Tissue Inhibitor Of Metalloproteinase-1 Concentrations Research Articles

220 Litter performance, serum collagen, and hormone concentrations in prolapsed and non-prolapsed sows

Abstract Pelvic organ prolapse is one of the top leading causes of sow mortality today and widely considered a multifactorial issue. Previous reports observed prolapsed sows having decreased serum concentrations of various trace minerals and increased tumor necrosis factor-alpha compared with non-prolapsed sows. Additionally, collagen, hormones, and previous litter performance are other factors proposed to be associated with POP. A study was completed to determine differences in serum collagen type 1 (COL1), matrix metalloproteinase 1 (MMP-1), tissue inhibitor of metalloproteinase 1 (TIMP-1), as well as relaxin and estradiol differences in the serum concentration between prolapsed and non-prolapsed sows. Furthermore, previous litter performance, lactation days, pigs born, stillborns, mummified, and pigs weaned on prolapse rate were evaluated. The study utilized 44 prolapsed sows and 44 non-prolapsed sows of similar parity, location, management, and stage of production. Blood was collected from the prolapsed and non-prolapsed sows upon discovery. Serum samples were analyzed using radioimmunoassay for estradiol content. Additionally, COL1, MMP-1, TIMP-1, and relaxin concentrations were determined from the serum using ELISA testing. Data were analyzed using the PROC GLIMMIX procedure in SAS. Prolapsed sows had decreased (P < 0.05) COL1 and TIMP-1 concentrations in the serum compared with the non-prolapsed sows. Prolapsed sows had marginally greater (P < 0.10) MMP-1 concentration compared with non-prolapsed sows. There were no differences (P > 0.10) between prolapsed and non-prolapsed serum concentraions of sows for estradiol and relaxin. Prolapsed sows had longer lactation days (P < 0.05) in the litter before prolapsing compared with non-prolapsed sows. Additionally, stillborns in the previous litter were marginally greater (P = 0.06) in prolapsed sows when compared with the non-prolapsed sows. There were no differences (P > 0.10) in pigs born, mummified, or pigs weaned between prolapsed and non-prolapsed sows. This study suggests that there is a reduced concentration of serum COL1 and TIMP-1 found in prolapsed sows compared with non-prolapsed sows and a marginally increased MMP-1 concentration in prolapsed sows. This could influence the structural integrity of the connective tissue that supports the pelvic organs. We found no differences in serum estradiol or relaxin levels. Additionally, lactation days and stillborn pigs in the litter prior to prolapsing could be contributing factors to prolapse. This work further supports the idea that prolapse is a multifactorial issue.

Investigation of Serum Markers of Hepatic Fibrosis in Equids

Liver disease is common in equine practice, and treatment and prognosis are dependent on histopathologic examination of biopsies. Liver biopsy is invasive and expensive which restricts its use. Serum markers are used to predict hepatic fibrosis in humans. This study aimed to investigate the enhanced liver fibrosis (ELF) test, based on serum Hyaluronic Acid (HA), procollagen III N-terminal peptide (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1) to detect hepatic fibrosis in equids. Four groups were included; two with increased serum concentrations of liver-derived enzymes and a liver biopsy (group H; 10 horses and ponies and group D; 10 donkeys) and two without any evidence of liver disease (group HC; 10 horses and ponies and group DC; 10 donkeys). All samples were analyzed for concentrations of HA, PIINP, and TIMP-1. Given the failure to detect TIMP-1 in most subjects, a novel eELF (equid ELF) score was calculated, based on HA and PIIINP. HA and PIIINP concentrations and the eELF score, were compared with determined hepatic fibrosis. HA, PIIINP, and eELF were significantly greater in horses and ponies with a histopathologic fibrosis score ≥ 2 compared with those < 2. A similar observation was found with donkeys for HA and eELF. A significant correlation was found between fibrosis score and HA, PIIINP, and eELF for horses and ponies, and between fibrosis score and HA and eELF in donkeys. Serum HA and the eELF score might be useful serum markers to predict and monitor hepatic fibrosis in horses, ponies, and donkeys.

Tear inflammation related indexes after cataract surgery in elderly patients with type 2 diabetes mellitus.

