Serum Levels Of TIMP-1 Research Articles

Tissue inhibitors of matrix metalloproteinases in serum are cardiac biomarkers in Emery-Dreifuss muscular dystrophy

Tissue inhibitors of matrix metalloproteinases (TIMPs) are known to be involved in cardiovascular diseases. Hitherto, they have not been examined in dilated cardiomyopathy in the course of Emery-Dreifuss muscular dystrophy (EDMD). To define TIMPs in serum because they might help in defining cardiac dysfunction at the early cardiological stages of this disease and detect preclinical stages of cardiomyopathy. Twenty-five EDMD patients connected with lamin A/C (AD-EDMD) or emerin (X-EDMD) deficiency and 20 healthy age-matched controls were examined. The serum levels of the tissue inhibitors TIMP-1, -2, -3 were quantified using the ELISA sandwich immunoassay procedure with appropriate antibodies. Serum levels of TIMP-1 were normal in autosomal AD-EDMD and increased in the majority of X-linked EDMD. The level of TIMP-2 was decreased in 25%/21% of AD-EDMD/X-EDMD cases. TIMP-3 serum level was significantly reduced in all the examined patients. Receiver operating curves indicated that in terms of sensitivity and specificity characteristics the performance of TIMP-3 (less that of TIMP-2) makes them the best markers of cardiac involvement among the examined TIMPs. Evidence shows that the levels of TIMP-3, and in some cases also TIMP-2, are decreased in EDMD. The decrease might be associated with an adverse effect on matrix metalloproteinases and remodelling of the myocardial matrix. The specific decrease of TIMP-3 indicates that this biomarker might help in early detection of cardiac involvement in EDMD. Up-regulation of TIMP-1 in the majority of patients with X-EDMD indicates increased myocardial extracellular matrix turnover, early onset of tissue remodelling, and may contribute to arrhythmia, frequently occurring in this form of the disease.

Gelatinase activities and TIMP-2 serum level in alcohol cirrhosis and chronic pancreatitis

There are some divergent data concerning the role of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitor of MMP (TIMP)-2 in the pathogenesis of alcoholic cirrhosis (AC) and chronic pancreatitis (CP). Our objective was to evaluate the activity of MMP-2, MMP-9 and TIMP-2 serum levels in patients with AC and CP. Twenty-one patients with diagnosis of AC and twenty-two with CP admitted to the outpatient clinic for a control visit were enrolled. All results were compared with age and sex-matched control group (n=19). The sera obtained from venous blood were stored at -70°C for further analysis. Activity of MMP-2 and MMP-9 were evaluated with gelatin zymography, TIMP-2 serum level was analyzed with the usage of ELISA method. A significant decrease of serum MMP-2 activity was noted in sera of AC and CP patients in comparison with control. Activity of MMP-9 was elevated only in CP patients and TIMP-2 serum level was elevated only in AC patients. Decreased activity of MMP-2 in AC patients can contribute to cirrhosis development. The high level of MMP-9 in serum related to CP patients theoretically can exacerbate the inflammatory process within the pancreas.

Serum metalloproteinase-9 is related to COPD severity and symptoms - cross-sectional data from a population based cohort-study.

