Coexistence of proangiogenic potential and increased MMP-9, TIMP-1, and TIMP-2 levels in the plasma of patients with critical limb ischemia / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

The objective of this study was to assess the angiogenic potential expressed as a quotient of vascular endothelial growth factor A (VEGF-A), as an indicator of proangiogenic activity, and the circulating receptors (soluble VEGF receptor protein R1 (sVEGFR-1) and sVEGFR-2), as indicators of the effect of angiogenic inhibition, depending on the concentrations of matrix metalloproteinase 2 (MMP-2) and MMP-9 and their tissue inhibitor 1 (TIMP-1) and TIMP-2 in the plasma of patients with lower extremity artery disease (LEAD). These blood parameters in patients with intermittent claudication (IC) and critical limb ischemia (CLI) were compared for select clinical and biochemical features. Stimulation of angiogenesis in the plasma of individuals with LEAD was evident as indicated by the significant increase in VEGF-A concentration along with reduced inhibition depending on circulating receptors sVEGFR-1 and sVEGFR-2. Critical ischemia was associated with higher VEGF-A, MMP-9, TIMP-1, and TIMP-2 concentrations than in the case of IC.

The role of serum ck-18, mmp-9 and tipm-1 levels in predicting r0 resection in patients with gastric cancer / O papel dos níveis séricos de ck-18, mmp-9 e tipm-1 na predição da ressecção r0 em pacientes com câncer gástrico

ABSTRACT Background: Gastric cancer is the 3rd most common cause of death in men and the 5th common in women worldwide. Today, surgery is the only curative therapy. Currently available advanced imaging modalities can predict R0 resection in most patients, but it can only be detected with certainty in the perioperative period. Aim: To determine the role of serum CK18, MMP9, TIMP1 levels in predicting R0 resection in patients with gastric cancer. Methods: Fifty consecutive patients scheduled for curative surgery with gastric adenocarcinoma diagnosed between 2013-2015 were included. One ml of blood was taken from the patients to analyze CK18, MMP9 and TIMP1. Results: CK18, MMP9 and TIMP1 levels were positively correlated with pathological N and the stage (p<0,05). CK-18, MMP-9 and TIMP-1 averages in positive clinical lymph nodes and in clinical stage 3, were found to be higher than the averages of those with negative clinical lymph nodes and in clinical stage 2 (p<0,05). Conclusion: Although serum CK-18, MMP-9 and TIMP-1 preoperatively measured in patients scheduled for curative surgery did not help to evaluate gastric tumor resectability, they were usefull in predicting N3-stage.

RESUMO Racional: Câncer gástrico é a terceira causa mais comum de morte em homens e a quinta em mulheres em todo o mundo. Atualmente a cirurgia é a única terapia curativa. As modalidades de imagem avançadas atualmente disponíveis podem prever a ressecção R0 na maioria dos pacientes, mas ela só pode ser detectada durante o perioperatório. Objetivo: Determinar o papel dos níveis séricos de CK18, MMP9 e TIMP1 na predição da ressecção R0 em pacientes com câncer gástrico. Métodos: Foram incluídos no estudo pacientes consecutivos agendados para operação curativa entre 2013-2015. Foi retirado 1 ml de sangue dos pacientes incluídos para estudar CK18, MMP9 e TIMP1. Resultados: Os níveis de CK18, MMP9 e TIMP1 foram positivamente correlacionados com o N patológico e o estadiamento (p<0,05). As médias CK-18, MMP-9 e TIMP-1 das pessoas com linfonodos positivos e aqueles em estágio clínico 3 foram superiores às médias das pessoas com linfonodos negativos e estágio clínico 2 (p<0,05). Conclusão: Embora as dosagens séricas de CK-18, MMP-9 e TIMP-1 em pacientes agendados para operação curativa por adenocarcinoma gástrico não ajudem a ter ideia de ressecabilidade tumoral, ela foi útil na predição de estadiamento N3.

MMP-9 Levels and IMT of Carotid Arteries are Elevated in Obese Children and Adolescents Compared to Non-Obese / Níveis de MMP-9 e EIMC mostram-se Elevados em Crianças e Adolescentes Obesos em Comparação a Não Obesos

Abstract Background: Childhood obesity is associated with increased risk of atherosclerosis and cardiovascular disease in adulthood. Increased intima-media thickness (IMT) of the carotid artery is linked to the initiation and progression of the chronic inflammatory processes implicated in cardiovascular disease. Matrix metalloproteinase-9 (MMP-9) plays an important role in the degradation of the extracellular matrix and, consequently, in the development, morphogenesis, repair and remodeling of connective tissues. Objectives: (i) to determine and compare the concentrations of MMP-9, tissue inhibitor of metalloproteinase -1 (TIMP-1), and MMP-9/TIMP-1 ratio in obese and non-obese children and adolescents; (ii) to investigate the association of these markers with common and internal IMT of carotid arteries. Methods: Cross-sectional study involving 32 obese and 32 non-obese (control) individuals between 8 - 18 years of age. Results: Significantly (p < 0.05) higher values of MMP-9 concentration, as well as a higher MMP-9/TIMP-1 ratio were detected in the obese group compared to control counterparts. Common and internal carotid IMT values were significantly higher (p < 0.001) in the obese group compared to the control group. Positive correlations were observed between the common carotid IMT values and MMP-9 concentrations as well as MMP-9/TIMP-1 ratio. Conclusions: Our data demonstrate that obese children and adolescents present higher mean IMT values, plasma MMP-9 and MMP-9/TIMP-1 ratio compared to the non-obese. Thus, these findings indicate that this group presents a risk profile for early atherosclerosis.