Quantitative studies on the changes in inflammation-related content in tears, especially the effect of diabetes, are lacking. In this study, we measured the preoperative and postoperative tear inflammatory mediator levels in cataract patients, focusing on the expression of inflammatory factors in postoperative cataracts in the diabetic, and investigated the effect of drugs on the control of postoperative inflammation. To study the expression of inflammatory factors in elderly people with type 2 diabetes after cataract surgery. Patients with a mean age of 70.3 ± 6.3 years were divided into group A (composed of elderly patients with cataracts and type 2 diabetes, n = 20 eyes) and group B (patients with age-related cataract, n = 20 eyes). Their tears were collected before each operation and on days 1 and 3, and weeks 1, 2, 3, and 4 post-surgery. Saline (150 μL) was dropped into the conjunctival sac of the surgical eye, followed by oculogyration in four directions. The fluid in the conjunctival sac was extracted using a sterile syringe and stored in Eppendorf tubes at -80 °C until measurement. The expression levels of matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), TIMP-2, interleukin-6 (IL-6), and IL-20 in tear fluid were measured using enzyme-linked immunosorbent assays. The postoperative expression levels of MMP-2, MMP-9, TIMP-2, IL-6, and IL-20 in group A were significantly higher than those in group B, whereas the concentration of TIMP-1 in group A remained lower than that in group B. The levels of MMP-2 and IL-6 in both groups continuously increased until the peak in the first postoperative week, and then gradually decreased over the next three weeks. Ultimately, MMP-2 declined to a lower level than that preoperatively at week 4, but IL-6 decreased to the same level as that preoperatively. The level of MMP-9 peaked in the first two weeks postoperative and then returned to the same level as 1-day post-operation. The concentration of TIMP-1 post-operation remained constant at a lower level than before surgery, and TIMP-2 Levels remained stable in both groups. IL-20 content started to increase in the third week after surgery. Inflammatory factor levels in tears fluctuated before and post-operation, which indicated more severe postoperative inflammation in the first two weeks.

Plasma TIMP-1 as a sex-specific biomarker for acute lung injury.

Acute respiratory distress syndrome (ARDS) confers high morbidity and mortality, with a death rate reaching 40%. Pre-clinical and clinical studies have cited sex-specific sex hormones as a critical contributor to divergent immunologic responses. Therefore, exploration of sex and sex hormone roles following lung injury and ARDS development is needed. Tissue inhibitor of metalloproteinase-1 (TIMP-1) was the first-discovered natural collagenase inhibitor and is located exclusively on the X chromosome. This study aimed to evaluate the prognostic role of circulating TIMP-1, and if concentration differences between males and females correlate with the mortality of ARDS patients. Human plasma samples from 100 ARDS patients enrolled in Albuterol to Treat Acute Lung Injury (ALTA) trial on the day of randomization were evaluated. The amount of TIMP-1 was measured using an enzyme-linked immunoassay (ELISA). Area under the receiver operating characteristic (AUROC) was computed to assess the predictive power of TIMP-1 for 30 and 90-day mortality. Chi-squared tests and Kaplan-Meier curves were computed to assess different variables and survival. AUROC analysis of TIMP-1 and 30-day mortality among females showed that TIMP-1 exhibited an AUC of 0.87 (95% confidence interval [CI] 0.78 to 0.97; P = 0.0014) with an optimal cut-off value of 159.7ng/mL producing a 100% sensitivity and 74% specificity. For 90-day mortality, AUROC analysis showed an AUC of 0.82 (95% confidence interval [CI] 0.67 to 0.97; P = 0.0016) with a similar cut-off value producing a 90% sensitivity and 76.47% specificity. Stratifying subjects by TIMP-1 concentration as high (≥ 159.7ng/mL) or low (< 159.7ng/mL) indicated that high TIMP-1 was associated with increased 30 and 90-day mortality rates (all P < 0.0001). Lastly, high TIMP-1 group was associated with worse other outcomes including ventilator-free days (VFDs) and ICU-free days (all P < 0.05). Circulating TIMP-1 appeared to be a promising biomarker for mortality among females with ARDS. The high TIMP-1 group showed worse VFDs and ICU-free days. Circulating TIMP-1 may be a sex-specific biomarker in the setting of ARDS and could improve ARDS phenotyping as well as provide a novel therapeutic target in females.

Effect of spironolactone therapy on the activity of the matrix metalloproteinase system in patients with heart failure after COVID-19

Aim. To assess the change in the activity of the matrix metalloproteinase (MMP) system after 6-month spironolactone therapy in patients with heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF) after coronavirus disease 2019 (COVID-19).Material and methods. The study included 90 patients treated at the University Clinical Hospital № 4 of the I.M. Sechenov First Moscow State Medical University with a laboratory-confirmed COVID-19. There were following inclusion criteria: age of 18-85 years; the presence of HFpEF and HFmrEF. The patients were randomized into two groups: group I (n=60) — patients with 6-month spironolactone therapy (25 mg/day) in addition to the standard therapy for HF, spironolactone was taken at a dose of 25 mg/day; Group II (comparison group, n=30) — patients who received standard therapy without spironolactone. All patients were determined plasma MMP concentrations.Results. There were no significant differences in the levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) between the groups when included in the study. A repeated investigation revealed a significant decrease in the concentrations of MMP-9 and TIMP-1 only in group I. In patients of group II, there were no significant changes in the plasma concentrations of MMP-9 and TIMP-1. The MMP-9/TIMP-1 ratio during the initial examination of patients did not have significant differences. After 6-months therapy, a significant decrease in the ratio of MMP-9/TIMP-1 was observed only in patients taking spironolactone.Conclusion. The results obtained confirm a significant decrease in MMP system activity after 6-month spironolactone therapy in patients with HFpEF and HFmrEF after COVID-19. The described antifibrotic effects of spironolactone make it possible to recommend the use of this drug in this category of patients to reduce the negative effect of MMPs on cardiovascular system.

