注射液可以改善脑梗死患者的预后,其机制可能与降低血清MMP-9水平有关。     

急性脑梗死溶栓患者血清基质金属蛋白酶-9的动态变化及临床意义

目的观察基质金属蛋白酶-9（MMP-9）在急性脑梗死溶栓治疗患者血清中的动态变化并探讨其临床意义。方法采取30例急性脑梗死溶栓患者（溶栓前、溶栓后6h、24h、7d、14d）的肘静脉血，检测其不同时期血清MMP-9水平，以同期收住院30例脑供血不足患者的血清MMP-9水平作为基线参考。同时对脑梗死患者溶栓前及溶栓后14d行NIHSS评分，溶栓前及溶栓后90d行日常生活能力评分（mRS）以作为近中期疗效判断指标，并按评分改善程度分组比较其MMP-9水平的差异。结果急性脑梗死患者溶栓前及溶栓后6h、24h、7d、14d血清MMP-9水平均较基线水平有显著提高，且呈动态变化，在溶栓后7d达高峰。溶栓后14dNIHSS评分改善程度与MMP-9峰值水平存在负相关（r=0．65），90dmRS评分不同改善程度组其血清MMP-9峰值水平存在差异。结论急性脑梗死溶栓患者血清MMP-9水平呈动态变化，7d达高峰。血清MMP-9峰值水平可以初步预测脑梗死患者溶栓近中期疗效。     

基质金属蛋白酶-9对大鼠动脉粥样硬化斑块内血管生成及斑块稳定性的影响

目的:研究基质金属蛋白酶-9（MMP-9）与动脉粥样硬化(AS)斑块内血管生成的关系及强力霉素干预的效果。方法: 将36只雄性Wistar大鼠随机分为对照组（A组,普通饮食喂养）、AS组（B组）和强力霉素干预组（C组）,B组和C组均给予高脂饮食＋维生素D3腹腔注射,C组同时给予强力霉素腹腔注射。采用酶法并以全自动生化分析仪测量血脂,双抗体夹心ABC-ELISA法检测血清MMP-9的水平。取主动脉切片行HE染色,观察斑块形态,计数易损斑块的数目。对内皮细胞标记物CD34行免疫组织化学染色法以检测斑块内新生血管密度。结果: B组和C组各项血脂的水平无明显差异,但均明显高于A组（P<0.05）。B组和C组血清MMP-9的水平明显高于A组（P<0.05）,B组又高于C组（P<0.05）。与B组比较,C组易损斑块数、CD34+面积/扫描面积(R)比均降低(P<0.01)。结论: 强力霉素能增强斑块稳定性,这种作用可能是通过降低MMP-9的水平进而减少了斑块内血管生成。     

Reverse ventricular remodelling after cardiac resynchronization therapy is associated with a reduction in serum tenascin-C and plasma matrix metalloproteinase-9 levels

BACKGROUND: In heart failure patients, cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling. AIM: The aim of this study was to evaluate whether changes in levels of circulating biomarkers of extracellular matrix metabolism correlate with the response to CRT. METHODS AND RESULTS: Clinical parameters, left ventricular (LV) volumes, and circulating levels of tenascin-C (TNC), matrix metalloproteinase-2 (MMP-2), MMP-9, and amino-terminal propeptide of brain natriuretic peptide (NT-proBNP) were assessed in 64 patients at baseline and 6 months follow-up. The majority of patients (72%) showed a >10% reduction in LV end-systolic volume at follow-up, and were classified as responders to CRT. The remaining patients were classified as non-responders. In responders, a significant decrease in circulating levels of TNC (from 60+/-40 ng/mL to 47+/-30 ng/mL, p<0.01), MMP-9 (from 55+/-30 AU to 44+/-27 AU, p<0.01), and NT-proBNP (from 2106+/-1805 pg/mL to 1132+/-1289 pg/mL, p<0.001) were observed at follow-up; MMP-2 levels were unchanged. In non-responders TNC, NT-proBNP, MMP-9 and MMP-2 levels remained unchanged. CONCLUSION: At 6 months follow-up, CRT was associated with reverse LV remodelling, and a significant decrease in TNC, MMP-9, and NT-proBNP levels. This suggests an important role of ECM modulation in the process of reverse ventricular remodelling in patients responding to CRT.     