BackgroundChronic obstructive pulmonary disease, COPD, is an increasing cause of morbidity and mortality worldwide, and an imbalance between proteases and antiproteases has been implicated to play a role in COPD pathogenesis. Matrix metalloproteinases (MMP) are important proteases that along with their inhibitors, tissue inhibitors of metalloproteinases (TIMP), affect homeostasis of elastin and collagen, of importance for the structural integrity of human airways. Small observational studies indicate that these biomarkers are involved in the pathogenesis of COPD. The aim of this study was to investigate serum levels of MMP-9 and TIMP-1 in a large Swedish population-based cohort, and their association with disease severity and important clinical symptoms of COPD such as productive cough.MethodsSpirometry was performed and peripheral blood samples were collected in a populations-based cohort (median age 67 years) comprising subjects with COPD (n = 594) and without COPD (n = 948), in total 1542 individuals. Serum MMP-9 and TIMP-1 concentrations were measured with enzyme linked immunosorbant assay (ELISA) and related to lung function data and symptoms.ResultsMedian serum MMP-9 values were significantly higher in COPD compared with non-COPD 535 vs. 505 ng/ml (P = 0.017), without any significant differences in serum TIMP-1-levels or MMP-9/TIMP-1-ratio. In univariate analysis, productive cough and decreasing FEV1% predicted correlated significantly with increased MMP-9 among subjects with COPD (P = 0.004 and P = 0.001 respectively), and FEV1% predicted remained significantly associated to MMP-9 in a multivariate model adjusting for age, sex, pack years and productive cough (P = 0.033).ConclusionProductive cough and decreasing FEV1 were each associated with MMP-9 in COPD, and decreasing FEV1 remained significantly associated with MMP-9 also after adjustment for common confounders in this population-based COPD cohort. The increased serum MMP-9 concentrations in COPD indicate an enhanced proteolytic activity that is related to disease severity, and further longitudinal studies are important for the understanding of MMP-9 in relation to the disease process and the pathogenesis of different COPD phenotypes.

Circulating Matrix Metalloproteinases, Tissue Inhibitors, Natriuretic Peptides, and Rigidity of the Great Arteries in Patients with HFpEF in 12 Month after Myocardial Infarction

The paper is focused on the evaluation of the serum levels of matrix metalloproteinases (MMP -2, MMP -3, MMP - 9), tissue inhibitors (TIMP -1 and TIMP -2), natriuretic peptides, pusle wave velocity in patients (pts) with heart failure with preserved ejection fraction (HFpEF) in 12 month after ST elevation myocardial infarction (STEMI). The study included 55 pts. The serum levels of MMP -2, MMP -3, MMP - 9, the precursor of matrix metalloproteinase -1 (proMMP -1), TIMP -1 and TIMP -2, high-sensitivity C-reactive protein (hsCRP) were determined by ELISA. BNP in whole blood was determined on panels Triage BNP test. The most pts had class II NYHA (49%), as was often II class angina (53%). Increases in levels of BNP were dependent on class of NYHA. The stiffness of the great arteries was associated with increasing in BNP and NT-proBNP. There were no changes in levels of proMMP-1, MMP 3, MMP-2, MMP-9. But the serum levels of TIMP-1, hsCRP were increased in pts with HFpEF after STEMI. A positive relationship between hsCRP and TIMP-1 was obtained. Moreover, we found decreasing in levels of MMP-3 in pts with increased rigidity without the risk of cardiovascular events.

Elevated serum matrix metalloproteinase-2 and -9 and their correlations with severity of disease in patients with community-acquired pneumonia.

To determine the role of matrix metalloproteinases (MMPs) and their relationship with the clinical course of community-acquired pneumonia (CAP). Sixty-two consecutively hospitalized patients with CAP were enrolled and their pneumonia severity index (PSI), time to clinical stability (TCS), treatment response, and complications were recorded. The pre- and posttreatment serum concentrations of MMPs and their inhibitors were analyzed by ELISA. The activities of MMPs were evaluated by gelatin zymography. MMP-2 and -9 serum levels and their activities were higher in CAP patients than controls (P < 0.001 and P < 0.001, respectively). Low-risk patients had lower levels of MMP-2 and TIMP-1 than high-risk patients (P = 0.044, P = 0.001, respectively). Pretreatment serum TIMP-1 level was higher in patients with TCS of >3 days (P = 0.004) and was correlated with oxygenation and PSI scores. Posttreatment serum levels of MMP-9 and TIMP-1 were decreased after antibiotics (P = 0.000 1 and P = 0.0 17, respectively). Although MMP-2, MMP-9, and TIMP-1 correlate with many poor prognostic factors, more studies are required to prove their possible role in predicting the severity of CAP.