Resumo Fundamento: A obesidade infantil está associada a um aumento do risco de aterosclerose e doenças cardiovasculares na fase adulta. O aumento da espessura da íntima-média carotídea (EIMC) está associado ao início e progresso do processo inflamatório crônico envolvido em doenças cardiovasculares. A metaloproteinase-9 da matriz (MMP-9) tem um papel importante na degradação da matriz extracelular e, consequentemente, no desenvolvimento, morfogênese, reparação e remodelação de tecidos conjuntivos. Objetivos: (i) determinar e comparar as concentrações de MMP-9, inibidor de tecido de metaloproteinase-1 (TIMP-1) e a razão MMP-9/TIMP-1 em crianças e adolescente obesos e não obesos; (ii) investigar a associação desses marcadores com a EIM das carótidas interna e comum. Métodos: Estudo transversal com 32 indivíduos obesos e 32 não obesos (controle) entre 8 e 18 anos de idade. Resultados: Foram detectados valores significativamente mais altos (p < 0,05) de concentrações de MMP-9 e da razão MMP-9/TIMP-1 no grupo de obesos em comparação ao grupo de não obesos. Valores de EIM das carótidas comum e interna mostraram-se significativamente mais altos (p < 0,001) no grupo de obesos em comparação ao grupo controle. Correlações positivas foram observadas entre os valores de EIM da carótida comum e concentrações de MMP-9 e razão MMP-9/TIMP-1. Conclusões: Nossos dados demonstram que crianças e adolescente obesos apresentam valores médios mais altos de EIMC, MMP-9 plasmática e da razão MMP-9/TIMP-1 em comparação aos não obesos. Portanto, esses achados indicam que esse grupo apresenta maior risco de aterosclerose precoce.

Plasma Levels and Diagnostic Utility of Macrophage Colony-Stimulating Factor, Matrix Metalloproteinase-9, and Tissue Inhibitor of Metalloproteinases-1 as New Biomarkers of Breast Cancer

BACKGROUND: Macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase-9 (MMP-9), and its specific tissue inhibitor - tissue inhibitor of metalloproteinases-1 (TIMP-1) may play an important role in the pathogenesis and spread of cancer. We investigated the plasma levels of M-CSF, MMP-9, and TIMP-1 in comparison with a commonly accepted tumor marker CA 15-3 in breast cancer patients and in control groups. METHODS: The cohort included 110 breast cancer patients in groups at stages I-IV. The control group consisted of 50 healthy volunteers and 50 benign tumor patients. Plasma levels of M-CSF, MMP-9, and TIMP-1 were determined by using ELISA, while CA 15-3 concentrations were determined by using chemiluminescent microparticle immunoassay (CMIA). RESULTS: The results showed significant differences in concentrations of the analyzed parameters and in levels of CA 15-3 between the groups of breast cancer patients and the two control groups. Diagnosis using these markers was equal to that using CA 15-3 in terms of sensitivity, predictive values of positive and negativetest results (PPV, NPV) and area under the ROC curve (AUC) in the studied groups. The diagnostic specificities of MMP-9, TIMP-1, M-CSF, and CA 15-3 showed equally high values (95%). The combined use of all tested parameters with CA 15-3 resulted in increased sensitivity, NPV, and AUC, especially in the combination of M-CSF with tumor markers (76%, 64%, and 0.8653). CONCLUSIONS: These findings suggest the tested parameters are useful in the diagnosis of breast cancer patients (except stage I), when combined with CA 15-3.

Prognostic roles of endostatin, matrix metalloproteinase-2 and 9 and tissue inhibitors of metalloproteinase-1 in advanced non-small cell lung cancer

Background and aim of the work: Previous studies verified that Endostatin, matrix metalloproteinase [MMP] -2 and -9, in addition to tissue inhibitors of metalloproteinase [TIMP] -1 may play a crucial role in prognosis of non-small cell lung cancer [NSCLC]. In this study we will investigate the changes in the pretreatment serum levels of these factors and to evaluate their clinical implication in patients with advanced non-small cell lung cancer [NSCLC]

Patients and methods: Pretreatment serum samples were collected from 25 patients and 10 control healthy individuals. The levels of Endostatin, MMP-2, MMP-9, and TIMP-1 were measured using a sandwich enzyme immunoassay kit

Results: The pretreatment serum levels of Endostatin and TIMP1 were significantly elevated and correlated with their stages and survival [P< 0.05], where, the serum level of Endostatin in healthy subjects was 81.20 +/- 23.99 ng/ml and in patients with NSCLC was 354.40 +/- 164.01 ng/ml. The serum level of TIMP1 in healthy subjects was 1.49 +/- 0.29 ng/ml and in patients with NSCLC was 2.96 +/- 0.58 ng/ml. The serum level of MMP2 and 9 were non-significantly decreased in serum of NSCLC patients [P > 0.05], where the serum activity of MMP2 in healthy subjects was 0.14 +/- 0.03 ng/ml and in patients with NSCLC was 0.09 +/- 0.03% and the serum activity of MMP9 in healthy subjects was 0.13 +/- 0.019 ng/ml and in patients with NSCLC was 0.10 +/- 0.03%