基质金属蛋白酶-9和基质金属蛋白酶组织抑制剂-1在高原地区慢性肺心病发病机制中的作用

目的探讨基质金属蛋白酶。9（MMP-9）及其基质金属蛋白酶组织抑制剂-1（TIMP-1）在高原慢性肺心病（HACCP）发病机制中的作用。方法选择高原肺心病急性加重期患者56例（A组）、缓解期患者51例（B组）和健康对照组40例（c组）,采用双抗体夹心酶联免疫吸附法（ELISA）测定诱导痰上清液中MMP-9、TIMP-1表达,并分析其与呼吸功能的关系。结果A组诱导痰中MMP-9、TIMP-1和MMP-9／TIMP-1比值[分别为（976．33±201．65）．g／ml、（624．35±151．22）ng／ml、（1．55±0．16）]显著高于B组[分别为（426．74±123．14）ng／ml、（326．404-112．21）ng／ml、（1．31±0．14）,t值为8．367～17．202,P〈0．01]和C组[分别为（142．55±66．11）ng／ml、（121．78±62．26）ng／ml、（1．14±0．11）,t值为13．642—25．832,P〈0．01];B组显著高于c组（t值为6．827～14．233,P〈0．01）。A、B组诱导痰上清液中MMP-9、TIMP-1、MMP-9／TIMP-1比值与诱导痰中性粒细胞、PaCO：均呈显著正相关（r=0．304～0．743,P〈0．01或P〈0．05）,与FEVl％、Pa02均呈显著负相关（r=-0．314～-0．689,P〈0．01或P〈0．05）。结论MMP-9、TIMP-1和MMP-9／TIMP-1比值失衡在HACCP发病机制中起了一定作用,并与中性粒细胞、PaCO：呈显著正相关,与FEV。％、PaO2呈显著负相关。     

Increased serum activity of matrix metalloproteinase-9 in patients with acute variceal bleeding

Background/Aims

Matrix metalloproteinases (MMP)-2 and -9 can degrade essential components of vascular integrity. The aim of this study was to investigate the association between those MMPs and variceal bleeding (VB).

Methods

Fifteen controls, 12 patients with acute ulcer bleeding (UB) group, 37 patients with varix (V group), and 35 patients with acute VB group were enrolled. Serum was obtained to measure MMP-2 and -9 activity by zymogram protease assays.

Results

The activity levels of these compounds were compared with the controls'' median value. The median MMP-9 activity was 1.0 in controls, 1.05 in the UB group, 0.43 in the V group, and 0.96 in the VB group. The level of MMP-9 activity was higher in the VB group than in the V group (p<0.001). In the VB group, there was a signifi cant decrease in MMP-9 activity over time after bleeding (p<0.001). The median MMP-2 activity level was 1.0 in controls, 1.01 in the UB group, 1.50 in the V group, and 1.55 in the VB group. The level of MMP-2 activity was similar in the VB and V groups.

Conclusions

The level of MMP-9 activity increased in association with VB. The role of MMP-9 in the pathogenesis of VB should be verified.     