Expression profiles of MMP-1 and TIMP-1 in lumbar intervertebral disc degeneration.

Lumbar intervertebral disc degeneration (IDD) is a common clinical pathology and has become a focus for research in recent years. Matrix metalloproteinases (MMPs) are enzymes responsible for the degradation of almost all extracellular matrix proteins (ECM). The over-expression of MMPs or tissue inhibitors of metalloproteinases (TIMPs) may disrupt the dynamic balance of the ECM. Therefore, in the current study, the expression levels of MMP-1 and TIMP-1 in lumbar IDD patients were evaluated in an attempt to elucidate their role in IDD pathogenesis and progression. In total, 60 IDD patients were recruited as the experimental group, along with 20 cases of lumbar vertebral injury without disc degeneration as the control group. Preoperative venous blood samples were collected, and intervertebral disc tissues were collected from the lesion during surgery. Serum and tissue levels of MMP-1 and TIMP-1 were quantified by enzyme-linked immunosorbent assay and immunohistochemical staining, respectively. Serum and tissue MMP-1 levels in IDD patients were significantly higher than those in the control group (P < 0.05). Additionally, sub-group analysis revealed that severe IDD patients had higher MMP-1 levels compared with mild or moderate IDD patients (P < 0.05). However, there were no significant differences in TIMP- 1 levels in either the serum or tissues of IDD patients compared to patients in the control group (P > 0.05). These results demonstrate that MMP-1 expression is increased in IDD, with higher expression observed in more severe cases, whereas TIMP-1 expression was similarly expressed in both normal and degenerated discs.

Low levels of tissue inhibitor of metalloproteinase-2 at birth may be associated with subsequent development of bronchopulmonary dysplasia in preterm infants.

PurposeBronchopulmonary dysplasia (BPD) is characterized by inflammation with proteolytic damage to the lung extracellular matrix. The results from previous studies are inconsistent regarding the role of proteinases and antiproteinases in the development of BPD. The aim of the present study was to investigate whether matrix metalloproteinase (MMP)-8, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2, and TIMP-1 levels in the serum of preterm infants at birth are related to the development of BPD.MethodsSerum was collected from 62 preterm infants at birth and analyzed for MMP-8, MMP-9, TIMP-2, and TIMP-1 by using enzyme-linked immunosorbent assay. MMPs and TIMPs were compared in BPD (n=24) and no BPD groups (n=38). Clinical predictors of BPD (sex, birth weight, gestational age, etc.) were assessed for both groups. The association between predictors and outcome, BPD, was assessed by using multivariate logistic regression.ResultsSex, birth weight, and mean gestational age were similar between the groups. BPD preterm infants had significantly lower TIMP-2 levels at birth compared with no BPD preterm infants (138.1±23.0 ng/mL vs. 171.8±44.1 ng/mL, P=0.027). No significant difference was observed in MMP-8, MMP-9, and TIMP-1 levels between the two groups. Multivariate logistic regression analysis indicated that the TIMP-2 levels were predictive of BPD after adjusting for sex, birth weight, gestational age, proteinuric preeclampsia, and intraventricular hemorrhage (β=-0.063, P=0.041).ConclusionLow TIMP-2 serum levels at birth may be associated with the subsequent development of BPD in preterm infants.

Identification of neutrophil activation markers as novel surrogate markers of CF lung disease.