Conclusions: Our results indicated that the circulating levels of Endostatin, and TIMP-1 in patients with NSCLC may be valuable future tools for treatment planning and monitoring of treatment, however, these blood tests need to be standardized and validated in large-scale prospective clinical trials

Role Of MMP-2 and MMP-9 in Resistance to Drug Therapy in Patients with Resistant Hypertension / Papel da MMP-2 e MMP-9 na Resistência à Terapia Medicamentosa em Pacientes com Hipertensão Arterial Resistente

AbstractBackground:Despite the increased evidence of the important role of matrix metalloproteinases (MMP-9 and MMP‑2) in the pathophysiology of hypertension, the profile of these molecules in resistant hypertension (RHTN) remains unknown.Objectives:To compare the plasma levels of MMP-9 and MMP-2 and of their tissue inhibitors (TIMP-1 and TIMP-2, respectively), as well as their MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios, between patients with controlled RHTN (CRHTN, n=41) and uncontrolled RHTN (UCRHTN, n=35). In addition, the association of those parameters with clinical characteristics, office blood pressure (BP) and arterial stiffness (determined by pulse wave velocity) was evaluate in those subgroups.Methods:This study included 76 individuals diagnosed with RHTN and submitted to physical examination, electrocardiogram, and laboratory tests to assess biochemical parameters.Results:Similar values of MMP-9, MMP-2, TIMP-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios were found in the UCRHTN and CRHTN subgroups (P>0.05). A significant correlation was found between diastolic BP (DBP) and MMP-9/TIMP-1 ratio (r=0.37; P=0.02) and DPB and MMP-2 (r=-0.40; P=0.02) in the UCRHTN subgroup. On the other hand, no correlation was observed in the CRHTN subgroup. Logistic regression models demonstrated that MMP-9, MMP-2, TIMP-1, TIMP-2 and their ratios were not associated with the lack of BP control.Conclusion:These findings suggest that neither MMP-2 nor MMP-9 affect BP control in RHTN subjects.

ResumoFundamento:A despeito da crescente evidência do importante papel das metaloproteinases da matriz extracelular (MMP-9 e MMP-2) na fisiopatologia da hipertensão, o perfil dessas moléculas na hipertensão arterial resistente (HAR) permanece desconhecido.Objetivo:Comparar os níveis plasmáticos de MMP-9 e MMP-2 e seus inibidores teciduais (TIMP-1 e TIMP-2, respectivamente), assim como as suas razões MMP-9/TIMP-1 e MMP-2/TIMP-2, entre pacientes com HAR controlada (HARC, n = 41) e HAR não controlada (HARNC, n = 35). Além disso, a associação desses parâmetros com as características clínicas, pressão arterial (PA) de consultório e rigidez arterial (determinada pela velocidade da onda de pulso) foi avaliada nesses subgrupos.Métodos:Este estudo incluiu 76 indivíduos com HAR submetidos a exame físico, eletrocardiografia e exames laboratoriais para a avaliação de parâmetros bioquímicos.Resultados:Valores semelhantes de MMP-9, MMP-2, TIMP-1, TIMP-2, e razões MMP-9/TIMP-1 e MMP-2/TIMP-2 foram encontrados nos subgrupos HARNC e HARC (p > 0,05). Observou-se uma correlação significativa entre PA diastólica (PAD) e razão MMP-9/TIMP-1 (r = 0,37; p = 0,02) e PAD e MMP-2 (r = -0,40; p = 0,02) no subgrupo HARNC. Por outro lado, não se observou correlação no subgrupo HARC. Os modelos de regressão logística demonstraram que MMP-9, MMP-2, TIMP-1, TIMP-2 e suas razões não se associaram com a falta de controle da PA.Conclusão:Esses achados sugerem que MMP-2 e MMP-9 não afetem o controle da PA em indivíduos com HAR.

Serum profiles of extracellualr matrix degradation inhibitors across the stages of liver fibrosis in chronic hepatitis C patients

Tissue inhibitor metalloproteinase-1 [TIMP-1] and alpha-2 macroglobulin [AMG] are extracellular matrix degeneration inhibitors that have been demonstrated to increase with liver fibrosis. However, date are lacking regarding their patterns of change. This study analyses their detailed serum profile across liver fibrosis stages in chronic hepatitis C [CHC]. Serum TIMP-1 and AMG measurements were evaluated for 78 adult male CHC patients versus liver fibrosis [F] stages [METAVIR F0-F4]. The performance characteristics for discrimination of sequential [close stages], significant [F >/= 2], and advanced [F >/= 3] fibrosis were assessed. Both TIMP-1 and AMG correlated significantly with fibrosis [r=0.31, p=0.005; r=0.37, p=0.001, respectively], but failed to discriminate sequential stages. For discrimination of significant fibrosis, the areas under receiver operating characteristics curves were small [0.59 and 0.57, respectively]. T a cut-off value of 743 ng/ml, TIMP-1 showed a 100% specificity [with 17.6% sensitivity], while at a cut-off of 3 gm/l, AMG showed 73.5% sensitivity [with 36.4% specificity]. A similarly modest discrimination was noted for advanced fibrosis. Interestingly, AMG showed an early rise with significantly higher values in F0 compared with healthy controls [3.6 +/- 1.1 vs. 1.8 +/- 0.6, respectively]. Neither TIMP-1 nor AMG could discriminate the sequential stages of fibrosis. Their modest performances for discrimination of significant and advanced fibrosis are related to the wide normal range f TIMP-1 and the early rise of AMG. A longitudinal monitoring would give a better understanding of their true changes, and examine whether patients having high AMG levels at F0 would be fast fibrosers or respond differently to therapy

