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PubMed1997

Phase I/II trial of batimastat, a matrix metalloproteinase inhibitor, in patients with malignant ascites.

Matrix metalloproteinases have been shown to be important in tumour invasion and metastasis, and the use of matrix metalloproteinase inhibitors in animal models has suggested that these agents may be useful in the control of malignant disease. This article reports the results of an early clinical trial of batimastat, one of the first generation of metalloproteinase inhibitors, in patients with malignant ascites. The drug was well absorbed via the intraperitoneal route and associated with few side-effects. Furthermore, a response to treatment was seen in about half the evaluable patients with advanced malignant disease. The results suggest that further research on the use of matrix metalloproteinase inhibitors in patients with malignant disease is worthwhile.

Aged↗
PubMed2002

Amniotic fluid matrix metalloproteinase-9 and interleukin-6 in predicting intra-amniotic infection.

OBJECTIVE: To assess the potential role of amniotic fluid (AF) matrix metalloproteinase-9 and interleukin-6 in predicting intra-amniotic infection. METHODS: Eighty-four women with singleton gestations with preterm contraction, preterm labor, preterm premature rupture of membranes, or clinical suspicion of intra-amniotic infection were studied. Amniotic fluid was obtained by transabdominal amniocentesis before starting any treatment. Intra-amniotic infection was defined as the presence of a positive AF culture. Amniotic fluid glucose concentration, leukocytes, matrix metalloproteinase-9, and interleukin-6 were determined. RESULTS: Amniotic fluid matrix metalloproteinase-9 and interleukin-6 levels were significantly higher in women with intra-amniotic infection than in those without. With intra-amniotic infection, levels of matrix metalloproteinase-9 significantly correlated with interleukin-6 (r = 0.813, P <.001). Each of matrix metalloproteinase-9 and interleukin-6 significantly correlated with AF leukocytes and inversely correlated with AF glucose. Using AF cutoff levels of 13.6 ng/mL for matrix metalloproteinase-9 and 11.4 ng/mL for interleukin-6, the sensitivity, specificity, and positive and negative predictive values for diagnosing intra-amniotic infection were 77% versus 73%, 100% versus 79%, 100% versus 61%, and 90% versus 86%, respectively. Combining AF matrix metalloproteinase-9 with interleukin-6 slightly improved the sensitivity and the negative predictive values in diagnosing intra-amniotic infection. CONCLUSIONS: Amniotic fluid matrix metalloproteinase-9 and interleukin-6 are significantly elevated in women with intra-amniotic infection. Amniotic fluid matrix metalloproteinase-9 is an accurate biochemical marker in predicting intra-amniotic infection with better sensitivity, specificity, and positive and negative predictive values than interleukin-6.

Adolescent↗
PubMed1998

Effect of matrix metalloproteinases activity on outflow in perfused human organ culture.

PURPOSE: To test the hypothesis that extracellular matrix turnover, mediated by the matrix metalloproteinases, modulates aqueous humor outflow facility in a human outflow model. METHODS: Matrix metalloproteinase activity was manipulated and outflow facility evaluated using perfused human anterior segment organ culture. Purified matrix metalloproteinases, tissue inhibitors of metalloproteinases (TIMPs), and several families of synthetic inhibitors of matrix metalloproteinases were added to the perfusion medium. Matrix metalloproteinase expression was increased by adding recombinant interleukin (IL)-1alpha. Kinetic inhibition analysis was conducted for stromelysin, gelatinase A, and gelatinase B with the various inhibitors. Live-dead staining was used to evaluate culture viability. RESULTS: Increasing metalloproteinase activity, by adding purified metalloproteinases or by inducing their expression by IL-1alpha treatment, increased outflow facility. Inhibition of endogenous trabecular metalloproteinase activity using TIMP or several families of synthetic metalloproteinase inhibitors reduced outflow rates. The elevation and the reduction of outflow rates were reversible, with changes requiring 1 to 3 days. Kinetic enzyme inhibition analysis produced 50% inhibitory concentration values for these inhibitors that were compatible with the concentration ranges for outflow inhibition. CONCLUSIONS. The ability of several specific matrix metalloproteinase inhibitors to reduce outflow facility implies that endogenous extracellular matrix turnover by these enzymes was required for the maintenance of trabecular outflow resistance, at least in this human culture model. These observations provide support for the hypothesis that controlled extracellular matrix turnover is important in the regulation of aqueous humor outflow facility.

Aqueous Humor↗
PubMed2004

Role of matrix metalloproteinases in hypertension-associated cardiac fibrosis.