Background and aimsCystic Fibrosis (CF) lung disease is characterized by progressively declining lung function and represents a major factor contributing to the high morbidity and mortality associated with CF. However, apart from spirometry, respiratory disease surrogate markers reliably indicating CF lung disease and the occurrence of pulmonary exacerbations (PEx) are still lacking. Within this study, we aimed to identify new experimental biomarkers for the detection of CF lung disease.Methods54 adult and 26 pediatric CF patients were included in the study and serum concentrations of MMP-1, -2, -8, -9, -13, TIMP-1, TIMP-2, YKL-40, hyaluronic acid, procollagen III peptide were quantified by ELISA. CF lung disease was diagnosed by lung function test, PEx was defined based on a clinical scoring established by Rosenfeld in 2001.ResultsAdults and children with moderate to severe CF lung disease exhibited significantly increased serum expression of MMP-8, MMP-9, YKL-40 and TIMP-1. Further, MMP-8, MMP-9 and YKL-40 were significantly increased in adult CF patients suffering from PEx compared to those without clinical signs of respiratory exacerbation. MMP-8, MMP-9, YKL-40, and TIMP-1 serum levels were unaffected by the presence or absence of CF liver disease or pancreatic insufficiency.ConclusionsMMP-8, MMP-9, and YKL-40 might serve as novel non-invasive biomarkers of CF lung disease and PEx.

The rtPA increases MMP-9 activity in serum during ischaemic stroke

Background and purposeTo find the relationship between rtPA treatment vs. MMP-9 activity, MMP-3, and TIMP-1 serum levels related to patients’ neurological status during acute ischaemic stroke (IS). Material and methods35 IS patients were enrolled. 14 of them underwent thrombolytic therapy with Actylise (rtPA group). The serum samples were obtained at 3 time-points for rtPA group (time-point 0: 1st–4th hour of stroke; time-point 1 – immediately after rtPA administration; time-point 2 – on day 5–7 from stroke onset). Remaining patients had venous blood collection at two time-points: time-point 1 – 5th–10th hour of stroke and time-point 2 – on day 5–7 of stroke. MMP-9 was analyzed with gelatin zymography, MMP-3 and TIMP-1 serum levels were analyzed with ELISA method. NIHSS improvement ratio (IR) was calculated as a difference between NIHSS score at the admission and discharge of patient. ResultsThe active form of MMP-9 (86kDa) was not observed in any analyzed samples. Total MMP-9 activity was significantly elevated at time-point 1 in rtPA group in comparison with non-rtPA group. MMP-3 serum level significantly decreased during rtPA administration in comparison with non-rtPA group and it was restored at time-point 2. MMP-3 negatively correlated with IR values (p=0.06). ConclusionsThrombolysis applied for IS treatment increases MMP-9 activity in serum, however, rtPA does not facilitate the conversion of pro-MMP-9 into the active form. Our results also suggest the involvement of MMP-3 to the biochemical processes occurring during acute phase of IS.

Evaluation of Systemic Levels of Neutrophilic Enzymes in Patients With Hypertension and Chronic Periodontitis

Inflammation stimulates neutrophils to release their enzymes into the extracellular matrix. The aim of the present study is to investigate the serum levels of matrix metalloproteinase (MMP)-8, MMP-9, tissue inhibitor of MMP (TIMP)-1, myeloperoxidase (MPO), and neutrophil elastase (NE) in patients with hypertension and chronic periodontitis (CP). A total of 95 patients were included in the study. Patients were categorized into three groups: healthy control (n = 29), hypertensive control (n = 32), and hypertensive CP (n = 34). Periodontal parameters were recorded, and serum samples were collected from each participant. Serum MMP-8, MMP-9, TIMP-1, MPO, and NE levels in circulation were assessed by enzyme-linked immunosorbent assay. The hypertensive CP group had significantly higher serum MMP-8, MMP-9, and NE levels than the healthy control group (P <0.05). All study groups had similar serum TIMP-1 levels (P >0.05). Significantly higher serum MPO levels were detected in patients with hypertension and CP than healthy controls and hypertensive controls (P <0.05); however, the difference in serum MPO levels was not significant between the healthy controls and hypertensive controls (P >0.05). There was no significant difference in MMP-8/TIMP-1 ratio among the study groups (P >0.05). MMP-9/TIMP-1 ratio was significantly higher in patients with hypertension and CP than healthy controls (P <0.05). The presence of hypertension along with CP has a considerable effect on serum neutrophilic enzyme levels, except TIMP-1. However, the levels of these enzymes do not seem to be affected by the presence of hypertension only. Further studies including patients who have only CP might help illuminate the effect of CP on these enzymes in patients with hypertension.