Performance of diagnostic biomarkers in predicting liver fibrosis among hepatitis C virus-infected Egyptian children

The aim of the present study was to identify specific markers that mirror liver fibrosis progression as an alternative to biopsy when biopsy is contraindicated, especially in children. After liver biopsies were performed, serum samples from 30 hepatitis C virus (HCV) paediatric patients (8-14 years) were analysed and compared with samples from 30 healthy subjects. All subjects were tested for the presence of serum anti-HCV antibodies. Direct biomarkers for liver fibrosis, including transforming growth factor-β1, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), hyaluronic acid (HA), procollagen type III amino-terminal peptide (PIIINP) and osteopontin (OPN), were measured. The indirect biomarkers aspartate and alanine aminotransferases, albumin and bilirubin were also tested. The results revealed a significant increase in the serum marker levels in HCV-infected children compared with the healthy group, whereas albumin levels exhibited a significant decrease. Significantly higher levels of PIIINP, TIMP-1, OPN and HA were detected in HCV-infected children with moderate to severe fibrosis compared with children with mild fibrosis (p < 0.05). The diagnostic accuracy of these direct biomarkers, represented by sensitivity, specificity and positive predictive value, emphasises the utility of PIIINP, TIMP-1, OPN and HA as indicators of liver fibrosis among HCV-infected children.

Alteração precoce da matriz extracelular e parâmetros diastólicos na síndrome metabólica / Early change of extracellular matrix and diastolic parameters in metabolic syndrome

FUNDAMENTOS: Síndrome Metabólica (SM) está associada com maior risco cardiovascular, porém não está claro se as alterações miocárdicas presentes nessa condição, como a disfunção diastólica, são consequência de mecanismos sistêmicos ou de efeitos diretos no miocárdio. OBJETIVOS: Comparar função diastólica, biomarcadores de atividade da Matriz Extracelular (MEC), inflamação e estresse hemodinâmico, em pacientes com SM e controles saudáveis. MÉTODOS: Pacientes com SM (n = 76) e controles saudáveis (n = 30) foram avaliados clinicamente e submetidos a exame ecocardiográfico e mensuração dos níveis plasmáticos de metaloproteinase-9 (MMP9), inibidor tecidual da metaloproteinase-1 (TIMP1), proteína C reativa ultrassensível (PCR-us), resistência insulínica (HOMA-RI) e NT-proBNP. RESULTADOS: O grupo SM apresentou menor onda E' (10,1 ± 3,0 cm/s vs. 11,9 ± 2,6 cm/s, p = 0,005), maiores valores para onda A (63,4 ± 14,1 vs. 53,1 ± 8,9 cm/s, p < 0,001), razão E/E'(8,0 ± 2,2 vs. 6,3 ± 1,2; p < 0,001), MMP9 (502,9 ± 237,1 vs. 330,4 ± 162,7 ng/mL, p < 0,001), PCR-us (p = 0,001) e HOMA-RI (p < 0,001), sem diferença nos níveis de TIMP1 e NT-proBNP. Na análise multivariada, apenas MMP9 foi independentemente associada a SM. CONCLUSÃO: Pacientes com SM apresentaram diferenças em medidas ecocardiográficas de função diastólica, na atividade da MEC, PCR-us e HOMA-RI em relação aos controles. Porém, somente MMP9 foi independentemente associada com SM. Esses achados sugerem que os efeitos precoces da SM sobre a atividade da MEC podem não ser detectados nas medidas ecocardiográficas de função diastólica usuais.

BACKGROUND: Metabolic syndrome (MS) is associated with increased cardiovascular risk. It is not clear whether myocardial changes showed in this syndrome, such as diastolic dysfunction, are due to the systemic effects of the syndrome, or to specific myocardial effects. OBJECTIVES: Compare diastolic function, biomarkers representing extracellular matrix activity (ECM), inflammation and cardiac hemodynamic stress in patients with the MS and healthy controls. METHODS: MS patients (n=76) and healthy controls (n=30) were submitted to a clinical assessment, echocardiographic study, and measurement of plasma levels of metalloproteinase-9 (MMP9), tissue inhibitor of metalloproteinase-1 (TIMP1), ultrasensitive-reactive-C-Protein (us-CRP), insulin resistance (HOMA-IR) and natriuretic peptide (NT-proBNP). RESULTS: MS group showed lower E' wave (10.1 ± 3.0 cm/s vs 11.9 ± 2.6 cm/s, p = 0.005), increased A wave (63.4 ± 14.1 cm/s vs. 53.1 ± 8.9 cm/s; p < 0.001), E/E' ratio (8.0 ± 2.2 vs. 6.3 ± 1.2; p < 0.001), MMP9 (502.9 ± 237.1 ng/mL vs. 330.4±162.7 ng/mL; p < 0.001), us-CRP (p = 0.001) and HOMA-IR (p < 0.001), but no difference for TIMP1 or NT-proBNP levels. In a multivariable analysis, only MMP9 was independently associated with MS. CONCLUSION: MS patients showed differences for echocardiographic measures of diastolic function, ECM activity, us-CRP and HOMA-IR when compared to controls. However, only MMP9 was independently associated with the MS. These findings suggest that there are early effects on ECM activity, which cannot be tracked by routine echocardiographic measures of diastolic function.

