Vernonia amygdalina inhibited osteoarthritis development by anti-inflammatory and anticollagenase pathways in cartilage explant and osteoarthritis-induced rat model.

Vernonia amygdalina (VA) is a medicinal tropical herb for diabetes and malaria and believed to be beneficial for joint pains. The antiosteorthritis effects of VA leaf in cartilage explant assays and on postmenopausal osteoarthritis (OA) rat model were investigated. The VA reduced the proteoglycan and nitric oxide release from the cartilage explants with interleukin 1ß (IL-1ß) stimulation. For the preclinical investigation, ovariectomized (OVX) female rats were grouped (n = 8) into nontreated OA, OA + diclofenac (5 mg/kg), OA + VA extract (150 and 300 mg/kg), and healthy sham control. Monosodium iodoacetate was injected into the knee joints to accelerate OA development. After 8 weeks, the macroscopic, microscopic, and histological images showed that the OA rats treated with VA 300 mg/kg and diclofenac had significantly reduced cartilage erosions and osteophytes unlike the control OA rats. The extract significantly down-regulated the inflammatory prostaglandin E2, nuclear factor κß, IL-1ß, ADAMTS-5, collagen type 10α1, and caspase3 in the OVX-OA rats. It up-regulated the anti-inflammatory IL-10 and collagen type 2α1 mRNA expressions, besides reducing serum collagenases (MMP-3 and MMP-13) and collagen type II degradation biomarker (CTX-II) levels in these rats. The VA (containing various caffeoyl-quinic acids, flavanone-O-rutinoside, luteolin, apigenin derivative and vernonioside D) suppressed inflammation, pain, collagenases as well as cartilage degradation, and improved cartilage matrix synthesis to prevent OA.

The association between serum metalloproteinase concentration, obesity, and hormone levels in reproductive-aged women.

INTRODUCTION: Increased levels and activity of some matrix metalloproteinases (MMPs) are described in obesity-related vascular diseases. Factors that influence MMP blood concentration are still being investigated. This research aims to evaluate the concentration of most types of MMPs: collagenases (MMP-1, -3, -8, -13), matrilysin (MMP-7), gelatinase (MMP-9), and metalloelastase (MMP-12) in serum of women in reproductive age in relation with their body mass index (BMI), age, oestradiol, and progesterone concentrations. MATERIAL AND METHODS: Blood samples were taken from 54 healthy reproductive-aged women with normal menstrual cycles. The weight and height of all women were measured, and body mass index (BMI) was calculated. Concentration of MMP-1, -3, -7, -8, -9, -12, and MMP-13 was evaluated using a Procarta Immunoassay Kit. Serum concentrations of oestradiol and progesterone were evaluated by immunochemiluminescence (32 in the proliferative and 20 in the secretory phase of menstrual cycle). The results of the study were statistically calculated using Pearson, Spearman, and Kruskal-Wallis tests. RESULTS: Positive correlation between MMP-7, -8, -9, -12, and -13 levels and BMI was demonstrated. Significantly higher concentrations of MMPs were found especially in obese women compared to women with normal BMI. In healthy, regularly menstruating premenopausal women, MMP levels did not correlate with oestradiol and progesterone concentrations. CONCLUSIONS: The results suggest that body mass can influence MMP serum concentration in women with regular menstrual cycles.

Levels of Matrix-Degrading Enzymes and Lubricin in Patients With Degenerative Joint Disease Requiring Arthroplasty.

Total joint arthroplasty (TJA) of the hip or knee (THA and TKA) is the primary surgical intervention for individuals with degenerative joint disease (DJD). Although it is commonly thought that shear force on the joint causes the degradation of articular cartilage, it is possible that there are other factors that contribute to the progression of DJD. It is plausible that specific enzymes that degrade the joint are upregulated, or conversely, there is downregulation of enzymes critical for joint lubrication. The aim of this study is to profile collagenase-1, elastase, heparanase, and lubricin levels in patients undergoing TJA in order to determine potential preexisting dysregulation that contributes to the pathogenesis of DJD. Deidentified blood samples were obtained from patients undergoing TJA 1 day pre- and 1 day postoperatively. Plasma samples were analyzed using enzyme-linked immunosorbent assay kits for elastase, collagenase-1, heparanase, and lubricin. In comparison to healthy controls, there were significant increases in circulating collagenase-1, elastase, and lubricin levels in both the preoperative and postoperative samples. There were no significant differences in heparanase levels in the preoperative or postoperative samples. Comparing the preoperative versus postoperative patient samples, only lubricin demonstrated a significant change. The results of this study confirm that patients undergoing TJA have preexisting alterations in the levels of matrix-degrading enzymes and lubricin. The alterations observed in this study may provide insight into the pathogenesis of DJD.