不同亚型卒中患者血清基质金属蛋白酶-2含量及其意义

目的 探讨不同亚型急性缺血性卒中患者血清基质金属蛋白酶-2(matrixmetaUoproteinase-2,MMP-2)含量的变化及其意义.方法 77例急性缺血性卒中患者按照TOAST标准进行病因学分型,大动脉粥样硬化性卒中(large-artery atherosclerosis,LAA)29例(37.66%),小动脉闭塞性卒中(small artery occlusion,sAO)23例(29.87%),心源性脑栓塞(cardioembolism,CE)13例(16.88%),原因不明的缺血性卒中(stroke ofundemomtrated etiology,SUE)7例(9.09%),其他确定原因引发的缺血性卒中(stroke ofother demonstrated etiology,SOE)5例(6.49%).用酶联免疫吸附试验(enzyme-1inked immtmosorbent assay,ELISA)检测急性缺血性卒中患者发病后24 h和7 d时血清MMP-2含量,并与42例对照者进行比较.结果 TOAST病因分型急性缺血性卒中组患者发病后24 h和7d血清MMP-2水平分别为(189.55±24.79)和(307.46±84.16)ng/ml,均显著高于对照组的(159.76 ±10.32)ng/ml(P均<0.05).在TOAST各亚型中,SOE和SUE因例数过少未做分析;在其他各型中,LAA、SAO和CE组发病后24 h血清MMP-2水平分别为(218.60±13.42)、(175.21 ±9.92)和(167.26±9.7)ng/ml,均显著高于对照组(P均<0.05);发病7d时分别为(404.75±10.30)、(293.18 ±10.91)和(211.81±11.14)ng/ml,也均显著高于对照组(P均<0.05).其中,以LAA组增高显著(P<0.01).结论 急性脑梗死患者血清MMP-2水平增高,TOAST各亚型患者组MMP-2水平变化不同,LAA组升高最显著,支持脑梗死亚型的病因不同的论点,血清MMP-2在LAA型脑梗死发病过程中起着重要作用.     

Serum matrix metalloproteinase-1 in patients with chronic viral hepatitis

BACKGROUND AND AIMS: Previously we found that serum matrix metalloproteinase (MMP)-1 activity decreased with progression of chronic liver disease. Our objectives in the present study were to observe the change in the serum MMP-1 protein concentration using recently developed specific enzyme immunoassays for MMP-1 and MMP-1 complexed with tissue inhibitor of metalloproteinases (TIMP)-1 and to elucidate the clinical usefulness of the serum MMP-1 test in chronic viral hepatitis. We measured the serum concentrations of MMP-1 and MMP-1/TIMP-1 complex using these immunoassays in 64 patients with histologically characterized chronic viral hepatitis. RESULTS: Serum MMP-1 concentration was inversely related to the histological severity of chronic hepatitis (P< 0.0001). It was closely associated with the histological degree of periportal necrosis (P< 0.0001), intralobular necrosis (P< 0.005), portal inflammation (P<0.0001) and liver fibrosis (P< 0.05). The serum concentration of MMP-1/TIMP-1 complex was also related to the histological severity of chronic hepatitis (P< 0.0001). It was associated with the degree of portal inflammation (P< 0.05), but not with the degree of periportal necrosis, intralobular necrosis or liver fibrosis. As serum MMP-1 level was closely associated with the histological degree of necroinflammation, we examined the ability of the serum MMP-1 test to differentiate active and inactive forms of hepatitis with a receiver operating curve. The results were compared with those of serum procollagen type III N-peptide (PIIINP) test. We found that the serum MMP-1 test was superior to the serum PIIINP test in assessing liver necroinflammation. CONCLUSIONS: In addition to the previously reported changes in enzyme activity, MMP-1 proteins in serum decreased during histological progression of chronic hepatitis. The serum MMP-1 test may be useful clinically to differentiate active and inactive types of hepatitis in patients with chronic viral hepatitis.     