Increase in Serum MMP-9 and TIMP-1 Concentrations during Alcohol Intoxication in Adolescents-A Preliminary Study.

Background: Alcohol consumption by adolescents is responsible for a number of adverse health and social outcomes. Despite the well-established effect of alcohol use on the development of alcoholic liver disease, the relationship between the pattern of alcohol consumption and liver fibrosis is still unclear. This study is a follow-up to work on liver damage from alcohol intoxication. The aim of our study was to explore the early effects of alcohol intoxication on liver fibrosis in adolescents. Methods: The prospective study included 57 adolescents aged 14–17 years admitted to the emergency department (ED) from February 2017 to June 2018 due to acute alcohol intoxication. Serum levels of amino terminal propeptide of type III procollagen (PIIINP), type IV collagen, matrix metallopeptidase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were determined by enzyme-linked immunosorbent assays. Results: There were significant differences in MMP-9 (p = 0.02) and TIMP-1 (p = 0.007) levels between the study and control groups. Liver parameters and selected markers of fibrosis were similar in groups in terms of blood alcohol concentrations (BAC). MMP-9 was positively correlated with alanine aminotransferase (ALT) (r = 0.38; p = 0.004) and total bilirubin (r = 0.39; p = 0.004). Positive significant correlations were also found between TIMP-1 and ALT (r = 0.47; p < 0.001), AST (r = 0.29; p = 0.03) and total bilirubin (r = 0.32; p = 0.02). In receiver operating characteristic (ROC) analysis, MMP-9 (AUC = 0.67, p = 0.02) and TIMP-1 (AUC = 0.69, p = 0.003) allowed for the differentiation of patients with and without alcohol intoxication. Conclusion: Our results show that even a single episode of alcohol intoxication in adolescents can lead to imbalance in markers of fibrosis.

Vaginal Microbiota, Genital Inflammation and Extracellular Matrix Remodelling Collagenase: MMP-9 in Pregnant Women With HIV, a Potential Preterm Birth Mechanism Warranting Further Exploration.

BackgroundPregnant women living with HIV infection (PWLWH) have elevated rates of preterm birth (PTB) in which HIV and cART are implicated. PWLWH also have a high prevalence of adverse vaginal microbiota, which associate with genital tract inflammation. The mechanism underlying PTB in PWLWH is unknown. We present the first data in PWLWH on genital-tract matrix-metalloproteinase-9(MMP-9), an important collagenase implicated in labour onset, and tissue inhibitor of metalloproteinases-1(TIMP-1) and explore correlations with local inflammation and vaginal bacteria.Material and MethodsCervical vaginal fluid (CVF) collected by a soft cup and high vaginal swabs (HVS) were obtained from PWLWH and HIV uninfected pregnant women (HUPW) at three antenatal time points. Maternal characteristics, combination antiretroviral therapy (cART) exposure, and pregnancy outcome were recorded. Concentrations of MMP-9, TIMP-1 and ten cytokines were measured by immunoassays. Vaginal microbiota composition was determined through 16S rRNA amplicon sequencing. MMP-9, TIMP-1 and cytokine concentrations were compared by HIV status, cART, and prematurity and in PWLWH correlations with polymorphonuclear leucocytes, cytokines and bacterial genera were explored.ResultsCVF was available for 50 PWLWH (108 samples) and 12 HUPW (20 samples) between gestation weeks 14-38. Thirty-six PWLWH conceived on cART and 14 initiated post-conception. There were five and one PTB outcomes in PWLWH and HUPW respectively. PWLWH had higher mean CVF concentrations of MMP-9 (p<0.001) and TIMP-1 (p=0.035) in the second trimester compared with HUPW with a similar trend in the third trimester. PWLWH also had higher CVF values of cytokines: IL-1β, IL-8, IL-12 and TNF-α in both trimesters compared to HUPW (p ≤ 0.003). In PWLWH, MMP-9 positively correlated with TIMP-1 (r=0.31, p=0.002) and CVF polymorphonuclear leucocytes (r=0.57, p=0.02). Correlations were observed between MMP-9 and three cytokines: IL-1β (r=0.61), IL-8 (r=0.57) and TNF-α (r=0.64), p<0.001, similarly for TIMP-1. Abundance of anaerobic pathobionts correlated with MMP-9: Gardnerella (r=0.44, p<0.001), Atopobium (r=0.33, p=0.005), and Prevotella genera (r=0.39, p<0.001). Conversely proportion of Lactobacillus genera negatively correlated with MMP-9 (rho=-0.46, p<0.001). MMP-9/TIMP-1 ratio increased with gestational age at sampling in PWLWH, but this was no longer significant after adjusting for confounders and no difference by prematurity was observed in this sub-study.ConclusionsHere we show strong correlations of MMP-9 to genital tract inflammation and sub-optimal bacterial genera in PWLWH indicating the ascending genital tract infection pathway may be a contributory mechanism to the high risk of PTB.