Antifibrotic effects of crocetin in scleroderma fibroblasts and in bleomycin-induced sclerotic mice

OBJECTIVE: To investigate the antifibrotic effects of crocetin in scleroderma fibroblasts and in sclerotic mice. METHODS: Skin fibroblasts that were isolated from three systemic scleroderma (SSc) patients and three healthy subjects were treated with crocetin (0.1, 1 or 10 μM). Cell proliferation was measured with an MTT assay. Alpha-smooth muscle actin was detected via an immunohistochemical method. Alpha 1 (I) procollagen (COL1A1), alpha 1 (III) procollagen (COL3A1), matrix metalloproteinase (MMP)-1 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA levels were measured using real-time PCR. SSc mice were established by the subcutaneous injection of bleomycin. Crocetin (50 mg/kg/d) was injected intraperitoneally for 14 days. Dermal thickness and lung fibrosis were assessed with Masson's trichrome staining. Plasma ET-1 was detected with an enzyme-linked immunosorbent assay (ELISA). Skin and lung ET-1 and COL1A1 mRNA levels were measured via real-time PCR. RESULTS: Crocetin inhibited the proliferation of SSc and normal fibroblasts, an effect that increased with crocetin concentration and incubation time. Crocetin decreased the expression of α-SMA and the levels of mRNA for COL1A1, COL3A1 and matrix metalloproteinase-1, while crocetin increased TIMP-1 mRNA levels in both SSc and normal fibroblasts. Skin and lung fibrosis was induced, and the levels of ET-1 in the plasma, skin and lungs were elevated in bleomycin-injected mice. Crocetin alleviated the thickening of the dermis and lung fibrosis; decreased COL1A1 mRNA levels in the skin and lung; and simultaneously decreased ET-1 concentrations in the plasma and ET-1 mRNA levels in the skin and lungs of the bleomycin-induced sclerotic mice, especially during the early phase (weeks 1-3). CONCLUSION: Crocetin inhibits cell proliferation, differentiation and collagen production in SSc fibroblasts. Crocetin alleviates skin and lung fibrosis in a bleomycin-induced SSc ...

Novel inflammatory biomarkers in acute coronary syndrome

No abstract available.

Interleukin-33, matrix metalloproteinase-9, and tissue inhibitor of matrix metalloproteinase-1 in myocardial infarction

BACKGROUND/AIMS: Acute coronary syndrome (ACS) is characterized by increased inflammatory processes and endothelial activation. We investigated the association between ACS and inflammatory mediators and matrix-degrading enzymes. METHODS: We prospectively enrolled 55 consecutive patients with ACS: 25 with unstable angina (UA) and 30 with non-ST elevated myocardial infarction (NSTEMI). For comparison, 25 age- and sex-matched subjects with no significant coronary artery stenosis were included as the control group. Peripheral serum levels of interleukin (IL)-33, matrix metalloproteinase (MMP)-9, tissue inhibitor of MMP-1, and C-reactive protein (CRP) were measured on admission, and at 12, 24, 48, and 72 hours after the initial evaluation. RESULTS: Compared to serum levels in the control group, serum levels of IL-33 decreased in the NSTEMI group (p < 0.05), and levels of MMP-9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 increased in the UA group (p < 0.01, p < 0.05, respectively) and NSTEMI group (p < 0.05, p < 0.05, respectively). IL-33 levels were significantly lower on admission than at 12 hours after the initial evaluation (p < 0.05). IL-33 levels were negatively correlated with MMP-9 levels (r = -0.461, p < 0.05) and CRP levels (r = -0.441, p < 0.05). CONCLUSIONS: Elevated levels of MMP-9, TIMP-1, and decreased levels of IL-33 play a role in the development and progression of ACS.

Correlations between Serum Inflammation Factors and Left Ventricular Remodeling in Acute ST Segment Elevation Myocardial Infarction

PURPOSE: To investigate the changes and correlations of the serum inflammation factors levels and left ventricular (LV) structure and function in patients with acute ST segment elevation myocardial infarction (STEMI). MATERIALS AND METHODS: A prospective study was performed on 70 STEMI patients and 70 control subjects. Serum levels of interleukin-6 (IL-6), soluble CD40 ligand (sCD40L), metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) were measured by sandwich enzyme-linked immunosorbent assay (ELISA), and cardiac structure and function were assessed by echocardiography at admission and 3-year follow-up. RESULTS: We found that the levels of serum IL-6, sCD40L and MMP-9 increased steadily among control subjects, remote myocardial infarction and acute STEMI patients, and the level of TIMP-1 elevated remarkly at 3-year follow-up visit in STEMI. The admission level of serum MMP-9 positively correlated with LV end-diastolic and end-diastole volume (r=0.294, p=0.022; r=0.269, p=0.036, respectively), and TIMP-1 positively correlated with E/A ratio (r=0.278, p=0.044) at 3-year follow-up. CONCLUSION: The study indicates that admission levels of serum MMP-9 and TIMP-1 closely correlated with left ventricular structure and function, which may be involved in the process of post-infarction remodeling of myocardium.