Cellular pharmacodynamic effects of Pycnogenol® in patients with severe osteoarthritis: a randomized controlled pilot study.

BACKGROUND: The standardized maritime pine bark extract (Pycnogenol®) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol® and its in vivo mechanism of action in OA patients. METHODS: Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol® twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients' chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples. RESULTS: The oral intake of Pycnogenol® downregulated the gene expression of various cartilage degradation markers in the patients' chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p ≤ 0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p ≤ 0.05) after three weeks intake of the pine bark extract. CONCLUSIONS: This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol® on symptom scores of patients suffering from OA. TRIAL REGISTRATION: ISRCTN10754119 . Retrospectively registered 08/10/2015.

[The system of matrix metalloproteinases and their role in patients with pulmonary tuberculosis]. / Sistema matriksnye metalloproteinazy/ingibitory pri infil'trativnom tuberkuleze legkikh i ee rol' v otsenke intensivnoi fazy terapii.

The aim of this study was to examine the relationship between serum levels of parameters of the system metalloproteinase (MMP)/inhibitors with severity of infiltrative pulmonary tuberculosis (ITL), changes in examined parameters during the intensive phase treatment (IPT), as well as possibility of their use for prediction of IPT effectiveness, along with acute-phase proteins (AFP). The study included ITL patients which were subdivided into two groups (I and II) with different rates of reparative changes. It was shown that: 1) ITL is characterized by impairements in the system MMP/inhibitors: the levels of MMP-1, -9 increased, MMP-3, -8, TIMP-1 remained at the reference values and a 2-macroglobulin was low. 2) Changes of the parameters of the system MMP/inhibitors were associated with markers of severity and activity of the process: MMP-1, with the presence of destruction and sensitivity of the pathogen (Mycobacterium tuberculosis; MBT) to anti-TB drugs, MMP-9, with the volume of destruction, MMP-8 - with activity of tuberculosis. 3) TIMP-1 and MMP-9 concentrations decreased during treatment in groups with different rates of reparative process, whereas proMMP-1, MMP-3,-8 remained unchanged. 4) Before and after IPT, the level of TIMP-1 was higher in the group of patients with slower rate of reparative processes. 5) After IPT the imbalance in the system MMP/inhibitor preserved thus suggesting continuation of the reparative process. 6) Use of combination of MMP and AFR is more informative in predicting efficacy of IPT.

Blood expression of matrix metalloproteinases 8 and 9 and of their inducers S100A8 and S100A9 supports diagnosis and prognosis of PDAC-associated diabetes mellitus.

BACKGROUND: Based on the knowledge that matrix metalloproteinases (MMPs) and S100A8/A9 synergistically work in causing PDAC-associated type 2 diabetes mellitus (T2DM), we verified whether tissue and blood MMP8, MMP9, S100A8 and S100A9 expression might help in distinguishing PDAC among diabetics. METHODS: Relative quantification of MMP8, MMP9, S100A8 and S100A9 mRNA was performed in tissues obtained from 8 PDAC, 4 chronic pancreatitis (ChrPa), 4 non-PDAC tumors and in PBMCs obtained from 30 controls, 43 T2DM, 41 ChrPa, 91 PDAC and 33 pancreatic-biliary tract tumors. RESULTS: T2DM was observed in PDAC (66%), in pancreatic-biliary tract tumors (64%) and in ChrPa (70%). In diabetics, with or without PDAC, MMP9 tissue expression was increased (p<0.05). Both MMPs increased in PDAC and MMP9 increased also in pancreatic-biliary tract tumors PBMCs. In diabetics, MMP9 was independently associated with PDAC (p=0.025), but failed to enhance CA 19-9 discriminant efficacy. A highly reduced S100A9 expression, found in 7 PDAC, was significantly correlated with a reduced overall survival (p=0.015). CONCLUSIONS: An increased expression of tissue and blood MMP9 reflects the presence of PDAC-associated diabetes mellitus. This finding fits with the hypothesized role of MMPs as part of the complex network linking cancer to diabetes.

Platelet-Associated Matrix Metalloproteinases Regulate Thrombus Formation and Exert Local Collagenolytic Activity.