Histology-based profile of inflammatory mediators in experimentally induced pulpitis in a rat model: screening for possible biomarkers.

AimTo profile molecular changes in lipopolysaccharide (LPS)‐induced experimental pulpitis in a rat model and explore the feasibility of a molecular‐based diagnostic strategy for pulpitis.MethodologySeventy‐three maxillary incisors of Sprague‐Dawley rats were used to establish pulpitis models with LPS. Inflammatory grading was performed in four equal sections of the pulp divided from the injured site to the root apex. An antibody array was used to compare the expression of 67 molecules between control pulp and inflamed pulp 12 and 72 h after LPS application. The levels of differentially expressed molecules in the control and inflamed pulp (collected at 3, 6, 9, 12, 24 and 72 h after LPS treatment) were examined via ELISA, and correlations between inflammatory scores and molecule expression were assessed. The molecule distributions in the pulp were investigated by immunofluorescence staining. Data were analysed with paired t‐test, one‐way anova, Kruskal–Wallis tests, and Spearman’s and Pearson’s correlations with significance set at P < 0.05.ResultsPolymorphonuclear neutrophils were observed in the injured site 3 h after LPS stimulation. Inflammatory infiltration peaked at 12 h and was limited to the injured site with osteodentine deposition at 72 h. Thirteen molecules were significantly differentially expressed between the control and LPS‐injured pulp. ELISA validated that tissue inhibitor of metalloproteinase‐1 (TIMP‐1) expression dramatically peaked at 12 h (compared with other time points, P < 0.05) and returned to baseline at 72 h. The TIMP‐1 concentration was strongly correlated with inflammation severity in the apical three‐quarters of the pulp, and the strongest correlation was found in the lower‐middle quarter (r = 0.786, P < 0.001). Immunofluorescence staining revealed that in the apical three‐quarters of the pulp, TIMP‐1 expression was significantly higher in the 12 h group than in the control and 3, 6, 24 and 72 h groups (P < 0.01).ConclusionThis study provides a molecular profile of LPS‐induced pulpitis in a rat model. TIMP‐1 had a strong positive correlation with the severity of dental pulp inflammation, verifying the feasibility of applying biomarkers to identify specific pathological conditions in pulpitis.

Plasma levels of tissue inhibitor of metalloproteinase-1 in patients with type 1 diabetes mellitus associate with early diabetic neuropathy and nephropathy.

Background:Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been suggested as a marker for abnormal regulation of tissue remodelling in type 1 diabetes. Metalloproteinase-9 (MMP-9) has been associated with matrix turnover, and Neutrophil gelatinase associated lipocalin (NGAL) is a marker of tubular injury in diabetic nephropathy. The aim was to analyse these biomarkers to unmask early diabetic complications.Methods:Thirty-three type 1 diabetes patients, aged 20–35 years, and disease duration 20 ± 5.3 years were included. Along with clinical examination, neurophysiological measurements, routine biochemistry, plasma concentrations of TIMP-1, MMP-9 and NGAL were determined with immunoenzymatic techniques.Results:TIMP-1 correlated with abnormal unilateral and bilateral vibratory sense foot perception (r = −0.49 and r = −0.51, respectively), foot neuropathy impairment assessment score (NIA; r = −0.55), neuropathy symptom assessment score (r = 0.42), microalbuminuria (r = 0.50) and eGFR (r = −0.45). MMP-9 correlated with impaired foot NIA (r = 0.51). Multiple regression analysis showed an association for TIMP-1 (p = 0.004) with impaired neurophysiological examinations and renal dysfunction along with NGAL (p = 0.016 and p = 0.015 respectively).Conclusions:This study suggests that plasma levels of TIMP-1, MMP-9 and NGAL may serve as useful biomarkers in unravelling subclinical neuropathy and nephropathy in type 1 diabetes.

Extracellular matrix collagen biomarkers levels in patients with chronic thromboembolic pulmonary hypertension.

