Matrix metalloproteinase-10 is upregulated by thrombin in endothelial cells and increased in patients with enhanced thrombin generation

OBJECTIVE: Thrombin is a multifunctional serine protease that promotes vascular proinflammatory responses whose effect on endothelial MMP-10 expression has not previously been evaluated. METHODS AND RESULTS: Thrombin induced endothelial MMP-10 mRNA and protein levels, through a protease-activated receptor-1 (PAR-1)-dependent mechanism, in a dose- and time-dependent manner. This effect was mimicked by a PAR-1 agonist peptide (TRAP-1) and antagonized by an anti-PAR-1 blocking antibody. MMP-10 induction was dependent on extracellular regulated kinase1/2 (ERK1/2) and c-jun N-terminal kinase (JNK) pathways. By serial deletion analysis, site-directed mutagenesis and electrophoretic mobility shift assay an AP-1 site in the proximal region of MMP-10 promoter was found to be critical for thrombin-induced MMP-10 transcriptional activity. Thrombin and TRAP-1 upregulated MMP-10 in murine endothelial cells in culture and in vivo in mouse aorta. This effect of thrombin was not observed in PAR-1-deficient mice. Interestingly, circulating MMP-10 levels (P<0.01) were augmented in patients with endothelial activation associated with high (disseminated intravascular coagulation) and moderate (previous acute myocardial infarction) systemic thrombin generation. CONCLUSIONS: Thrombin induces MMP-10 through a PAR-1-dependent mechanism mediated by ERK1/2, JNK, and AP-1 activation. Endothelial MMP-10 upregulation could be regarded as a new proinflammatory effect of thrombin whose pathological consequences in thrombin-related disorders and plaque stability deserve further investigation

Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis

INTRODUCTION: Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis. METHODS: This was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls. RESULTS: Sepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-alpha/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-alpha and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45). CONCLUSIONS: The novel findings of our study on patients with severe sepsis (to our knowledge, the largest series reporting data about MMP levels in sepsis) are that reduced MMP-9/TIMP-1 ratios and increased MMP-10 levels may be of great pathophysiologic significance in terms of severity and mortality, and that TIMP-1 levels may represent a biomarker to predict the clinical outcome of patients with sepsis

Assessment of the correlation between the activity of anti-cyclic citrullinated peptide IgG, topoisomerase I, and centromere proteins in Mexican patients with progressive systemic sclerosis

Objective: To evaluate sera titers for antibodies anti-cyclic citrullinated peptide and their correlation against sera levels of anti-topoisomerase I and anti-centromere antibodies in Mexican patients with systemic sclerosis. Patients and methods: Consecutive outpatients with systemic sclerosis who attending to rheumatology clinic at a second level hospital facility. The antibodies anti-cyclic citrullinated peptide, anti-topoisomerase I and anti-centromere were determined by enzymatic immunoassay (ELISA). Statistical analysis: Spearman for correlation between numerical variables with nonparametric distribution. Fisher exact test or ? 2 to compare proportions and Student t test for dimensional variables. Results: Thirty female patients were included; aged 53 Zapotitlán 13, the disease duration at the time of the study was 10 Zapotitlán 9. Twenty-three patients (77%) exhibited diffuse disease. Anti-centromere, anti-topoisomerase I, and anti-cyclic citrullinated peptide were detected in nine, nine and three patients respectively. The correlation analysis showed the independence of autoantibodies anti-centromere and anti-topoisomerase I with respect to the levels of anti-cyclic citrullinated peptide. Conclusions: This study confirms the low frequency of anti-cyclic citrullinated peptide antibodies in patients with systemic sclerosis. A lack of correlation between autoantibodies considered as "mutually excluded" anti-topoisomerase I and anti-centromere, indicating that the analysis of the relevance for anti-cyclic citrullinated peptide in systemic sclerosis must include other clinical and serological variables

Pulmonary function in ankylosing spondylitis: Association with clinical variables

To evaluate the association between pulmonary function and clinical variables in ankylosing spondylitis (AS) and to compare the pulmonary function of patients with AS with that of healthy controls, 61 AS patients and 74 healthy controls were included. In AS, we assessed clinical disease indices (BASDAI, BASFI, BASG), morning stiffness, number of hypersensitive entheses, metrology measures, 6-min walking test, acute phase reactants, radiological presence of "bamboo spine," and severity of radiological involvement in sacroiliac and vertebral joints. AS and healthy controls had similar age and gender. All the parameters of pulmonary function were significantly diminished in AS than in healthy controls (p < 0.001), with a higher proportion of restrictive pattern (57.4 vs. 5.4 %). In AS, pulmonary function correlated negatively with BASDAI, BASFI, BASG, morning stiffness, number of hypersensitive entheses, occiput-wall distance, and ESR, and positively with 6-min walking test. There was no association between pulmonary function with radiological stage of vertebral joints and sacroiliac joints, "bamboo spine," disease duration, or chest expansion. A higher frequency of AS patients had a decreased pulmonary function and results of the 6-min walking test. These abnormalities in AS were more related with disease activity than with mobility limitation. � 2013 Springer-Verlag Berlin Heidelberg