AB0447 Regulation of Serum Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases-1 following Rituximab Therapy in Patients with Rheumatoid Arthritis Refractory to Anti-Tumor Necrosis Factor Blockers

BackgroundSerum matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play important role in the pathogenesis of rheumatoid arthritis (RA).ObjectivesIn our article we evaluated the regulatory effects of the infusions...

Serum angiopoietin-2 and soluble VEGF receptor 2 are surrogate markers for plasma leakage in patients with acute dengue virus infection

BackgroundEndothelial cell dysfunction is believed to play an important role in the pathogenesis of plasma leakage in patients with acute dengue virus (DENV) infection. Several factors, produced by activated endothelial cells, have been associated with plasma leakage or severe disease in patients with infectious diseases. ObjectivesThe aim of this study was to investigate which of these markers could serve as a surrogate marker for the occurrence of plasma leakage in patients with acute DENV infection. Study designA case-control study was performed in patients with acute DENV infection in Santos, Brazil. Plasma leakage was detected with X-ray and/or ultrasound examination at admission. Serum levels of soluble endoglin, endothelin-1, angiopoietin-2, VEGF, soluble VEGFR-2, MMP-2, MMP-9, TIMP-1 and TIMP-2 were determined using commercially available ELISAs. ResultsIncreased levels of angiopoietin-2, endothelin-1 and MMP-2 and decreased levels of soluble VEGFR-2 were significantly associated with the occurrence of plasma leakage. An unsupervised cluster analysis confirmed that angiopoietin-2 and soluble VEGFR-2 were strongly associated with clinical apparent vascular leakage. ConclusionAngiopoietin-2 and soluble VEGFR-2 can serve as surrogate markers for the occurrence of plasma leakage in patients with acute DENV infection.

Upregulation of gelatinases and epithelial-mesenchymal transition in small airway remodeling associated with chronic exposure to wood smoke.

BackgroundPeribronchiolar fibrosis is an important feature of small airway remodeling (SAR) in cigarette smoke-induced COPD. The aim of this study was to investigate the role of gelatinases (MMP9, MMP2) and epithelial-mesenchymal transition (EMT) in SAR related to wood smoke (WS) exposure in a rat model.MethodsForty-eight female Sprague-Dawley rats were randomly divided into the WS group, the cigarette smoke (CS) group and the clean air control group. After 4 to 7 months of smoke exposure, lung tissues were examined with morphometric measurements, immunohistochemistry and Western blotting. Serum MMP9 and TIMP1 concentrations were detected by ELISA. In vitro, primary rat tracheal epithelial cells were stimulated with wood smoke condensate for 7 days.ResultsThe COPD-like pathological alterations in rats exposed chronically to WS were similar to those exposed to CS; the area of collagen deposition was significantly increased in the small airway walls of those exposed to WS or CS for 7 months. The expression of gelatinases in rats induced by WS or CS exposure was markedly increased in whole lung tissue, and immunohistochemistry showed that MMP9, MMP2 and TIMP1 were primarily expressed in the airway epithelium. The serum levels of MMP9 and TIMP1 were significantly higher in rats secondary to WS or CS exposure. Few cells that double immunostained for E-cadherin and vimentin were observed in the airway subepithelium of rats exposed to WS for 7 months (only 3 of these 8 rats). In vitro, the expression of MMP9 and MMP2 proteins was upregulated in primary rat tracheal epithelial cells following exposure to wood smoke condensate for 7 days by Western blotting; positive immunofluorescent staining for vimentin and type I collagen was also observed.ConclusionsThese findings suggest that the upregulation of gelatinases and EMT might play a role in SAR in COPD associated with chronic exposure to wood smoke.