OBJECTIVE: Platelets are increasingly implicated in processes beyond hemostasis and thrombosis, such as vascular remodeling. Members of the matrix metalloproteinase (MMP) family not only remodel the extracellular matrix but also modulate platelet function. Here, we made a systematic comparison of the roles of MMP family members in acute thrombus formation under flow conditions and assessed platelet-dependent collagenolytic activity over time. APPROACH AND RESULTS: Pharmacological inhibition of MMP-1 or MMP-2 (human) or deficiency in MMP-2 (mouse) suppressed collagen-dependent platelet activation and thrombus formation under flow, whereas MMP-9 inhibition/deficiency stimulated these processes. The absence of MMP-3 was without effect. Interestingly, MMP-14 inhibition led to the formation of larger thrombi, which occurred independently of its capacity to activate MMP-2. Platelet thrombi exerted local collagenolytic activity capable of cleaving immobilized dye-quenched collagen and fibrillar collagen fibers within hours, with loss of the majority of the platelet adhesive properties of collagen as a consequence. This collagenolytic activity was redundantly mediated by platelet-associated MMP-1, MMP-2, MMP-9, and MMP-14 but occurred independently of platelet α-granule release (Nbeal2(-/-) mice). The latter was in line with subcellular localization experiments, which indicated a granular distribution of MMP-1 and MMP-2 in platelets, distinct from α-granules. Whereas MMP-9 protein could not be detected inside platelets, activated platelets did bind plasma-derived MMP-9 to their plasma membrane. Overall, platelet MMP activity was predominantly membrane-associated and influenced by platelet activation status. CONCLUSIONS: Platelet-associated MMP-1, MMP-2, MMP-9, and MMP-14 differentially modulate acute thrombus formation and at later time points limit thrombus formation by exerting collagenolytic activity.

[INFLUENCE OF QUINAPRIL IN COMBINATION WITH ANGIOLINE ON THE CONNECTIVE TISSUE COMPONENTS IN THE RATS SERUM WITH EXPERIMENTAL HYPERTENSION].

One of the most active inhibitors angiotensin-converting enzyme is quinapril that has a high affinity for tissue ACE, improves endothelial vasodilation, has a wide therapeutic range and beneficient influence on heart rate. A new biological active compound with antioxidant action that has endothelioprotective, cardioprotective, antiischemic action is angiolin. In experimental arterial hypertension in the animals blood serum the activity of collagenase, the content of free and protein connecting fractions of hydroxyproline and indicators that reflect the metabolism of glycosaminoglycans have been increased. Angiolin increases the activity of collagenase free and protein connecting fractions of hydroxyproline comparing to control. Concentration glycosoaminoglycan (GAG) also exceeds the standard data. Quinapril has similar to angiolin action directed effect to the connective tissue components, though losing as proteinconecting of hydroxiproline action. Cooperative application quinapril with angioline most effectively influence the metabolic processes stabilization in experimental animals.

Clinical and immunological aspects of post-kala-azar dermal leishmaniasis in Bangladesh.

We conducted active surveillance for kala-azar and post-kala-azar dermal leishmaniasis (PKDL) in a population of 24,814 individuals. Between 2002 and 2010, 1,002 kala-azar and 185 PKDL cases occurred. Median PKDL patient age was 12 years; 9% had no antecedent kala-azar. Cases per 10,000 person-years peaked at 90 for kala-azar (2005) and 28 for PKDL (2007). Cumulative PKDL incidence among kala-azar patients was 17% by 5 years. Kala-azar patients younger than 15 years were more likely than older patients to develop PKDL; no other risk factors were identified. The most common lesions were hypopigmented macules. Of 98 untreated PKDL patients, 48 (49%) patients had resolution, with median time of 19 months. Kala-azar patients showed elevated interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), and interleukin 10 (IL-10). Matrix metalloproteinase 9 (MMP9) and MMP9/tissue inhibitor of matrix metalloproteinase-1 (TIMP1) ratio were significantly higher in PKDL patients than in other groups. PKDL is frequent in Bangladesh and poses a challenge to the current visceral leishmaniasis elimination initiative in the Indian subcontinent.

Red yeast rice improves lipid pattern, high-sensitivity C-reactive protein, and vascular remodeling parameters in moderately hypercholesterolemic Italian subjects.