Limited data exist on changes in the extracellular matrix (ECM) collagen biomarkers levels during chronic thromboembolic pulmonary hypertension (CTEPH) development. This study aimed to investigate ECM collagen biomarkers levels in stable patients with CTEPH. Patients with CTEPH and healthy persons were enrolled. Serum levels of procollagen III N-terminal peptide (PIIINP), carboxyterminal propeptide of type I procollagen (PICP), matrix metalloproteinases (MMP2), MMP9, and tissue inhibitor of metalloproteinases 1(TIMP1) were measured by ELISA. Clinical data coincident with samples were collected. The pulmonary endarterectomy (PEA) and control pulmonary artery tissue samples were analyzed for genetic and immunohistochemical differences. The serum concentrations of PIIINP, PICP, MMP2, and MMP9 decreased significantly in CTEPH patients compared to healthy controls (P < 0.001 for each). CTEPH patients had higher serum concentrations of TIMP1 (median, 111.97 [interquartile range, 84.35-139.93]) compared to healthy controls (74.97 [44.03-108.45] ng/mL, P < 0.001). The MMP2 to TIMP1 ratio was lower in patients than in the controls (P < 0.001). After adjusting for the body mass index (BMI), the MMP2 to TIMP1 ratio correlated negatively with pulmonary vascular resistance (PVR) (r = - 0.327, P = 0.025). Increased TIMP1 (P = 0.04) gene expression was identified in tissues of CTEPH patients. Immunohistochemistry results of vascular walls substantiated qRT-PCR results. This study indicates that ECM collagen biomarkers levels were significantly different in stable patients with CTEPH and healthy controls with significantly increased TIMP1 and decreased MMP2 and MMP9. Differences in TIMP1 expression should be expected not only among healthy controls and patients serum, but also across pathological tissue regions. These findings suggest that the state of vascular remodeling in pulmonary vascular bed in stable patients may be represented by ECM collagen biomarkers levels. We conclude that TIMP1 may play an important role in pulmonary vascular reconstruction in stable CTEPH patients.

The role of epicardial fat tissue in atrial fibrillation onset in patients with hypertension

Abstract Aim To study the influence of epicardial fat tissue (EFT) on atrial fibrillation (AF) occurrence in hypertensive patients. Materials and methods The study included 195 patients with hypertension aged from 38 to 72 years (mean age was 61.5±1.8 years). All patients were divided into two groups: group I included 95 hypertensive patients with paroxysmal AF; 100 patients with hypertension in sinus rhythm were enrolled into group II. Echocardiography was performed to evaluate the thickness of EFT in a parasternal long-axis view. The EFT volume was assessed with computed tomography (CT) scan. The plasma concentration of tissue inhibitor of metalloproteinase-1 (TIMP-1) and metalloproteinase-9 (MMP-9) was measured to evaluate the myocardial fibrosis process. Results There was no significant difference between the studied groups of patients in body mass index: 34.43±1.2 kg/m2 in group I vs 31.97±1.67 kg/m2 in the group II. Waist circumference was significantly higher in group I in comparison with the group II patients: 118.9±3.3 cm vs 110.2±1.4 cm, respectively (p=0.038). EFT thickness was significantly higher in patients with paroxysmal AF (11.6±0.8 mm) in comparison with the patients in sinus rhythm (8.6±0.4 mm) (p&amp;lt;0.001). In group I patients a significant increase of EFT volume (4.6±0.4) in comparison with II group (3.5±0.25) (p=0.002) was noted. A significant positive correlation was revealed in hypertensive patients with paroxysmal AF between EFT volume and left atrial (LA) volume (r=0.7, p=0.022). Also, the plasma concentrations of TIMP-1 and MMP-1 were significantly higher in patients with paroxysmal AF and hypertension. There was a strong positive correlation between EFT volume and plasma concentration of TIMP-1 (r=0.72; p=0.01) and between the EFT volume and the LA volume (r=0.7, p=0.022) in group I patients. Multivariate regression analysis revealed the significant influence of increased EFT thickness more than 10 mm (prevalence ratio (PR) 4.1; 95% CI 1.1; 15.6) and EFT volume more than 6 ml (PR 3.7; 95% CI 1.0; 14.2) on AF occurrence. Conclusion Increased EFT thickness (more than 10 mm) and EFT volume (more than 6 ml) are predictors of AF onset in hypertensive patients. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): The complex subject of the Department

Usefulness of metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in clinical characterisation of children with newly diagnosed Crohn's disease.