PURPOSE OF REVIEW: The potential contribution of alterations in matrix metalloproteinase activity to the development of myocardial fibrosis in hypertensive heart disease is reviewed. RECENT FINDINGS: A number of experimental and clinical studies provide information on alterations in the balance between matrix metalloproteinase-1 or collagenase and tissue inhibitor of matrix metalloproteinases-1, which result in depressed proteolytic activity of the enzyme in animals and humans with hypertensive heart disease. While some recent data point to a genetic origin of such an imbalance, other findings suggest that depressed collagenase activity may contribute to disturbances of cardiac function via facilitation of myocardial fibrosis. On the other hand, emerging information is providing the basis for the notion that other matrix metalloproteinases, namely gelatinases, may participate in the process of myocardial fibrosis through stimulation of fibrillar collagen synthesis. Some fragmented matrix peptides or matrikines may be the mediators of the profibrotic action of these matrix metalloproteinases. SUMMARY: The matrix metalloproteinases represent an important biological system within the myocardium designed to maintain the complex and dynamic microenvironment of the extracellular matrix. Improved understanding of how this system is dysregulated in hypertensive heart disease will probably provide new insights into, and strategies for, heart failure.

Fibrosis↗
PubMed2002

[Morphogenesis of thoracic aorta aneurysms: investigation of matrix metalloproteinases and their tissue inhibitors].

The matrix metalloproteinases are a large group of proteases with a central role of the degradation of all types of extracellular matrix. The present study investigated expression of matrix metalloproteinases (MMP-1, -2, -9) and their inhibitors (TIMP-1, -2) in chronic Aneurysm of the Thoracic Aorta (ATA) and Post-Stenotic Dilatation of the ascending aorta due to valvular aortic stenosis (PSD). Fragments of the ascending aorta that had been taken from the patients during coronary by-pass surgery were used as controls. Immunohistochemical investigation showed that medical SMC in the samples taken from aortas with ATA and PDS expressed a stronger immunoreactivity for MMP-1, -2, -9 and TIMP-1, -2 as compared to controls. It can be suggested that during formation of ATA and PSD, production of MMPs and TIMPS by medial smooth muscle cells is of great importance.

Age Factors↗
PubMed1996

Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids.

Fluid from acute surgical wounds and from nonhealing pressure ulcers was examined for the presence of several matrix metalloproteinases. Gelatin zymography demonstrated the presence of two major gelatinases with apparent molecular masses of 72 kDa and 92 kDa and two minor gelatinases with apparent mobilities of 68 kDa and 125 kDa. Antigen-specific sera identified the 72-kDa protein as matrix melloproteinase-2. The same sera also reacted with the 68-kDa protein, which is consistent with it being an activated form of matrix metalloproteinase-2. Antigen-specific sera identified the 92-kDa and 125-kDa proteins as matrix metalloproteinase-9. Levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 were elevated more than 10-fold and 25-fold, respectively, in fluids from pressure ulcers compared with fluids from healing wounds. Examination of total potential and actual collagenolytic activity revealed that fluid from pressure ulcers contained significantly greater levels of both total and active collagenase compared with that of acute surgical wounds. In addition, an enzyme-linked immunosorbent assay demonstrated that fluids from pressure ulcers contained significantly more collagenase complexed with the inhibitor, tissue inhibitor of metalloproteinases. Together, these observations suggest that an imbalance exists between levels of matrix metalloproteinases and their inhibitors in the fluids of pressure ulcers and that this is primarily the result of elevated levels of the matrix metalloproteinases. The presence of excessive levels of activated forms of matrix-degrading enzymes at the wound surface of pressure ulcers may impede the healing of these wounds and may be relevant to the development of new rationales for treatment.

Animals↗
PubMed2005

Dose responses to inhalation of endotoxin, hay dust suspension and Aspergillus fumigatus extract in horses as measured by levels and activation of matrix metalloproteinase-9.