Association between serum tissue inhibitor of matrix metalloproteinase-1 levels and mortality in patients with severe brain trauma injury.

ObjectiveMatrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) play a role in neuroinflammation after brain trauma injury (TBI). Previous studies with small sample size have reported higher circulating MMP-2 and MMP-9 levels in patients with TBI, but no association between those levels and mortality. Thus, the aim of this study was to determine whether serum TIMP-1 and MMP-9 levels are associated with mortality in patients with severe TBI.MethodsThis was a multicenter, observational and prospective study carried out in six Spanish Intensive Care Units. Patients with severe TBI defined as Glasgow Coma Scale (GCS) lower than 9 were included, while those with Injury Severity Score (ISS) in non-cranial aspects higher than 9 were excluded. Serum levels of TIMP-1, MMP-9 and tumor necrosis factor (TNF)-alpha, and plasma levels of tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 plasma were measured in 100 patients with severe TBI at admission. Endpoint was 30-day mortality.ResultsNon-surviving TBI patients (n = 27) showed higher serum TIMP-1 levels than survivor ones (n = 73). We did not find differences in MMP-9 serum levels. Logistic regression analysis showed that serum TIMP-1 levels were associated 30-day mortality (OR = 1.01; 95% CI = 1.001–1.013; P = 0.03). Survival analysis showed that patients with serum TIMP-1 higher than 220 ng/mL presented increased 30-day mortality than patients with lower levels (Chi-square = 5.50; P = 0.02). The area under the curve (AUC) for TIMP-1 as predictor of 30-day mortality was 0.73 (95% CI = 0.624–0.844; P<0.001). An association between TIMP-1 levels and APACHE-II score, TNF- alpha and TF was found.ConclusionsThe most relevant and new findings of our study, the largest series reporting data on TIMP-1 and MMP-9 levels in patients with severe TBI, were that serum TIMP-1 levels were associated with TBI mortality and could be used as a prognostic biomarker of mortality in TBI patients.

Active Matrix Metalloprotease-9 Is Associated with the Collagen Capsule Surrounding the Madurella mycetomatis Grain in Mycetoma

Madurella mycetomatis is the main causative organism of eumycetoma, a persistent, progressive granulomatous infection. After subcutaneous inoculation M. mycetomatis organizes itself in grains inside a granuloma with excessive collagen accumulation surrounding it. This could be contributing to treatment failure towards currently used antifungal agents. Due to their pivotal role in tissue remodelling, matrix metalloproteinases-2 (MMP-2) and 9 (MMP-9) or tissue inhibitor of metalloproteinases (TIMP) might be involved in this process. Local MMP-2 and MMP-9 expression was assessed by immunohistochemistry while absolute serum levels of these enzymes were determined in mycetoma patients and healthy controls by performing ELISAs. The presence of active MMP was determined by gelatin zymography. We found that both MMP-2 and MMP-9 are expressed in the mycetoma lesion, but the absolute MMP-2, -9, and TIMP-1 serum levels did not significantly differ between patients and controls. However, active MMP-9 was found in sera of 36% of M. mycetomatis infected subjects, whereas this active form was absent in sera of controls (P<0.0001). MMP-2, MMP-9, and TIMP-1 polymorphisms in mycetoma patients and healthy controls were determined through PCR-RFLP or sequencing. A higher T allele frequency in TIMP-1 (+372) SNP was observed in male M. mycetomatis mycetoma patients compared to controls. The presence of active MMP-9 in mycetoma patients suggest that MMP-9 is activated or synthesized by inflammatory cells upon M. mycetomatis infection. Inhibiting MMP-9 activity with doxycycline could prevent collagen accumulation in mycetoma, which in its turn might make the fungus more accessible to antifungal agents.