Despite a recent health claim by the European Agency on Food Safety, the effect of high doses of dietary monacolin supplements from red yeast rice on cholesterolemia has not been tested in Italian subjects. Our aim via a crossover, double-blind, placebo-controlled randomized clinical trial was to test if a short-term treatment with 10 mg monacolins could improve lipid pattern, high-sensitivity C-reactive protein (hs-CRP), and vascular remodeling biomarkers in a small cohort of Mediterranean subjects. Thus, 25 healthy, mildly hypercholesterolemic subjects were enrolled, and after 4 weeks of a stabilization diet, subjects were randomized to the sequence placebo-washout-monacolins or monacolins-washout-placebo, with each period being 4 weeks long. At each study step, a complete lipid pattern, safety parameters, hs-CRP, and matrix metalloproteinases 2 and 9 levels were measured. When compared to the placebo group, monacolins-treated patients experienced a more favorable percent change in total cholesterol (-12.45%, 95% CI -16.19 to -8.71), low-density lipoprotein cholesterol (-21.99%, 95% CI -26.63 to -17.36), non-high-density lipoprotein cholesterol (-14.67%, 95% CI -19.22 to -10.11), matrix metalloproteinase 2 (-28.05%, 95% CI -35.18 to -20.93), matrix metalloproteinase 9 (-27.19%, 95% CI -36.21 to -18.15), and hs-CRP (-23.77%, 95% CI -30.54 to -17.01). No significant differences were observed in regards to triglycerides, high-density lipoprotein cholesterol, and safety parameters. On the basis of our data, we demonstrate that a 10-mg monacolin nutraceutical appears to safely reduce cholesterolemia, hs-CRP, and markers of vascular remodeling in Italian subjects. These results have to be confirmed in larger patient samples and longer studies.

[Effects of acute normobaric hypoxia on free plasma amino acids metabolism in humans].

We demonstrated significant changes in levels of several plasma free amino acids--proline, hydroxyproline, glycine, and phenylalanine--in healthy volunteers in response to severe acute normobaric hypoxia (breathing nitrogen-oxygen mixture with 9% of O2). We assume that demonstrated an increase of free proline, hydroxyproline, and glycine in plasma in the 10th minute of hypoxia was caused by increased collagenolysis due to hypoxic activation of matrix metalloproteinases. Significantly increased levels of free phenylalanine in the 10th and 20th minutes of hypoxia were the consequences of autophagy activation. Our results suggest that acute severe normobaric hypoxia has specific effects on plasma free amino acids in healthy humans.

[Features of biochemical changes in blood serum according to the form of progression of idiopathic and dysplastic coxarthrosis].

Carried out biochemical studies of blood serum (collagenase activity, glycosamineglicans and hydroxyproline fractions) of 72 patients with hip idiopathic osteoarthrosis and 30 patients with dysplastic osteoarthrosis of the iv-th stage in.accordance with J. H. Kellgren and J. S. Lavrence depending on the form of pathologic process progression. It has been proved that both with idiopathic and dysplastic coxartrosis metabolism of basic protein of osteochonrous tissue was broken both in catabolic and in synthetic phase of this process. The most deep changes 1 of biochemical values (collagenase, free and proteinbinded hydroxyprolines, the content of glycosamines) have been observed with rapid form of course progression of idiopathic and dysplastic coxarthrosis. Definite appropriateness promotesin.patients better understanding of coxarthrosis pathogenese, development of diagnostic and medical measures for patients with this severe orthopedic pathology.

[Biochemical indices of connective tissue metabolism in patients with chronic hepatitis B and C].

37 patients with chronic hepatitis B and C were examined. Patients were divided into 3 groups depending on the degree of connective tissue dysplasia. We investigated: free and protein-bounded hydroxyproline, collagenase activity, total alkaline phosphatase and its bone fraction, creatinine, calcium and phosphorus content in the blood serum and urine. It has been found the dependence of collagen synthesis from the state of connective tissue. The higher is the degree of dysplasia, the more intensive is the process of collagen synthesis (P < 0.05). The index of corellation between protein-bounded and free fraction can be used as a biochemical marker for determination the stage of pathological process in the liver and for monitoring the effectiveness of therapy.

Serum levels of metalloproteinases and their inhibitors during infection with pathogens having integrin receptor-mediated cellular entry.