The aim of this study was to determine the relation of non-invasive markers representing gut mucosal damage (metalloproteinase-9 (MMP-9)) and remodelling (tissue inhibitor of metalloproteinase-1 (TIMP-1)) with Crohn's disease (CD) phenotype, disease activity scores (clinical and endoscopic) and radiological evaluation of the ileum in newly diagnosed children. Serum and faecal MMP-9 and TIMP-1 concentrations were determined with the sandwich enzyme-linked immunoassay technique. The performance of each marker with reference to the Paris classification, disease activity scores and magnetic resonance enterography results was assessed using non-parametric tests. A total of 32 children with CD demonstrated higher levels of serum and faecal MMP-9 and TIMP-1 compared with a control group including children without gastrointestinal inflammatory disease (all P < 0.05). Only the serum MMP-9 concentration was significantly higher in children with L3 (ileocolonic) compared with children with L1 (distal ileum). The serum TIMP-1 level was significantly higher in patients with an magnetic resonance enterography-detected ileum involvement longer than 51 mm and in children with severe disease activity compared with other patients. The serum MMP-9 level was lower in patients with stenosis combined with prestenotic dilation compared with children without stenosis. Increased serum and faecal MMP-9 and TIMP-1 concentrations are some reliable markers of inflammation in newly diagnosed children with CD, but without facilitating clear phenotyping of the disease.

Plasma Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 as Prognostic Biomarkers in Critically Ill Patients.

Matrix metalloproteinase 9 (MMP-9) plays an important role in inflammatory and pathological processes by enabling the inflow of leukocytes to the site of infection or tissue damage. MMP-9 and tissue inhibitor of metalloproteinase 1 (TIMP-1) have been described as potential prognostic biomarkers in various clinical settings. The aim of the study was to evaluate the usefulness of plasma levels of MMP-9 and TIMP-1 as well as the MMP-9/ TIMP-1 ratio in predicting the outcome in patients admitted to the intensive care unit (ICU). The study included 56 critically ill patients with multiple organ failure. Plasma levels of MMP-9 and TIMP-1 were determined on hospitalization day 1, 2, 3 and 7. Nineteen (35.7%) patients died. The level of TIMP-1 was statistically significantly higher on day 1 and 7 of hospitalization in non-survivors, as compared to survivors (p=0.01). A statistically significant positive correlation was found between MMP-9 and TIMP-1. The MMP-9/TIMP-1 ratio was comparable in both groups during of observation (0.62 on day 1). The MMP-9/TIMP-1 ratio was positively correlated with the level of lactate and negatively correlated with platelet count. Likewise, TIMP-1 was positively correlated with the level of lactate. The level of MMP-9 was higher in the non-survivor group only on day 7 of observation. In conclusion, although TIMP-1 and MMP-9 concentrations were higher in non-survivors and the MMP-9/TIMP-1 ratio was related to some parameters of critical illness, further research is needed to verify whether they can serve as reliable biomarkers for early prognostication of ICU patients.

Treatment With Platelet Lysate Inhibits Proteases of Synovial Fluid in Equines With Osteoarthritis

Osteoarthritis (OA) is the most prevalent arthropathy in sport horses. The administration of a platelet lysate (PL) is an alternative method for the treatment of musculoskeletal conditions. The mechanisms by which PL exerts its beneficial effects have not been determined, and less is known about its effect on the activity of the proteolytic enzymes of the synovial fluid of equines with OA. In this work, the effect of the administration of PL to horses with OA was analyzed both clinically and molecularly by determining the levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), glycosaminoglycans (GAGs), and tissue inhibitor of metalloproteinase 1 (TIMP-1) in synovial fluid. One mL of PL was administered intra-articularly followed by the extraction of synovial fluid on days 0, 10, 30, and 60. Results were evaluated by an analysis of variance for repeated measures. The levels of MMP-9 decreased significantly (P < .05) on day 10 after treatment with PL. A disintegrin and metalloproteinase with thrombospondin motifs 5 decreased significantly on days 10 (P < .05), 30 (P < .05), and 60 (P < .01) after treatment. The levels of synovial TIMP-1 increased significantly on day 30 (P < .001) after treatment. Glycosaminoglycans showed a significant increase on days 10 (P < .05) and 30 (P < .01). A significant decrease was found for MMP-2 on day 10 (P < .01), 30 (P < .01), and 60 (P < .001). In conclusion, the beneficial effects of PL in OA could be attributed to the decreased activity of MMP-2, MMP-9, and ADAMTS-5 and the increased concentration of GAGs and TIMP-1 after the administration of platelet-rich plasma.

Chromosome 4q25 variants and biomarkers of myocardial fibrosis in patients with atrial fibrillation.