Significance of circulating matrix metalloproteinase-9 to tissue inhibitor of metalloproteinases-2 ratio as a predictor of disease progression in patients with metastatic renal cell carcinoma receiving sunitinib

ObjectivesTo assess the significance of circulating matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) as predictors of disease progression in patients with metastatic renal cell carcinoma (mRCC) receiving sunitinib. Materials and methodsCirculating levels of MMP-2, MMP-9, TIMP-1, and TIMP-2 in sera from 52 patients with mRCC treated with sunitinib were measured at the baseline and on the first day of each treatment cycle until progression using enzyme-linked immunosorbent assays. ResultsThe baseline level of MMP-9 in nonresponders to sunitinib was significantly higher than that in responders, whereas the baseline level of TIMP-2 in nonresponders was significantly lower than that in responders. However, there were no significant differences in the serum levels of MMP-2 and TIMP-1 between responders and nonresponders. The serum MMP-9/TIMP-2 ratio at the baseline in nonresponders was also significantly higher than that in responders. Univariate analysis showed that the MMP-9/TIMP-2 ratio, but not MMP-9 and TIMP-2 levels, was significantly correlated with progression-free survival, and the MMP-9/TIMP-2 ratio, in addition to the Memorial Sloan-Kettering Cancer Center classification and C-reactive protein level, appeared to be independently associated with progression-free survival on multivariate analysis. Furthermore, despite the lack of significant differences in the serum levels of MMP-9 and TIMP-2 between the baseline and the time of progression, the MMP-9/TIMP-2 ratio at the time of progression was significantly elevated compared with the baseline ratio. ConclusionsAn imbalance between the serum MMP-9 and TIMP-2 levels could be a novel biomarker to predict disease progression in patients with mRCC under treatment with sunitinib.

TIMP-1 polymorphisms in a Chinese Han population with intracerebral hemorrhage

Remodeling of extracellular matrix (ECM) and breakdown of blood–brain barrier (BBB) are crucial events in the pathogenesis of intracerebral hemorrhage (ICH). Matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-2, are the most important degrading enzymes in the ECM and BBB. These proteolytic effects are controlled predominantly by tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 is the main endogenous inhibitor of MMP-9. Two polymorphisms in the TIMP-1 gene (rs4898 and rs2070584) were selected through a literature review and successfully genotyped in a study sample of 410 ICH patients and 305 controls. Differences in genotype and allele frequencies of identified polymorphisms were determined. Furthermore, the serum levels of TIMP-1 were measured in a subgroup of 96 ICH patients on days 1 after ICH onset and 76 controls. Analyses showed that C allele of rs2070584 was significantly associated with the development of ICH in male subjects (p = 0.037, OR = 1.535, 95%CI 1.025–2.300). Multiple logistic regression analysis under three genetic models demonstrated both rs4898 and rs2070584 were not risk factors for ICH in female subjects. Furthermore, serum levels of TIMP-1 were significantly higher in ICH patients than those in normal controls. However, the serum levels of TIMP-1 showed a nonsignificant decrease, depending on the alleles and genotypes of rs2070584 both in male and female cases. In conclusion, this is the first association study of the TIMP-1 gene variants with ICH. Our data suggest that C allele of rs2070584 is a risk factor for ICH development in the Chinese male population. However, the precise function of this variant needs further investigation.