BACKGROUND: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes with numerous roles in the normal immune response to infection. However, excess MMP activity following infection may lead to immunopathological processes that cause tissue damage. Their activity in normal tissues is subject to tight control, which is regulated by its specific endogenous tissue inhibitors (TIMPs). It is known that MMPs bind to cell surface proteins (e.g. integrins) and that such interactions can have modulatory effects on MMP functionality. The objective of this study was to determine whether there are differences in MMP and TIMP production during the acute phase of infection with different pathogens that use ß-integrins as their receptors for cell entry. METHODS: We measured the total amounts of soluble MMP-2, MMP-9, TIMP-1, and TIMP-2 in the sera from patients infected with Dobrava virus (DOBV), Coxiella burnetii, or uropathogenic Escherichia coli. Statistical analyses were used to correlate MMP/TIMP serum levels with different clinical laboratory parameters. RESULTS: The results showed that both of the bacterial infections generally manifested the stronger effect on MMP production, while in contrast, viral infection introduced stronger changes to metalloproteinase inhibitors. MMPs and TIMPs were significantly correlated with some of the clinical laboratory parameters in both bacterial infections, but no correlations were found for DOBV infection. CONCLUSIONS: These findings suggest diverse mechanisms by which MMP activity could be implicated in the pathology of these 2 bacterial infections versus the viral DOBV infection, despite the type of their cellular entry receptors.

[Matrix metalloproteinases and their inhibitors in ovarian cancer progression--diagnostic and therapeutic implications]. / Rola metaloproteaz macierzowych i ich inhibitorów w progresji raka jajnika--implikacje diagnostyczne i terapeutyczne.

Matrix metalloproteinases are proteolytic enzymes which degrade extracellular matrix proteins. Along with their specific inhibitors--issue inhibitors of metalloproteinases--they play an important role in the spreading of malignant tumours. The research conducted in recent years has shown that metalloproteinases and their inhibitors contribute substantially to the ovarian cancer progression, participating both in in situ tumours growth, and the spreading of neoplasm via peritoneal fluid. The assessment of serum concentration of some metalloproteinases and their inhibitors appeared to be useful in differential diagnosis between malignant, borderline and benign ovarian tumours. In numerous research, it was revealed that the expression of metalloproteinases in primary tumours and in metastatic changes has a prognostic value. Moreover, the pre-operational assessment of concentration of TIMP-1 in blood serum allows to select the cases of an ovarian cancer with an aggressive phenotype and unfavourable prognosis. Despite great expectations, the usage of synthetic inhibitors of metalloproteinases did not bring significant changes and improvement to ovarian cancer treatment.

[The diagnostic value of the detection of hepatic fibrosis serum markers in chronic viral hepatitis].

The diagnostic significance of serum markers of fibrosis was investigated in 92 patients with chronic viral hepatitis (CVH) by studying the collagenolythic activity of blood, proteasic inhibitor activity, collagen metabolism products (oxyproline fraction), and fibronectin. At the same time, the patients underwent puncture biopsy of the liver, which made it possible to determine the degree of process activity and the stage of its chronization. As the degree of fibrosis grew, the collagenase serum activity increased significantly, while the alpha1-proteinase inhibitor activity fell, the content of oxyproline (its fractions) increased, and the fibronectin level decreased. Hence, the measurement of the noted parameters allows for noninvasive diagnostics of CVH stages.

[Statins and their influence on inflammatory processes in internal carotid artery stenosis]. / Statine und ihr Einfluss auf entzündliche Prozesse in arteriosklerotischen Plaques bei Patienten mit Stenose der Arteria carotis interna.

Arterio-arterial emboli originating from a high-grade stenosis of the internal carotid artery are a common cause for cerebral ischemias. Inflammatory processes are not only pivotal in the development of atherosclerotic vessel wall changes, but also for their clinical destabilization. Inflammatory cells, like macrophages, can turn a chronic high-grade carotid stenosis into a high-risk area for the development of arterial thromboses by way of a complex pathogenesis involving the elevation of proinflammatory factors, biosynthesis of collagen-degrading matrix metalloproteinases and expression of prothrombotic tissue factor. This process could affect the occurrence of perioperative complications during carotid endarterectomies. Statins are potent cholesterol-lowering agents. Among other lipid-independent effects, statins appear to play a significant role in preventing cardiovascular events. A number of studies have shown that statins possess plaque-stabilizing effects and that they improve cerebral autoregulation. A growing evidence supports the preoperative administration of statins in patients with high-grade stenoses of the internal carotid artery.

Noninvasive biochemical markers of liver fibrosis.