REASONS FOR PERFORMING STUDY: Airway matrix metalloproteinases (MMPs) increase after endotoxin (LPS) exposure, but there are no reports describing dose-dependent increases or activation following exposure. OBJECTIVES: To study matrix metalloproteinase-9 (MMP-9) and -2 (MMP-2) responses in bronchoalveolar lavage fluid (BALF) from heaves-susceptible and control horses following inhalation of hay dust suspension (HDS), LPS and Aspergillus fumigatus extract (AFE). METHODS: Heaves-susceptible (n = 7) and control (n = 6) horses received inhalation challenges with 3 different doses of HDS and LPS. Heaves-susceptible horses (n = 6) also received 3 different doses of AFE and one dose of AFE depleted of endotoxin (AFE-LPS). BALF collected following inhalation challenges was analysed using gelatin zymography. Gelatinolytic bands were identified as complex, pro-MMP-9, active MMP-9, pro-MMP-2 and active MMP-2 based on molecular weights. RESULTS: Each challenge substance induced a dose-dependent elevation in gelatinolytic activity. The dose-dependency was most evident for pro-MMP-9 and total MMP-9 levels in heaves-susceptible horses following LPS challenges. CONCLUSIONS: There is a dose-dependent elevation in MMP-9 in BALF of heaves-susceptible and control horses following inhalation challenge with organic dust and some of its components, elevation being more marked in heaves-susceptible horses. Organic dust components vary in their pro-inflammatory potential. POTENTIAL RELEVANCE: This study supports the role of MMPs in the pathogenesis of heaves and highlights the potential value of protease inhibitors in attenuating the airway inflammatory response to inhaled organic dust.

Animals↗
PubMed2005

Functional basis for the overlap in ligand interactions and substrate specificities of matrix metalloproteinases-9 and -2.

The MMPs (matrix metalloproteinases) MMP-9 and -2 each possess a unique CBD (collagen-binding domain) containing three fibronectin type II-like modules. The present experiments investigated whether the contributions to ligand interactions and enzymatic activities by the CBD of MMP-9 (CBD-9) corresponded to those of CBD in MMP-2 (CBD-2). The interactions of recombinant CBD-9 with a series of collagen types and extracellular matrix molecules were characterized by protein-protein binding assays. CBD-9 bound native and denatured type I, II, III, IV and V collagen, as well as Matrigel and laminin, with apparent K(d) values of (0.1-6.8)x10(-7) M, which were similar to the K(d) values for CBD-2 [(0.2-3.7)x10(-7) M]. However, CBD-9 bound neither native nor denatured type VI collagen. We also generated two modified MMPs, MMP-9(E402A) and MMP-2(E404A), by site-specific mutations in the active sites to obtain enzymes with intact ligand binding, but abrogated catalytic properties. In subsequent competitive binding assays, CBD-9 and MMP-9(E402A) inhibited the interactions of MMP-2(E404A) and, conversely, CBD-2 and MMP-2(E404A) competed with MMP-9(E402A) binding to native and denatured type I collagens, pointing to shared binding sites. Importantly, the capacity of CBD-9 to disrupt the MMP-9 and MMP-2 binding of collagen translated to inhibition of the gelatinolytic activity of the enzymes. Collectively, these results emphasize the essential contribution of CBD-9 to MMP-9 substrate binding and gelatinolysis, and demonstrate that the CBDs of MMP-9 and MMP-2 bind the same or closely positioned sites on type I collagen.

Animals↗
PubMed2000

Effect of heparin and related glycosaminoglycan on PDGF-induced lung fibroblast proliferation, chemotactic response and matrix metalloproteinases activity.

Fibroblast migration, proliferation, extracellular matrix protein synthesis and degradation are the key events in various biological and pathological processes in pulmonary fibrosis. In addition, biopsy specimens from the lungs of patients with pulmonary fibrosis show increased numbers of mast cells which have metachromatic granules containing heparin, histamine and proteases. Little is known about how these products influence pulmonary fibrosis. In the present study, we investigated the effect of heparin and related glycosaminoglycans on PDGF-induced lung fibroblast proliferation and chemotactic response in vitro. In addition, we examined the effect of heparin on both the induction of matrix metalloproteinases (MMPs) and MMPs activity in lung fibroblasts in vitro. Heparin, de-N-sulphated heparin but not heparan sulphate inhibited PDGF-induced lung fibroblast proliferation. In contrast, only heparin inhibited PDGF-stimulated human lung fibroblast chemotaxis. Negatively charged poly-L-glutamic acid had no effect on either fibroblast proliferation or chemotaxis. Thus the negative charge alone cannot account for the ant-proliferative and anti-chemotactic effects of heparin. Furthermore, heparin and heparan sulphate also had no inhibitory effect on induction of MMPS, including MMP-1 (interstitial collagenase), MMP-2 (gelatinase A) and MMP-9 (gelatinase B). Only heparin inhibited both MMP-1 and MMP-2/MMP-9 activity. Additionally, tissue inhibitor of metalloproteinase type 1 (TIMP-1) and type 2 (TIMP-2) inhibited PDGF-stimulated human lung fibroblast chemotaxis. The ability of heparin to inhibit fibroblast chemotaxis may account for the inhibitory effect of heparin on MMP activity. The above results suggested that heparin and related glycosaminoglycans differentially regulate PDGF-induced lung fibroblast proliferation, chemotaxis and MMPs activity and further that these effects may have a key role in extracellular matrix remodeling in inflammatory lung disease.

