Plasma Tissue Inhibitor Of Metalloproteinase Research Articles

Change in Proteolytic Profile in Heifers After Oligofructose Overload.

Laminitis in cattle is an important underlying cause of lameness, which leads to a significant reduction in economic and animal welfare. Nevertheless, the disordered pathological processes of laminitis remain unclear. Several proteinases are probably involved in the disorder of basement membrane (BM) metabolism in laminitis, for instance, matrix metalloproteinases (MMPs), neutrophil elastase (NE), and myeloperoxidase (MPO). This study aimed to investigate the change in proteolytic profile in circulating and lamellar tissues using an oligofructose (OF) overload-induced laminitis model in heifers. Twelve clinically healthy and nonlame Chinese Holstein heifers were recruited and randomly divided into two groups: OF-induced and control (CON). The OF-induced heifers group (n = 6) was administered 17 g/kg of body weight (BW) of OF dissolved in 2 L/100 kg of BW of tap water via the oral-rumen tube. The CON group (n = 6) was given an equal volume of tap water. The plasma samples were collected 0, 6, 12, 18, 24, 36, 48, 60, and 72 h after administration, and the lamellar samples were collected 72 h after euthanasia. The plasma samples were analyzed by zymography and reverse zymography. Histological examination, zymography, reverse zymography, and Western blot of lamellar samples were conducted. In the plasma of the OF-induced group, the pro-MMP9 activity increased from 36 h (P < 0.001) to 60 h (P < 0.05). Moreover, the plasma tissue inhibitors of metalloproteinase 1 (TIMP1) activity decreased after 18 h (P < 0.05), while the ratio of pro-MMP9 to TIMP1 and TIMP2 increased after 18 h (P < 0.001) and 48 h (P < 0.05), respectively. The act-MMP2, pro-MMP9, and act-MMP9 activities increased in the lamellar tissue of the OF-induced group compared with the CON group (P < 0.05). In addition, the expression of lamellar NE protein was higher in the OF-induced group (P < 0.01), while no change was found in lamellar MPO protein compared with the CON group. In conclusion, increased pro-MMP9 combined with decreased TIMP1 activity in the circulation might have caused the activation of blood neutrophils, while the activation of proteolytic enzymes in lamellar tissue probably led to the dysfunction of BM in the OF-induced group.

COVID-19 patients in intensive care develop predominantly oliguric acute kidney injury.

BackgroundAcute kidney injury (AKI) is a syndrome of reduced glomerular filtration rate and/or reduced urine flow associated with mortality in corona virus disease 2019 (COVID‐19). AKI is often associated with renal tissue damage, which may lead to chronic kidney disease. Biomarkers of tissue damage may identify patients of particular risk.MethodsIn a prospective observational study of 57 patients admitted to intensive care, AKI incidence and characteristics was evaluated according to KDIGO criteria and related to days after admission. Urinary albumin, Neutrophil Gelatinase‐Associated Lipocalin (NGAL), Kidney Injury Molecule 1 (KIM‐1) and Plasma Tissue Inhibitor of MetalloProteinase 2 (TIMP‐2) were analysed in 52 patients at admission.The majority (n = 51, 89%) of patients developed AKI, and 27 (47%) patients had predominantly oliguric AKI where oliguria was more severe than plasma Creatinine increase. Severe oliguria within first 2 days after admission was common (n = 37, 65%), whereas stage 2 and 3 AKI due to Creatinine occurred later than day 2 in 67% (12/18) of cases. Renal replacement therapy was started in 9 (16%) patients, and 30‐day mortality was 28%. Urinary biomarkers were increased in a majority of patients, but did not robustly predict KDIGO stage. Most patients had microalbuminuria, and severe albuminuria (albumin Creatinine ratio > 30 mg/mmol) was found in n = 9 (17%) patients.ConclusionsA majority of patients with COVID‐19 admitted to the ICU develop AKI. The functional deficit is often low urinary volume, and initial levels of biomarkers are generally increased without clear relation to final AKI stage.

Prognostic impact of preoperative plasma tissue inhibitor of metalloproteinase 1 (pTIMP-1) in colorectal cancer (CRC) patients (Pts): A pooled analysis of 1,024 stage II/III pts.