The assessment of liver fibrosis provides useful information not only for diagnosis but also for therapeutic decision. Although needle biopsy of the liver is the gold standard for fibrosis assessment, it has some technical limitations and risks. This has led to the development of noninvasive biochemical markers of liver fibrosis: direct markers which reflect extracellular matrix turnover and indirect markers which reflect alterations in hepatic function. Markers associated with matrix deposition or degradation and some cytokines implied in fibrosis may be used as individual markers or as combination of markers to generate an algorithm to evaluate the stage of fibrosis. Also, fibrosis may be predicted by using indirect markers as a single routine laboratory test or multicomponent indirect fibrosis tests. Serum markers are of great value not only in patients at risk for liver biopsy, but also as a part of the assessment of patients with chronic liver disease avoiding the invasive methods.

Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease.

BACKGROUND: Chronic hypertension may cause left ventricular (LV) remodeling, alterations in cardiac function, and the development of chronic heart failure (CHF). Changes in the composition of the extracellular matrix (ECM) known to occur in hypertension are believed to be causally related to these structural, functional, and clinical outcomes. However, whether the determinants of ECM composition, such as the balance between ECM proteases (matrix metalloproteinases [MMPs]) and their tissue inhibitors [TIMPs]), are altered in hypertensive heart disease is unknown. METHODS AND RESULTS: Plasma MMP-2, -9, and -13 values, TIMP-1 and -2 values, and Doppler echocardiography images were obtained for 103 subjects divided into 4 groups: (1) reference subjects (CTL) with no evidence of cardiovascular disease, (2) hypertensive (HTN) subjects with controlled blood pressure and no LV hypertrophy, (3) hypertensive subjects with controlled blood pressure and with LV hypertrophy (HTN+LVH) but no CHF, and (4) hypertensive subjects with controlled blood pressure, LVH, and CHF (HTN+LVH+CHF). Compared with CTL, patients with HTN had no significant changes in any MMP or TIMP. Patients with HTN+LVH had decreased MMP-2 and MMP-13 values and increased MMP-9 values. Only patients with HTN+LVH+CHF had increased TIMP-1 values. A TIMP-1 level >1200 ng/mL was predictive of CHF. CONCLUSIONS: Patients with hypertension but normal LV structure and function had normal MMP/TIMP profiles. Changes in MMP profiles that favor decreased ECM degradation were associated with LVH and diastolic dysfunction. An increased TIMP-1 level predicted the presence of CHF. Although these findings should be confirmed in a larger prospective study, these data do suggest that changes in the MMP/TIMP balance may play an important role in the structural, functional, and clinical manifestations of hypertensive heart disease.

TIMP-1/MMP-9 imbalance in brain edema in rats with fulminant hepatic failure.

BACKGROUND: Fulminant hepatic failure (FHF) is a devastating disease. When coma sets in, brain edema develops, changing FHF into a lethal condition. Liver transplantation is the definitive treatment. However, a third of these patients die as the result of brain edema before a donor becomes available. Tissue inhibitor of matrix metalloproteinase (MMP), or TIMP, and MMP-9 are implicated in ischemic brain edema. We thus hypothesized that an imbalance in TIMP-1/MMP-9 relationship plays a role in the development of increased brain extravasation and edema in FHF. MATERIALS AND METHODS: FHF was induced with a single intraperitoneal injection of D-galactosamine (250 mg/kg). Control rats received saline. GM6001, a synthetic MMP inhibitor, was administered (30 mg/kg) every 12 h for 3 doses starting at 12 h after D-galactosamine injection. MMP-9 was assayed with standard gelatin zymography. Brain extravasation, a measurement of the blood-brain barrier permeability, was determined with Evans blue. Brain edema was determined using specific gravity method. RESULTS: The active MMP-9 in the systemic circulation was significantly increased in the comatose FHF as compared to the precoma FHF and control animals (6.5 +/- 0.7 versus 4.6 +/- 0.4 versus 2.6 +/- 0.5 pg/microg, respectively; P < 0.05). Conversely, TIMP-1 was steadily decreased in precoma and coma FHF rats by 35% and 45%, respectively. Blocking MMP-9 activity with GM6001 significantly attenuated brain extravasation and edema in rats with FHF. CONCLUSIONS: Our study strongly supports that the perturbation of decreased TIMP-1 and increased MMP-9 contributes to the pathogenesis of brain edema in FHF. Our findings present a potential therapeutic approach to effectively increase the window of opportunity for life-saving liver transplantation.