Inflammatory Marker Expression and Its Implication in Korean Ischemic Stroke Patients / 대한진단검사의학회지

BACKGROUND: Ischemic stroke is a complex condition influenced by many factors. Previous studies have demonstrated that inflammatory markers might play a role in such vascular diseases. Therefore the purpose of this study was to compare the expression of inflammatory markers in Korean ischemic stroke patients and to investigate their relationship to APOE polymorphism. METHODS: The patient group consisted of 275 patients with large artery atherosclerosis (LAA, n=169) and small artery occlusion (SAO, n=106). One hundred and nineteen age matched healthy subjects were recruited as the control group. Serum levels of three inflammatory markers (matrix metalloproteinase, MMP-9; tissue inhibitor of metalloproteinase-1, TIMP-1; and high-sensitivity C-reactive protein, hs-CRP) were measured in each patient by using commercially available kits. Comparison of clinical risk factors, inflammatory marker levels, and APOE genotypes between the stroke patient group and control group and between the two patient subgroups was assessed. RESULTS: Comparison of the stroke group to control group showed significantly elevated levels of circulating MMP-9 (P<0.01) and hs-CRP (P=0.01). Comparison between the individual subgroups revealed a significantly higher level of only TIMP-1 in the LAA subgroup compared to the SAO subgroup (P<0.01). There was no significant difference in inflammatory marker levels among each allele carrier. CONCLUSIONS: The present study revealed the obvious tendency of increased circulating inflammatory markers in the patients with acute ischemic attack, especially MMP-9 and hs-CRP. Our observations suggest that measurement of serum MMP-9, TIMP-1, and hs-CRP levels may be useful in the diagnosis of ischemic stroke patients.

Evaluation of selected markers of liver fibrosis in chronic hepatitis C virus patients

To evaluate the usefulness of serum hyaluronan [HA], matrix rnetalloproteinase-9 [MMP-9] and tissue inhibitor of metalloproteinase-1 TIMP-1 as well as AST/ALT ratio [whether as isolated or combined variables] in discrimination of stages of fibrosis in chronic hepatitis C [CHC] patients. Internal Medicine, Medical Biochemistry and Pathology Departments, Faculty of Medicine, Cairo University and Internal Medicine Department. Theodor Research Institute. Thirty six patients with CHC and twelve age and sex-matched healthy subjects as a control group. Histological staging of fibrosis [F0. F1, F2, F3 and F4] was performed in liver biopsy specimen according to the METAVIR Score. Serum levels of HA, MMP-9 and TIMP-l were determined by the Enzyme Linked Immunosorbent Assay [ELISA]. The AST/ALT ratio was calculated. Levels of serum HA and TIMP-I were significantly increased in all stages of fibrosis versus the control group. The AST/ALT ratio was significantly increased while the MMP-9 was significantly decreased in the F2, F3 and F4 stages only versus the controls. Using receiver operating characteristic analysis, the area under the curve [AUC] of the score to discriminate extensive fibrosis [F3] and cirrhosis [F4] stages of CHC from early stages of CHC [FO. Fl, F2] were 0.98 for TIMP-1. with a sensitivity of' 100% and specificity 72.9% . As for HA, the AUC was 0.93% with a sensitivity of' l00f and specificity 57.8% . By multivariate regression analysis, only HA followed by TIMP-1 wee independently associated with extensive fibrosis and/or cirrhosis and were accurate in discriminating F3/F4 stages from the early F0/F1/F2 stages. Furthermore, a combination of the our studied parameters increased the accuracy. The present results suggest that the serum fibrotic markers, especially HA and TIMP-1, may be clinically useful in discriminating early fibrotic stages from the late extensive fibrosis and cirrhosis stages in patients with CHC, especially if combined with other variables, as MMP-9 and AST/ALT ratio

Evaluation of some liver fibrosis markers in chronic liver diseases

Liver fibrosis is a dynamic bi-directional process involving phases of progression and regression. Its diagnosis is dependent on histopathological examination of biopsy specimens. The aim of this study was to evaluate some non invasive serum markers of liver fibrosis and to correlate them with liver biopsy. Fifty patients with chronic liver diseases matched with 10 age and sex healthy blood donors were included in the study. For both groups; estimation of serum matrix metalloproteinase 9[MMP-9], tissue inhibitor of metalloproteinase 1[TIMP-1] by ELISA technique and haptoglobin by RID, scoring of the age-platelet index [API], AST to platelet ratio index[APRI],and prothrombin time [PT] were done. For the patients, histopathological examination of liver biopsy specimens for assessment of necroinflammatory grade [A] and fibrosis stage [F] applying the METAVIR scoring system. API showed a significant positive correlation with both fibrosis and necroinflammatory activity, by using ROC curve for discrimination of significant fibrosis [F>/= 2] and moderate to severe necroinflammatory activity [A>/= 2], the AUROCs were 0.88 +/- 0.09 and 0.69 +/- 0.16 respectively. In case of Platelet count the AUROC was 0.80 +/- 0.12 for the diagnosis of established cirrhosis [F4]. PT showed a significant positive correlation with fibrosis progression, and it was a sensitive predictor of significant fibrosis and the AUROCs, for [F >/= 2] and [F4] were 0.67 +/- 0.15 and 0.76 +/- 0.15 respectively. While APRI showed a significant positive correlation with both fibrosis stage and necroinflammatory grade and the AUROCs were 0.68 +/- 0.15 and 0.69 +/- 0.15, for [F >/= 2] and [F4] respectively .The mean serum level of MMP-9 was significantly higher in patients than controls [P < 0.05] and showed a significant negative correlation with fibrosis stage [P < 0.05]. By using ROC curve to assess MMP-9 for discrimination of significant fibrosis [F>/= 2] and cirrhosis [F4], the AUROCs were 0.67 +/- 0.17 and 0.69 +/- 0.18 respectively, while for [A>/= 2], it was0.75 +/- 0.16. The mean value of serum TIMP-1 was significantly higher in patients than controls [P < 0.05], with significant positive correlation with necroinflammatory grade[P < 0.05]. The AUROCs for [F>/= 2] and [F4] were 0.58 +/- 0.2 and 0.53 +/- 0.19 respectively, while for [A>/= 2], it was 0.67 +/- 0.17. Haptoglobin showed a significant negative correlation with fibrosis progression[r=-0.4, P < 0.05] and AUROC for [F>/= 2] and [F4] were 0.75 +/- 0.17 and 0.78 +/- 0.15 respectively. MMP-9 was a fair marker of fibrosis as well as inflammatory activity, and TIMP-1 was a sensitive and to a lesser extent specific marker of advanced liver disease, discriminating inflammatory activity rather than fibrosis stage. On the other hand API was the best marker that can discriminate significant fibrosis, while platelet count for diagnosis of cirrhosis. Among the assessed serum markers, haptoglobin, API and PT were the most sensitive predictors of significant fibrosis, while haptoglobin and API were the most sensitive predictors of cirrhosis. Finally, these serum assays, although promising, are still in need of being refined with further prospective studies