3576 Background: Identification of a marker with strong prognostic impact on clinical outcomes would aid in the management of pts with primary, curatively resected CRC. We conducted a pooled individual pt data analysis to confirm the prognostic value of pTIMP-1 for overall survival (OS) in stage II and III CRC. Methods: pTIMP-1 was determined in plasma using immunoassays. Samples and clinical data were included from 5 studies with a total of 1,042 stage II/III pts resected between 1991 – 2006 (Holten-Andersen (HA), 2000 [n=378], HA, 2004 [n=226], Waas, 2005 [52], Birgisson, 2010 [225], Nielsen, 2011[n=161]). To provide comparable measures across studies, pTIMP-1 values were rescaled using fractional ranks (FR, based on ranks and sample size). Pts were grouped by the median of the pTIMP-1 FR score. Stratified log-rank tests and multivariate Cox models assessed the association between OS and pTIMP-1 FR. Results: Overall, 59% were male; median age 69 years; 56% had stage II disease and 50% had colon cancer. The median follow-up was 5.5 years with 457 deaths. Continuous pTIMP-1 FR as a linear effect was significantly associated with OS (p &lt; .0001, HR=1.38 for a 0.3 unit increase in FR score, 95% CI 1.25 to 1.52).Pts with pTIMP-1 FR above vs below the median had significantly shorter OS (HR, 1.72; 95% confidence interval[CI], 1.42 to 2.08, p &lt;0.0001), which remained significant after adjusting for age, gender, stage, disease location, and serological CEA (HR, 1.31; 95%CI, 1.07 to 1.60; p = 0.009). Results by stage are shown in the table. No evidence of an interaction between pTIMP-1 and stage or disease location (colon vs. rectal) was observed (all p &gt; 0.6). Conclusions: pTIMP-1 is a strong prognostic marker for predicting OS independent of age, gender, CEA, stage and site of disease in curatively resected stage II and III CRC. [Table: see text]

Usefulness of Plasma Tissue Inhibitors of Metalloproteinases as Markers of Prognosis After Acute Myocardial Infarction

Alterations in the balance of matrix metalloproteinase to tissue inhibitor of metalloproteinase (TIMP) are seen after acute myocardial infarction (AMI) and are associated with adverse left ventricular remodeling and prognosis in this setting. We aimed to investigate the association between TIMP levels and the occurrence of major adverse cardiac events (MACEs) after AMI. We measured plasma TIMP-1, -2, and -4 levels in 1,313 patients presenting with AMI. Subjects were followed over a median period of 520 days for the occurrence of MACEs. Clinical risk was assessed using the Global Registry of Acute Coronary Events (GRACE) score. All TIMP levels correlated with patient age and inversely with estimated glomerular filtration rate (all p values <0.001). Levels were higher in women versus men (p <0.001) and in subjects with a history of diabetes (TIMP-1, p <0.001; TIMP-2, p = 0.002; TIMP-4, p <0.001) or hypertension (TIMP-1, p = 0.031; TIMP-2, p <0.001; TIMP-4, p <0.001). TIMP-1 and TIMP-4 were higher in subjects with previous MI or angina (p <0.001). TIMP levels increased incrementally with quartiles of GRACE score (p <0.001). All TIMPs showed univariate association with the occurrence of MACEs (p <0.001). Areas under the receiver operator characteristic curve for prediction of MACE at 1 year were 0.61 for TIMP-1, 0.57 for TIMP-2, and 0.64 for TIMP-4. Combination of TIMPs with GRACE risk score revealed a greater area under the curve than GRACE score alone (0.72 vs 0.69, p = 0.0015). On multivariable Cox proportional hazards analysis, GRACE score (p <0.001) and plasma TIMPs (log TIMP-1, p = 0.017; log TIMP-2, p <0.001; log TIMP-4, p = 0.011) independently predicted MACEs. Using Kaplan-Meier analysis, the risk of MACEs increased incrementally with the number of TIMPs above their respective median (p <0.001 for all comparisons, log-rank test). In conclusion, higher plasma TIMP-1, -2, and -4 after AMI are associated with MACEs and provide additional prognostic information to that obtained from GRACE clinical risk scores alone.

Evaluation of an Improved Tissue Inhibitor of Metalloproteinase 1 Dual Monoclonal Sandwich Immunoassay

Background: It has previously been shown that increased levels of plasma tissue inhibitor of metalloproteinase 1 (TIMP-1) is associated with shorter survival for patients with colorectal cancer (CRC). Furthermore, plasma TIMP-1 levels have been found to be elevated in patients with early-stage CRC. Objective:It was the aim of this study to develop a new dual monoclonal antibody (mAb) sandwich immunoassay for TIMP-1 in order to achieve better resolution of non-cancer and cancer plasma specimens. Methods: Chemiluminescence immunoassay techniques were used to screen 240 combinations of TIMP-1 mAbs for their ability to interact with each other and to allow for further characterization of the sandwiching antibody pairs. Five mAb pair combinations were selected for assessment of their ability to resolve non-cancerous and cancerous plasma specimens by TIMP-1 measurement. Based on this testing, a final assay format was chosen for further validation. The results for the final assay were compared with measurements obtained in a TIMP-1 ELISA that had previously demonstrated the ability to resolve healthy blood donors and CRC specimens. Results: The clinical results support that the new dual monoclonal immunoassay has statistical discrimination equivalent to the ELISA. Additionally, the immunoassay had a high reproducibility and specificity. Conclusion: The clinical evaluation of five TIMP-1 immunoassays resulted in the development of a new immunoassay. The new TIMP-1 immunoassay showed superior analytical performance to our previously used ELISA.