Decrease in serum matrix metalloproteinase-9 and matrix metalloproteinase-3 levels in Zucker fa/fa obese rats after treatment with swertiamarin

Diabetes mellitus encompasses a group of chronic metabolic conditions associated with cardiovascular complications such as atherosclerosis, cardiomyopathy and nephropathy. In the present study, the authors investigated the beneficial effects of swertiamarin in diabetes and its associated cardiovascular complications in Zucker fa/fa rats. Six male Zucker fa/fa rats in each group were treated for 28 days with swertiamarin (75 mg/kg/day, intraperitoneally) or pioglitazone (30 mg/kg orally). Blood samples were collected and evaluated for several parameters. Elevated serum glucose, triglyceride, nonesterified free-fatty acid and cholesterol levels were found in untreated Zucker fa/fa rats. Serum matrix metalloproteinase (MMP)-9 and MMP-3 levels were also found to be significantly higher in untreated Zucker fa/fa rats. Treatment with swertiamarin significantly (P<0.05) reduced serum glucose, triglyceride, nonesterified free-fatty acid and cholesterol levels, and also reduced serum MMP-9 and MMP-3 levels compared with untreated rats. Swertiamarin also significantly (P<0.05) decreased serum levels of urea compared with untreated Zucker fa/fa rats. Overall, the data suggest that swertiamarin produced beneficial effects with respect to diabetes-induced cardiovascular complications such as atherosclerosis and nephropathy. A swertiamarin-induced decrease in serum MMP-9 and MMP-3 levels is one of the possible mechanisms responsible for improvement of these complications.     

Melatonin decreases matrix metalloproteinase-9 activation and expression and attenuates reperfusion-induced hemorrhage following transient focal cerebral ischemia in rats

We have previously shown that melatonin reduces postischemic rises in the blood-brain barrier (BBB) permeability and improves neurovascular dysfunction and hemorrhagic transformation following ischemic stroke. It is known that activation of the matrix metalloproteinases (MMPs) plays a crucial role in the pathogenesis of brain edema and hemorrhagic transformation after ischemic stroke. We, herein, investigated whether melatonin would ameliorate MMP-2 and MMP-9 activation and expression in a rat model of transient focal cerebral ischemia. Adult male Sprague-Dawley rats were subjected to a 90-min middle cerebral artery (MCA) occlusion using an intraluminal filament. Melatonin (5 mg/kg) or vehicle was intravenously injected upon reperfusion. Brain infarction and hemorrhage within infarcts were measured, and neurological deficits were scored. The activity and expression of MMP-2 and MMP-9 were determined by zymography, in situ zymography and Western immunoblot analysis. Cerebral ischemia-reperfusion induced increased pro-MMP-9 and MMP-9 activity and expression 24 hr after reperfusion onset. Relative to controls, melatonin-treated animals, however, had significantly reduced levels in the MMP-9 activity and expression (P < 0.01), in addition to reduced brain infarct volume and hemorrhagic transformation as well as improved sensorimotor neurobehavioral outcomes. No significant change in MMP-2 activity was observed throughout the course experiments. Our results indicate that the melatonin-mediated reductions in ischemic brain damage and reperfusion-induced hemorrhage are partly attributed to its ability to reduce postischemic MMP-9 activation and increased expression, and further support the fact that melatonin is a suitable as an add-on to thrombolytic therapy for ischemic stroke patients.     

基质金属蛋白酶-9在急性胰腺炎相关性肺损伤中表达的研究

目的 探讨基质金属蛋白酶-9在急性胰腺炎相关性肺损伤中的表达及其临床意义。方法 SD大鼠腹腔注射L-精氨酸制备急性坏死型胰腺炎(ANP)模型。透射电镜下观察肺脏组织超微结构改变；采用免疫组化法分析MMP-9在大鼠肺脏、胰腺组织中的表达及定位。对ANP死亡患者尸检的肺脏和胰腺标本蜡块进行HE染色和免疫组化分析。结果 透射电镜观察ANP大鼠肺泡基底膜水肿、坏死、断裂,肺脏间质水肿、坏死、大量粒细胞浸润,毛细血管内皮水肿、坏死、断裂；免疫组化结果显示肺间质、基底膜及间质浸润的炎症细胞和胰腺间质、基底膜均MMP-9表达阳性。ANP尸检标本胰腺和肺脏组织有明显的坏死和结构破坏,且MMP9表达阳性。结论 MMP-9在ANP大鼠和死亡患者胰腺和肺脏组织表达均阳性,MMP-9可能在APALI的发病过程中起着重要作用。     