Natural Haemozoin Induces Expression and Release of Human Monocyte Tissue Inhibitor of Metalloproteinase-1

Recently matrix metalloproteinase-9 (MMP-9) and its endogenous inhibitor (tissue inhibitor of metalloproteinase-1, TIMP-1) have been implicated in complicated malaria. In vivo, mice with cerebral malaria (CM) display high levels of both MMP-9 and TIMP-1, and in human patients TIMP-1 serum levels directly correlate with disease severity. In vitro, natural haemozoin (nHZ, malarial pigment) enhances monocyte MMP-9 expression and release. The present study analyses the effects of nHZ on TIMP-1 regulation in human adherent monocytes. nHZ induced TIMP-1 mRNA expression and protein release, and promoted TNF-α, IL-1β, and MIP-1α/CCL3 production. Blocking antibodies or recombinant cytokines abrogated or mimicked nHZ effects on TIMP-1, respectively. p38 MAPK and NF-κB inhibitors blocked all nHZ effects on TIMP-1 and pro-inflammatory molecules. Still, total gelatinolytic activity was enhanced by nHZ despite TIMP-1 induction. Collectively, these data indicate that nHZ induces inflammation-mediated expression and release of human monocyte TIMP-1 through p38 MAPK- and NF-κB-dependent mechanisms. However, TIMP-1 induction is not sufficient to counterbalance nHZ-dependent MMP-9 enhancement. Future investigation on proteinase-independent functions of TIMP-1 (i.e. cell survival promotion and growth/differentiation inhibition) is needed to clarify the role of TIMP-1 in malaria pathogenesis.

Circulating levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with incisional hernia

Incisional hernia formation is a common complication to laparotomy and possibly associated with alterations in connective tissue metabolism. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are closely involved in the metabolism of the extracellular matrix. Our aim was to study serum levels of multiple MMPs and TIMPs in patients with and without incisional hernia. Out of 305 patients who underwent laparotomy, 79 (25.9%) developed incisional hernia over a median follow-up period of 3.7 years. Pooled sera from a subset (n = 72) of these patients were screened for MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, TIMP-1, TIMP-2, and TIMP-4 using a multiplex sandwich fluorescent immunoassay supplemented with gelatin zymography. The screening indicated differences in serum MMP-9 and TIMP-1 levels. Consequently, MMP-9 and TIMP-1 levels were measured in serum in the whole patient cohort with enzyme-linked immunosorbent assay. There were no significant differences in either MMP-9 (p = 0.411) or TIMP-1 (p = 0.679) levels between hernia and hernia-free patients. MMP-9 was significantly increased in smokers compared with nonsmokers (p = 0.016). In conclusion, a possible involvement of MMPs and TIMPs in the pathogenesis of incisional hernia formation was not reflected systemically.

Circulating biomarkers of collagen metabolism in arterial hypertension

Increasing experimental evidence indicates that alterations in the extracellular matrix are implicated in hypertension and its chronic complications. Selected markers of extracellular matrix metabolism were investigated as potential biomarkers for hypertensive remodelling and correlated with the severity and extent of target organ damage (TOD) in patients with essential hypertension. We studied 159 consecutive patients being treated for essential hypertension. An exhaustive evaluation of the heart, kidney and blood vessel damage was performed, and plasma levels of plasma procollagen type I (PICP), matrix metalloproteinase-1 (MMP-1) and its inhibitor (tissue inhibitor metalloproteinase-1, TIMP-1) were determined. Patients were categorized into four groups: no TOD (33 patients), level 1 TOD (52 patients), level 2 TOD (44 patients) and level 3 TOD (30 patients). The serum levels of MMP-1 and TIMP-1 were higher in patients with TOD than in hypertensive patients without TOD. Increasing levels of these molecules were progressively associated with an increase in the number of organs damaged, with highest levels of markers in patients with level 3 TOD (heart, kidney and blood vessels). There were no differences in PICP levels between groups. We found a slight but significant correlation between TIMP-1 and all hypertensive organ damage. Logistic regression analysis showed that age, smoking, diabetes mellitus, abdominal perimeter, MMP-1 and TIMP-1 were independently related to the level of TOD. Circulating concentration of MMP-1 and TIMP-1 is associated with an extended hypertensive disease, with more TOD. TIMP-1 may have a role as a biomarker of total remodelling burden in hypertensive patients.