Little is known about how genetic predisposition and fibrosis relate in atrial fibrillation (AF). Hence, we sought to determine whether the genetic variants and biomarkers for fibrosis enhance prediction of outcomes after catheter ablation. Consecutive patients who underwent catheter ablation of AF (paroxysmal, 158; nonparoxysmal, 137) or supraventricular tachycardia without AF (n = 70) were studied retrospectively. Plasma levels of transforming growth factorβ1 (TGF-β1), tissue inhibitor of metalloproteinase 1 (TIMP-1), and 4q25 single-nucleotide polymorphisms (SNPs) (rs10033464 and rs220073) were measured. Mean plasma levels of both TGF-β1 and TIMP-1 were higher in patients with AF than in the control (all P < .001). Plasma levels of TIMP-1 were higher in patients with recurrence compared with those without recurrence (P = .039). Patients with variant alleles of rs10033464 showed increased recurrence after catheter ablation in patients with paroxysmal AF including after adjustment (P = .027). Patients with TIMP-1 < 107 ng/mL and no variant allele (GG) at rs10033464 had lower recurrence rates compared with other groups in those with paroxysmal AF (logrank; P = .007), whereas there was no significant difference among those patients with persistent forms of AF. Inclusion of biomarkers and genotype improved discrimination of AF recurrence in patients with paroxysmal AF (C-statistic .499 vs .600). The combination of plasma TIMP-1 concentrations less than 107 ng/mL and the absence of a variant allele at rs10033464 was associated with lower recurrence rates in patients with paroxysmal AF. This study suggests that 4q25 SNPs and biomarkers for fibrosis may provide additive value in risk stratification for AF recurrence after catheter ablation.

Alterations of elastin in female reproductive tissues arising from advancing parity

Female reproductive tissues undergo significant alterations during pregnancy, which may compromise the structural integrity of extracellular matrix proteins. Here, we report on modifications of elastic fibers, which are primarily composed of elastin and believed to provide a scaffold to the reproductive tissues, due to parity and parturition. Elastic fibers from the upper vaginal wall of virgin Sprague Dawley rats were investigated and compared to rats having undergone one, three, or more than five pregnancies. Optical microscopy was used to study fiber level changes. Mass spectrometry, 13C and 2H NMR, was applied to study alterations of elastin from the uterine horns. Spectrophotometry was used to measure matrix metalloproteinases-2,9 and tissue inhibitor of metalloproteinase-1 concentration changes in the uterine horns. Elastic fibers were found to exhibit increase in tortuosity and fragmentation with increased pregnancies. Surprisingly, secondary structure, dynamics, and crosslinking of elastin from multiparous cohorts appear similar to healthy mammalian tissues, despite fragmentation observed at the fiber level. In contrast, elastic fibers from virgin and single pregnancy cohorts are less fragmented and comprised of elastin exhibiting structure and dynamics distinguishable from multiparous groups, with reduced crosslinking. These alterations were correlated to matrix metalloproteinases-2,9 and tissue inhibitor of metalloproteinase-1 concentrations. This work indicates that fiber level alterations resulting from pregnancy and/or parturition, such as fragmentation, rather than secondary structure (e.g. elastin crosslinking density), appear to govern scaffolding characteristics in the female reproductive tissues.

Vitamin D supplementation has no effect on matrix metalloproteinases-2, -9, and tissue inhibitor matrix metalloproteinase-1 in subjects with metabolic syndrome: A pilot study.

The present randomized, double-blind, placebo controlled study aimed to evaluate the effect of vitamin D supplementation on matrix metalloproteinases-2, -9 (MMP-2 and MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in subjects with metabolic syndrome. Forty-six eligible subjects were randomly assigned to either vitamin D or placebo groups for 16 weeks. The participants were asked to take 50,000IU vitamin D or matching placebo every week. Metabolic and anthropometric indices, serum MMP-2, MMP-9, TIMP-1 and high-sensitivity C-reactive protein (hsCRP) were assessed before and after intervention. Moreover, dietary intake, sun exposure and physical activity were also determined. The trial was registered at http://www.irct.ir (No. IRCT201409033140N14). Participants were 40.20±4.60 y and 45.50% males. Compared to the baseline values, MMP-9 and TIMP-1 concentrations were decreased after 16 weeks in the intervention group (p=0.03 and p=0.04, respectively). However, the changes of MMP-2, MMP-9, TIMP-1 and hsCRP in the intervention group were not significant compared to the placebo group (p>0.05). Furthermore, the metabolic or anthropometric indices between two study groups remained unchanged (p>0.05). The findings of the present study demonstrated no effect of vitamin D supplementation on MMP-2, MMP-9 and TIMP-1 concentrations in subjects with metabolic syndrome. However, there is a need for more longitudinal trials to investigate the role of vitamin D on atherosclerosis and cardiovascular diseases in subjects with metabolic syndrome.