Becaplermin↗
PubMed2005

Matrix metalloproteinase induction in post-transplant obliterative bronchiolitis.

BACKGROUND: Epithelial cell injury, inflammation, fibrosis, and airway obliteration are associated in post-transplant obliterative bronchiolitis. Fibrosis is a consequence of fibroblastic activity and of collagen deposition after disturbances in the balance of protein formation and degradation. Proteolytic enzymes such as the matrix metalloproteinases mediate degradation. To assess matrix metalloproteinases during obliterative bronchiolitis development, we studied porcine, heterotopic bronchial allografts. METHODS: A total of 119 allografts or autografts were harvested serially at 3 to 60 days after transplantation and processed for histology and in situ hybridization for matrix metalloproteinases 2 and 9. Immunocytochemistry for vimentin and alpha-smooth-muscle-cell actin was performed with specific antibodies. RESULTS: Implants had initial ischemic injury to airway epithelium and to the bronchial wall. Recovery was rapid in autografts and in immunosuppressed allografts. In matrix metalloproteinase-2 mRNA activity in fibroblasts, correlation with endothelial expression and expression in macrophages occurred during intense fibroproliferation. We observed intense matrix metalloproteinase-9 positivity during onset of inflammation and fibroproliferation in endothelial cells (p < 0.01), fibroblasts (p < 0.05), macrophages (p < 0.05), and lymphocytes (p < 0.05). Matrix metalloproteinase-9 mRNA activity in fibroblasts correlated with that in endothelial and inflammatory cells and also proved predictive of early obliteration. CONCLUSIONS: Matrix metalloproteinase-2, and especially matrix metalloproteinase-9, gene activity was associated with onset of inflammation and fibroblastic proliferation in allografts, predicting early obliteration. Although this may be the case in the model described, its role in human-allograft post-transplant obliterative bronchiolitis requires further supportive data.

Animals↗
PubMed2002

[Extracellular matrix metalloproteinases--perspectives of their use in medicine].

Extracellular matrix turnover disturbances are implicated in many human diseases. Matrix Metalloproteinases (MMP) are believed to play a pivotal role in maintaining the intricate balance between extracellular matrix synthesis and degradation. These enzymes are active in the cleavage of many matrix proteins. There is evidence that matrix metalloproteinases activity changes in many pathological conditions, including inflammatory and degenerative disorders as well as tumour progression and metastases. This review focuses on the recent view on physiological and pathological function of MMPs. Authors aimed also to show the putative role of matrix metalloproteinases as a diagnostic tool in future medicine.

Biomarkers, Tumor↗
PubMed2005

Membrane-type 1 matrix metalloproteinase is required for normal alveolar development.

Matrix metalloproteinases (MMPs) are expressed during lung development, but their role may be limited, as mice deficient in MMP-3, 7, 9, or 12 develop a normal adult lung. Because membrane-type 1 matrix metalloproteinase (MT1-MMP) is expressed in the developing lung epithelium, we examined the lung structure of MT1-MMP-deficient (-/-) mice. Branching morphogenesis was normal, but alveolar development was abnormal in the MT1-MMP-/- lungs with 40% less alveolar surface area at 1 month (P < 0.01). MT1-MMP-/- airways and alveoli had an abnormal ultrastructural appearance, but epithelial cell differentiation markers were distributed similarly in both strains. There was no evidence of excess extracellular matrix deposition or inflammation at the time points examined. In contrast, by adulthood MMP-2-/- mice had normal alveolar size and structure, indicating normal alveolar development was not dependent on the ability of MT1-MMP to activate pro-MMP-2. These data indicate that MT1-MMP is required for normal lung development.

Animals↗
PubMed2003

Prognostic significance of the immunoexpression of matrix metalloproteinase MMP2 and its inhibitor TIMP2 in laryngeal cancer.