Association of ERAP2 polymorphisms in Colombian HLA-B27+ or HLA-B15+ patients with SpA and its relationship with clinical presentation: axial or peripheral predominance

Objective: To determine the association between endoplasmic reticulum aminopeptidase (ERAP)1 and ERAP2 single-nucleotide polymorphisms (SNPs) and human leukocyte antigens (HLA)-B27+ or HLA-B15+ patients with spondyloarthritis (SpA). Methods: 104 patients with SpA according to Assessment of Spondyloarthritis International Society criteria were included in the study. HLA typing was performed by PCR. The polymorphisms were determined by real-time PCR on genomic DNA using customised probes for SNPs rs27044, rs17482078, rs10050860 and rs30187 in ERAP1, and rs2910686, rs2248374 and rs2549782 in ERAP2. Results: 70 of the104 patients with SpA were HLA-B27+ and 34 were HLA-B15+. The distribution of ERAP1 and ERAP2 SNPs between the HLA-B15+ and HLA-B27+ patients with SpA did not reveal differences. Likewise, no differences in the frequencies of ERAP1 SNP haplotypes and alleles HLA-B15 or HLA-B27 were found. Interestingly, however, the frequencies of three particular haplotypes formed by ERAP2 SNPs rs2549782/rs2248374/rs2910686 varied between HLA-B15+ and HLA-B27+ patients: the ERAP2 SNPs haplotype TGT was more common in HLA-B15+ patients with SpA (OR 2.943, 95/100 CI 1.264 to 6.585; P=0.009), whereas the ERAP2 SNP haplotypes TGC and CAT were more associated with HLA-B27+ patients with SpA: (OR 4.483, 95/100 CI 1.524 to 13.187; p=0.003) and (OR 9.014, 95/100 CI 1.181 to 68.807; p=0.009), respectively. Conclusion: An association was found between HLA-B15+ patients with SpA and haplotype TGT of ERAP2 SNPs. On the other hand, HLA-B27+ patients with SpA were associated with ERAP2 haplotypes TGC and CAT. These associations could be related to the clinical presentation of the disease, specifically with a peripheral or axial predominance, respectively

Matrix metalloproteinase-9, -10, and tissue inhibitor of matrix metalloproteinases-1 blood levels as biomarkers of severity and mortality in sepsis

INTRODUCTION: Matrix metalloproteinases (MMPs) play a role in infectious diseases through extracellular matrix (ECM) degradation, which favors the migration of immune cells from the bloodstream to sites of inflammation. Although higher levels of MMP-9 and tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) have been found in small series of patients with sepsis, MMP-10 levels have not been studied in this setting. The objective of this study was to determine the predictive value of MMP-9, MMP-10, and TIMP-1 on clinical severity and mortality in a large series of patients with severe sepsis. METHODS: This was a multicenter, observational, and prospective study carried out in six Spanish Intensive Care Units. We included 192 (125 surviving and 67 nonsurviving) patients with severe sepsis and 50 age- and sex-matched healthy controls in the study. Serum levels of MMP-9, MMP-10, TIMP-1, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-10 were measured in patients with severe sepsis at the time of diagnosis and in healthy controls. RESULTS: Sepsis patients had higher levels of MMP-10 and TIMP-1, higher MMP-10/TIMP-1 ratios, and lower MMP-9/TIMP-1 ratios than did healthy controls (P < 0.001). An association was found between MMP-9, MMP-10, TIMP-1, and MMP-9/TIMP-1 ratios and parameters of sepsis severity, assessed by the SOFA score, the APACHE-II score, lactic acid, platelet count, and markers of coagulopathy. Nonsurviving sepsis patients had lower levels of MMP-9 (P = 0.037), higher levels of TIMP-1 (P < 0.001), lower MMP-9/TIMP-1 ratio (P = 0.003), higher levels of IL-10 (P < 0.001), and lower TNF-alpha/IL-10 ratio than did surviving patients. An association was found between MMP-9, MMP-10, and TIMP-1 levels, and TNF-alpha and IL-10 levels. The risk of death in sepsis patients with TIMP-1 values greater than 531 ng/ml was 80% higher than that in patients with lower values (RR = 1.80; 95% CI = 1.13 to 2.87;P = 0.01; sensitivity = 0.73; specificity = 0.45). CONCLUSIONS: The novel findings of our study on patients with severe sepsis (to our knowledge, the largest series reporting data about MMP levels in sepsis) are that reduced MMP-9/TIMP-1 ratios and increased MMP-10 levels may be of great pathophysiologic significance in terms of severity and mortality, and that TIMP-1 levels may represent a biomarker to predict the clinical outcome of patients with sepsis