Association of serum levels of fibrosis-related biomarkers with disease activity in patients with IgG4-related disease

BackgroundThe aim of this study was to identify fibrosis-related serological surrogate outcome measures in patients with immunoglobulin G4-related disease (IgG4-RD).MethodsThis was a clinical observational study of 72 patients with untreated IgG4-RD from four institutions in Japan. The serum concentrations of growth differentiation factor 15 (GDF-15), CCL2, hyaluronic acid (HA), amino-terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by enzyme-linked immunosorbent assays. The enhanced liver fibrosis (ELF) score was calculated from the TIMP-1, PIIINP, and HA values. We evaluated associations between the values of these biomarkers and laboratory data, the IgG4-RD responder index (IgG4-RD RI) score, and organ involvements.ResultsCompared with the 44 healthy controls, the patients with IgG4-RD showed significantly elevated serum concentrations of GDF-15, MCP-1, HA, PIIINP, and TIMP-1 and ELF scores. The patients’ serum concentrations of GDF-15, CCL2, HA, and TIMP-1 (but not PIIINP) were positively correlated with each other. Among them, serum GDF-15 most efficiently distinguished patients with IgG4-RD from healthy controls. Serum GDF-15 was not associated with the IgG4-RD RI score or the number of organ involvements but was independently associated with the presence of retroperitoneal fibrosis and with parotid gland involvement.ConclusionsWe observed increased serological surrogate outcome measures of fibrosis in IgG4-RD. GDF-15 may precisely reflect the fibrotic degree in patients with IgG4-RD.

Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): a multicohort analysis

The prevalence of malignant pleural effusion is increasing worldwide, but prognostic biomarkers to plan treatment and to understand the underlying mechanisms of disease progression remain unidentified. The PROMISE study was designed with the objectives to discover, validate, and prospectively assess biomarkers of survival and pleurodesis response in malignant pleural effusion and build a score that predicts survival. In this multicohort study, we used five separate and independent datasets from randomised controlled trials to investigate potential biomarkers of survival and pleurodesis. Mass spectrometry-based discovery was used to investigate pleural fluid samples for differential protein expression in patients from the discovery group with different survival and pleurodesis outcomes. Clinical, radiological, and biological variables were entered into least absolute shrinkage and selection operator regression to build a model that predicts 3-month mortality. We evaluated the model using internal and external validation. 17 biomarker candidates of survival and seven of pleurodesis were identified in the discovery dataset. Three independent datasets (n=502) were used for biomarker validation. All pleurodesis biomarkers failed, and gelsolin, macrophage migration inhibitory factor, versican, and tissue inhibitor of metalloproteinases 1 (TIMP1) emerged as accurate predictors of survival. Eight variables (haemoglobin, C-reactive protein, white blood cell count, Eastern Cooperative Oncology Group performance status, cancer type, pleural fluid TIMP1 concentrations, and previous chemotherapy or radiotherapy) were validated and used to develop a survival score. Internal validation with bootstrap resampling and external validation with 162 patients from two independent datasets showed good discrimination (C statistic values of 0·78 [95% CI 0·72-0·83] for internal validation and 0·89 [0·84-0·93] for external validation of the clinical PROMISE score). To our knowledge, the PROMISE score is the first prospectively validated prognostic model for malignant pleural effusion that combines biological and clinical parameters to accurately estimate 3-month mortality. It is a robust, clinically relevant prognostic score that can be applied immediately, provide important information on patient prognosis, and guide the selection of appropriate management strategies. European Respiratory Society, Medical Research Funding-University of Oxford, Slater & Gordon Research Fund, and Oxfordshire Health Services Research Committee Research Grants.

Analysis of inflammatory markers and metals in nasal lavage fluid of welders

ABSTRACTWelding fumes may produce adverse health effects in the respiratory tract. To assess the relationship between exposure to welding fumes and inflammation in the upper airways, 190 male welders were examined from the WELDOX study (median age 40 yr, 54.7% smokers, and 32.9% atopics). Inhalable welding fumes were collected in the breathing zone of welders during a single shift. Chromium (Cr), nickel (Ni), manganese (Mn), and iron (Fe) were measured in the welding-fume samples and in postshift nasal lavage fluid (NALF). In addition, the numbers of particles and inflammatory biomarkers, including total and differential cell counts, interleukin (IL)-8, leukotriene (LT) B4, 8-isoprostane (8-iso-PGF2α), tissue inhibitor of metalloproteinase-1 (TIMP-1), and immunoreactive matrix metalloproteinase (MMP)-9, were determined. Metal concentrations in NALF correlated with airborne concentrations. No significant association was found between airborne metal concentrations and biomarkers of inflammation in NALF, whereas increasing metal concentrations in NALF resulted in increased concentrations of total protein, IL-8, MMP-9, and TIMP-1. LTB4 and 8-iso PGF2α were elevated at higher concentrations of Cr or Ni in NALF. The same was true for Fe, although the effects were less pronounced and of borderline significance. In conclusion, our results showed a significant association between the concentrations of metals and soluble inflammatory markers in the NALF of welders. The noninvasive collection of NALF is applicable in field studies, where it may serve as a suitable matrix to simultaneously assess biomarkers of exposure and effect in the upper respiratory tract in workers who are occupationally exposed to airborne hazardous substances.