Association of serum levels of tissue inhibitors of metalloproteinase-1 with clinical outcome in children with biliary atresia.

The purpose of this study was to determine the possible role of serum levels of tissue inhibitors of metalloproteinase-1 (TIMP-1) in the pathogenesis of the progressive inflammation and fibrosis in biliary atresia (BA). Serum concentrations of TIMP-1 were measured in 57 BA patients and 15 healthy controls using commercially available enzyme-linked immunosorbent assays. The mean ages of the BA patients and the controls were 6.1 +/- 0.6 and 6.7 +/- 1.1 years, respectively. The patients were categorized into two groups according to their clinical outcomes: patients with jaundice (total bilirubin > or = 2 mg/dl) and patients without jaundice (total bilirubin < 2 mg/dl). In our study, serum levels of TIMP-1 were significantly higher in the BA patients than in healthy subjects (4.8 +/- 0.4 vs. 3.5 +/- 0.3 ng/ml, respectively; p < 0.05). Additionally, serum levels of TIMP-1 significantly increased in the BA patients with jaundice in comparison to those without jaundice (6.3 +/- 0.7 vs. 3.1 +/- 0.3 ng/ml, respectively; p = 0.001). Patients with persistent jaundice had lower levels of albumin but had greater levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma glutamyl transpeptidase compared with patients without jaundice. Furthermore, patients with portal hypertension (PH) had higher TIMP-1 levels than those without PH (5.3 +/- 0.4 vs. 1.9 +/- 0.3 ng/ml, respectively; p < 0.001). It is concluded that serum levels of TIMP-1 increased in patients with BA. The significant increase in TIMP-1 levels is related to the presence of PH and the severity of jaundice. The elevated TIMP-1 levels may reflect the degree of hepatic fibrosis and development of PH. The data suggest that TIMP-1 may play a role in the pathophysiology of post-Kasai BA.

value of plasma matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 estimation as biomarkers of ulcerative colitis activity

Overexpression of mucosal metalloproteinases [MMP] have been demonstrated recently in inflammatory bowel disease. Their activity can be counterbalanced by the tissue inhibitor of metalloproteinases [TIMP]. The aim of this study was to evaluate the effect of ulcerative colitis [UC] on MMP-1 and TIMP-1 plasma concentrations, as two possible biomarkers of the disease activity. MMP-1 and TIMP-1 plasma concentrations were measured with an enzyme immunoassay in 16 patients uuth endoscopically confirmed active UC and 12 healthy controls. Plasma concentrations of both MMP-1 [13.7 +/- 0.2 ng/ml] and TIMP-1 [799 +/- 140 ng/ml] were significantly elevated in UC patients In comparison to healthy controls [11.9 +/- 0.9 ng/ml. and 220 +/- 7 ng/ml respectively]. There was no correlation between TIMP-1 and MMP-1 concentrations [r=-0.02]. TIMP-1 levels revealed significant positive correlations with scored endoscopic degree of mucosal injury, disease activity index and clinical activity index values as well as C-reactive protein concentration. There was no correlation between MMP-1 and laboratory, clinical or endoscopic indices of the disease activity. These results confirm the role of both MMP-1 and TIMP-1 in the pathogenesis of ulcerative colitis. However only TIMP-1 can be useful as a biomarker of the disease activity, demonstrating association, with clinical endoscopic pictures

Plasma leptin, tumor necrosis factor-alpha and tissue inhibitor of metalloproteinase-1 in chronic hepatitis C patients and their relation to hepatic fibrosis