BACKGROUND: Matrix metalloproteinases (MMPs) are implicated in several pathological conditions, including cancer invasion and metastases. Among the MMPs associated with the tumor cell surface, gelatinase A (MMP2) is believed to be particularly important for cancer invasion. MATERIAL/METHODS: The immunoexpression of matrix metalloproteinase MMP2 and its inhibitor TIMP2 was investigated in 40 laryngeal carcinomas, in order to estimate the prognostic significance of these factors. The tissue sections were studied morphometrically using computer image analysis. RESULTS: The mean value of MMP2 immunoexpression in squamous cell carcinoma in patients without lymph node involvement was 7.36I7.3, and the mean value of MMP2 immunostaining in patients with lymph node metastases was 23.24I14.9. The difference between groups was statistically significant (P<0.001). Statistical analysis did not reveal a significant difference in TIMP2 expression between groups with metastases (mean: 11.38I7.7) and without (mean: 11.47I9.1). The survival time of patients with tumors with higher MMP2 expression (greater than the median, 9.6) was significantly shorter (P<0.004) than those with tumors showing low MMP2 expression (<9.6). The survival analysis revealed no significant difference between the survival time of patients in groups with high (> the median, 10.6) and low (<10.6) expression of TIMP2. CONCLUSIONS: Our results suggest that MMP2 expression may be of prognostic importance in laryngeal cancer. However, imbalances in the extracellular activities of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases, linked to pathological tissue destruction, are more complex and need further investigation.

Carcinoma, Squamous Cell↗
PubMed1989

Purification of the neutral proteoglycan-degrading metalloproteinase from human articular cartilage tissue and its identification as stromelysin matrix metalloproteinase-3.

The 'neutral' proteoglycan-degrading metalloproteinase of human articular cartilage was purified 3,500-fold by use of an anti-(matrix metalloproteinase-3) immunoglobulin G affinity column. Molecular masses of the latent and multiple active forms and specificity of action on casein, transferrin, gelatin and fibronectin were identical with those of authentic stromelysin (matrix metalloproteinase-3) from cultured human rheumatoid synovial fibroblasts. The optimum pH of this proteinase on proteoglycan monomer was pH 5.5, and on Azocoll, 6.2; digestion of fibronectin and gelatin was more extensive at pH 5.5 than at 7.5.

Cartilage, Articular↗
PubMed1992

Gene synthesis and expression in E. coli for pump, a human matrix metalloproteinase.

The gene for PUMP (putative metalloproteinase), a human matrix metalloproteinase, was synthesized by a PCR-based method. The DNA fragment of 546 bases containing the PUMP gene was generated by overlap extension of six long oligonucleotides (length ranging from 101 to 116 bases) and subsequent amplification by two short terminal oligonucleotide primers (length from 20 to 48 bases) in one pot without using restriction and ligation enzymes. The synthetic gene was cloned into a T7 expression vector in two ways to express PUMP as a non-fusion protein. Both constructs showed high level expression in E. coli.

Amino Acid Sequence↗
PubMed2001

In vivo molecular target assessment of matrix metalloproteinase inhibition.

A number of different matrix metalloproteinase (MMP) inhibitors have been developed as cytostatic and anti-angiogenic agents and are currently in clinical testing. One major hurdle in assessing the efficacy of such drugs has been the inability to sense or image anti-proteinase activity directly and non-invasively in vivo. We show here that novel, biocompatible near-infrared fluorogenic MMP substrates can be used as activatable reporter probes to sense MMP activity in intact tumors in nude mice. Moreover, we show for the first time that the effect of MMP inhibition can be directly imaged using this approach within hours after initiation of treatment using the potent MMP inhibitor, prinomastat (AG3340). The developed probes, together with novel near-infrared fluorescence imaging technology will enable the detailed analysis of a number of proteinases critical for advancing the therapeutic use of clinical proteinase inhibitors.

Animals↗
PubMed1995

Matrix metalloproteinase inhibition: a review of anti-tumour activity.

BACKGROUND: Matrix metalloproteinases are a homologous family of proteolytic enzymes. Collectively, these proteinases are capable of degrading all components of the extracellular matrix, including proteolytically resistant fibrillar collagens. Extracellular matrices constitute the principal barrier to tumour growth and spread, and there is now experimental evidence that malignant tumours utilise matrix metalloproteinases to overcome this barrier. Inhibitors of matrix metalloproteinases may therefore be of therapeutic value in the treatment of metastatic disease. DESIGN: This review describes the activity of matrix metalloproteinases inhibitors (MMPIs), in experimental tumour models and in phase I/II clinical studies. RESULTS: Studies with MMPIs in vitro have shown that these agents are not cytotoxic but can inhibit the degradation of extracellular matrix by tumour cells. In experimental tumour models in vivo, MMPI treatment caused inhibition of tumour growth and metastatic spread in both rodent syngeneic and human xenograft models. MMPIs have also been shown to inhibit angiogenesis, a process essential for the rapid growth of most malignancies. CONCLUSIONS: MMPI therapy has the potential to arrest tumour growth and spread. As a non-cytotoxic 'tumourostatic' approach it may offer an ideal complement to surgery, radiotherapy and chemotherapy in the successful long-term treatment of metastatic disease.

Animals↗