骨关节炎兔血清中软骨寡聚基质蛋白和基质金属蛋白酶-3水平

目的 探讨血清软骨寡聚基质蛋白(COMP)与基质金属蛋白酶(MMP)-3检测应用于临床评估骨关节炎(OA)软骨病理改变的可能性.方法 伸直位石膏管型制动16只兔右后膝关节制作OA模型.以造模时间不同分为造模2周、造模6周,左后膝关节未造模故为对照组.X线影像学与病理观察模型关节的变化;评估关节软骨降解程度(OA积分);ELISA检测兔血清COMP、MMP-3水平;分析血清COMP、MMP-3水平与OA积分间的相关性.结果 (1)造模2周影像学变化较造模前不明显;造模6周兔胫骨平台边缘不光滑,关节间隙变窄,表面有毛刺样增生,胫骨平台及股骨内髁外侧可见唇样增生.(2)OA关节病变的形态学观察:造模2周兔关节软骨表面粗糙,表层裂隙;软骨细胞弥漫增多,排列紊乱;OA积分为(4.000±2.204)分.造模6周兔关节软骨表层可见较多裂隙延伸向下深达辐射层;裂隙周围可见脱水固缩坏死的软骨细胞且排列紊乱,部分成簇增生,各层结构不易分辨,有血管翳通过;OA积分为(10.620±1.408)分,与造模2周比,P=0.000.(3)造模2周兔血清COMP[(3.64±0.18)μg/L]、MMP-3[(1.99±0.81)μg/L]水平高于造模前[COMP(3.35±0.20)μg/L,MMP-3(1.61±0.71)μg/L];造模6周兔血清COMP[(3.96±0.44)μg/L]、MMP-3[(3.44±0.91)μg/L]水平高于造模前和造模2周,差异有统计学意义(P值均＜0.05).血清COMP、MMP-3水平与OA积分呈线性相关关系(r值均＞0.710,P值均小于0.05).结论 OA血清中COMP和MMP-3水平对评估OA软骨降解程度具有重要意义.

Abstract：

Objectiye To study the levels of cartilage oligomeric matrixprotein (COMP) and matrix metalloproteinase-3 (MMP-3) in the serum fluid of osteoarthritic rabbit models and their relationships with the severity of pathological changes, so as to investigate their correlation with osteoarthritis(OA). Methods The osteoarthritic animal models were get from immobilizing the right knees of 18 rabbits in full extension using plaster cast. Knee joint pathological changes of 2,6 weeks were examined for pathological severity of OA; ELISA sandwich method was used to measure the levels of COMP and MMP-3 in serum before and after modeling( at 2, 6 weeks respectively); X ray of model keens was also obtained in different period.Correlation analysis was performed to demonstrate the relationship between the levels of COMP, MMP-3 in the serum and the pathological severity of OA. Results ( 1 ) Morphological observations: immobilizing the right knees of rabbits in full extension using plaster cast was a reliable methed for osteoarthritic animal models and the typical histopathologic character was seen; the severity of osteoarthritisgradually increased with time extended. (2) The levels of COMP[(3.64 ±0. 18)μg/L], MMP-3 [(1.99 ±0. 81 ) μg/L]in the serum of 2 weeks osteoarthritic animal models were higher than those before immobilizing with plaster cast [COMP(3.35 ±0. 20) μg/L,MMP-3( 1.61 ±0. 71 ) μg/L]. The levels of COMP[(3.96 ±0. 44) μg/L],MMP-3[(3.44 ±0. 91) μg/L] of 6 weeks were much higher,with a significant difference(P ＜0.05). The levels of COMP, MMP-3 in serum had a linear correlation with the pathological severity of OA (r ＞0. 710,and P ＜ 0. 05 ). Conclusion The levels of COMP and MMP-3 in serum can help to predict and evaluate the progression of OA.