Hepatitis C virus [HCV] infection is a major cause of chronic hepatitis which frequently leads to progressive hepatic fibrosis and ultimately liver cirrhosis. Many humoral factors and cytokines are known to have profibrogenic and proinflammatory role in chronic hepatitis C patients [CHC] including leptin and TNF-alpha that act in an orchestrated manner with other factors to augment hepatic fibragenesis and. High circulating levels of leptin have been observed in CHC patients, and activated hepatic stellate cells [HSCS] are the effector cells producing leptin in addition to the adipose tissue cells. These HSCS secrete also tissue inhibitor of metalloproteinase-l [TIMP-1] which is one of TIMPS that interact with matrix metalloproteinases [MMPS] to regulate the turnover of extracellular matrix. The role of TIMP-1 in hepatic fibrogenesis and its possible value as a serum marker predicting liver fibrosis was reported in many studies. The aim of this study was to evaluate the possible role of leptin and TN F-alpha in hepatic. fibrogenesis and the possible role of TIMP-1 in determining the progression of liver fibrosis in a cohort of CHC patients. We aimed to evaluate the potential use of these serum markers to predict hepatic fibrosis. We measured leptin and TNF-alpha in the plasma of 55 CHC patients and 25 age and sex matched control persons by radioimmunoassay. Serum TIMP-1 was measured in both CHC patients and control persons by ELISA method. Liver disease in CHC patients was evaluated by the stage of hepatic fibrosis, grading of necroinflammation and grading of hepatic steatosis in liver biopsy. The mean age of CHC patients was 42.2 years [27-69 years] and the mean age of normal control persons was 4l.5[25-67 years]. Plasma - leptin, TNF-alpha and TIMP-1 were significantly higher in CHC patients compared to the normal controls [P<0.001 for leptin, P<0.05 for TNF-alpha, P<0.05 for TIMP-1]. Leptin correlated with BMI [body mass index] in CHC patients [males: r=0.51 P<0.01, [females: r=0.75 P<0.001], while both TNF-alpha and TIMP-1 did not correlate with any of clinical or biochemical parameters in CHC patients. Leptin levels increased as hepatic fibrosis stage progressed both in male and female CHC patients [males P<0.01, females P<0.001]. TNF-alpha levels and TIMP-1 levels were significantly higher in advanced stages of hepatic fibrosis [P<0.01 for TNF-alpha, P<0.001 forTIMP-1]. Plasma leptin and TNF-alpha levels showed no correlation with hepatic steatosis or histological necroinflammatory activity in CHC patients- Serum TIMP-1 levels did not correlate with hepatic steatosis but correlated with histological activity in CHC patients [Knodells score: r=0.91 P<0.001; Scheuer's Score: r=0.84 P<0.001]. Serum leptin levels did not correlate with TNF-a levels [r=0.18 P>0.05] or TIMP-1 levels [r=0.21 P>0.05]. Our data showed that serum leptin increased in CHC patients according to the severity of hepatic fibrosis. It seems to play a role in regulating hepatic fibrosis in addition to TNF-alpha and other profibrogenic cytokines. TIMP-1 levels increased similarly in advanced stage of hepatic fibrosis and it seems to be involved in determining the progression of hepatic fibrosis. These serum markers are potentially good tools to assess hepatic fibrosis in CHC patients and they may be useful to assess the response to antiviral therapy. They may represent therapeutic targets in the future to modulate or stop hepatic fibrosis

Serum levels of matrix metalloproteinase 9 [MMP-9] and tissue inhibitor metalloproteinase 1 [TIMP-1] in lung cancer patients: correlation with carcinoembryonic antigen [CEA] level

There is evidence of the dysregulation of the balanced interaction between matrix metalloproteinases [MMPs] and their inhibitors, tissue inhibitors of metalloproteinases [TIMPs] in cancer which is thought to facilitate tumor cell invasion and metastasis. The role of MMP-9 and TIMP-1 was evaluated in different pathological types of lung cancer. Sera were collected from 52 lung cancer patients [10 had large cell carcinoma, 9 small cell carcinoma, 19 squamous cell carcinoma and 14 metastatic adenocarcinoma] as well as from 20 healthy control subjects. MMP-9 and TIMP-1 serum levels were measured using a sandwich enzyme immunoassay technique. Serum level of carcinoembryonic antigen [CEA] was also measured in the same subjects using a one step sandwich enzyme immunoassay technique. The study revealed a significant increase in the serum level of MMP9 in lung cancer patients as compared to controls [p < 0.001], with the highest value being found in patients with large cell carcinoma. A significant increase in TIMP-1 level was also found in lung cancer patients [p < 0.001], with no marked variation amongst different pathological types. A significant increase was also found in MMP9/T1MP1 ratio in patients versus controls [p < 0.001] with the highest value being measured in patients with large cell carcinoma. A significant positive correlation was found between the serum level of MMP-9 and TIMP-1 [r = 0.3, p < 0.05] and also with MMP-9/ TIMP-1 ratio [r - 0.99, p < 0.05] in lung cancer patients. Regarding CEA level, it showed a significant increase in lung cancer patients as compared to controls [p < 0.05], with the highest value being obtained from patients with squamous cell carcinoma. No significant correlation was found between CEA serum level and either MMP9 or TIMP1 [p > 0.05]. Analysis of the diagnostic value of CEA, MMP-9 and TIMP-1 in lung cancer patients revealed that CEA had 40.38% sensitivity, 100% specificity and positive predictive value [PPV], 39.2% negative predictive value [NPV] and 56.4% diagnostic efficiency [DE]. On the other hand, MMP-9 had 90.4% sensitivity, 95% specificity, 97.9% PPV, 82.6% NPV and 91.7% DE. The sensitivity, specificity, PPV, NPV and DE of TIMP-1 were 98.1%, 95%, 98.1%, 95% and 97.2% respectively. It can be concluded that increased serum levels of MMP-9, TIMP-1 and their ratio are found in lung cancer patients independently of CEA level. Both MMP-9 and TIMP-1 may serve as tumor markers, with TIMP-1 seems to be the most efficient with the highest diagnostic efficiency