Effect of alcohol withdrawal on liver transaminase levels and markers of liver fibrosis.

Acute alcohol withdrawal causes changes in hepatic blood flow and metabolism that may result in liver damage. This study aims to assess liver function tests and markers of hepatic fibrogenesis following alcohol withdrawal in alcoholics with clinically compensated liver disease. Serial liver function tests and clinical assessments were performed on 22 male alcoholics during alcohol withdrawal. Plasma tissue inhibitor of metalloproteinase 1 (TIMP1), an inhibitor of collagen degradation, and plasma amino-terminal procollagen III peptide (PIIINP), a collagen precursor molecule, were measured in these alcoholics and in 11 control subjects. Transaminase levels did not change significantly over 7 days when all subjects were analyzed together. However, 32% of subjects showed a marked transaminase rise. These subjects did not differ from the others in baseline characteristics or short-term outcome, but had a greater benzodiazepine requirement. Only one subject consumed paracetamol (acetaminophen; 1-2 g/day). He had the largest transaminase rise. By comparing PIIINP assays, intact PIIINP concentration appears to increase following alcohol withdrawal. The TIMP1 levels were elevated in alcoholic subjects, but did not change following withdrawal. Increasing PIIINP suggests that hepatic fibrogenesis increases, or hepatic clearance falls, during acute alcohol withdrawal. The TIMP1 elevation in these alcoholics suggests that the inhibition of collagen degradation occurs while liver disease is still compensated. The period following alcohol withdrawal may be a time of marked increased susceptibility to paracetamol. The biochemical changes we observed were not associated with adverse short-term outcome, but the cumulative effect after repeated episodes of abrupt withdrawal may be of concern.

Plasma tissue inhibitor of metalloproteinase-1 and pro-collagen III N peptide are elevated in left ventricular hypertrophy

Essential hypertension (EH) aortic stenosis (AS) and hypertrophic obstructive cardiomyopathy (HOCM) can cause left ventricular hypertrophy (LVH). LVH is associated with increased collagen concentrations in the heart but the mechanisms causing LVH in EH, AS and HOCM are different. Collagen synthesis (fibrogenesis) can be monitored by measurement of pro-collagen III N peptide (PIIINP) which measures synthesis of mature collagen III. Inhibition of degradation was assessed by plasma tissue inhibitor of metalloproteinase -1 (TIMP-1) which inhibits the activity of metalloproteinases. We investigated levels of TIMP-1 and PIIINP in patients with the three types of LVH. Patients with EH had never been treated or had been off treatment for one month and patients with AS had blood samples taken preoperatively for PIIINP and TIMP-1. The results for the EH, AS and HOCM groups were compared with seventeen normotensive controls. Heparinised plasma was used in the assays for TIMP-1 and PIIINP which were measured by ELISA and RIA respectively. (See Table) p<0.05 in comparison to controls p<0.05 in comparison to controls Elevated levels of collagen in the left ventricule in EH arise from both increased collagen synthesis as well as decreased collagen degradation whereas in AO and HOCM the increased heart collagen is associated with increased collagen III synthesis. This suggests that LVH can arise by different biochemical mechanisms.

Quantitation of TIMP-1 in plasma of healthy blood donors and patients with advanced cancer.

A kinetic enzyme-linked immunosorbent assay (ELISA) for plasma tissue inhibitor of metalloproteinase (TIMP)-1 was developed in order to examine the potential diagnostic and prognostic value of TIMP-1 measurements in cancer patients. The ELISA enabled specific detection of total TIMP-1 in EDTA, citrate and heparin plasma. The assay was rigorously tested and requirements of sensitivity, specificity, stability and good recovery were fulfilled. TIMP-1 levels measured in citrate plasma (mean 69.2 ± 13.1 μg l−1) correlated with TIMP-1 measured in EDTA plasma (mean 73.5 ± 14.2 μg l−1) from the same individuals in a set of 100 healthy blood donors (Spearman's rho = 0.62, P < 0.0001). The mean level of TIMP-1 in EDTA plasma from 143 patients with Dukes' stage D colorectal cancer was 240 ± 145 μg l−1 and a Mann–Whitney test demonstrated a highly significant difference between TIMP-1 levels in healthy blood donors and colorectal cancer patients (P < 0.0001). Similar findings were obtained for 19 patients with advanced breast cancer (mean 292 ± 331 μg l−1). The results show that TIMP-1 is readily measured in plasma samples by ELISA and that increased levels of TIMP-1 are found in patients with advanced cancer. It is proposed that plasma measurements of TIMP-1 may have value in the management of cancer patients. © 1999 Cancer Research Campaign