Matrix Metalloproteinases In Pathophysiology Research Articles

Matrix Metalloproteinase-Mediated Neuroinflammation in Vascular Cognitive Impairment of the Binswanger Type.

Vascular cognitive impairment (VCI) is a heterogeneous group of diseases linked together by cerebrovascular disease. Treatment of VCI has been hindered by the lack of a coherent pathophysiological process that could provide molecular targets. Of the several forms of VCI, the small vessel disease form is both the most prevalent and generally has a progressive course. Binswanger's disease (BD) is the small vessel form of VCI that involves extensive injury to the deep white matter. Growing evidence suggests that there is disruption of the blood-brain barrier (BBB) secondary to an inflammatory state. Matrix metalloproteinases (MMPs) are increased in the brain and CSF of patients with BD, and have been shown to disrupt the BBB in animal studies, suggesting that they may be biomarkers and therapeutic targets. Multimodal biomarkers derived from clinical, neuropsychological, imaging, and biochemical data can be used to narrow the VCI population to the progressive inflammatory form that will be optimal for treatment trials. This review describes the role of the MMPs in pathophysiology and their use as biomarkers.

The role of matrix metalloproteinases in the pathophysiology and progression of human nervous system malignancies: a chance for the development of targeted therapeutic approaches?

Background: Matrix metalloproteinases (MMPs) are a group of zinc- dependent endopeptidases involved in the degradation of extracellular matrix components. MMPs have been implicated in a wide variety of physiological processes, such as angiogenesis, wound healing and tissue remodeling. However, recent studies have revealed a significant role for MMPs in tumorigenesis pathophysiology and prediction of patients' clinical outcome. Alterations in the regulation of MMP expression are thought to play an important role in the development and progression of central nervous system (CNS) malignancies. Objective/methods: This study provides an up-to-date review of the literature on the pathophysiologic involvement of MMPs in the development and progression of human CNS malignancies, as well as the potential use of natural and/or synthetic MMP-inhibitors (MMPIs) as a targeted therapeutic approach to this group of neoplasms. Results/conclusions: The currently available data provide clear evidence for the involvement of MMPs in the pathophysiology of astrocytomas, glioblastomas, meningiomas, medulloblastomas/primitive neuroectodermal tumors and pituitary tumors. The use of MMPIs in the treatment of CNS malignancies has, until now, reached controversial (but mainly disappointing) results that can nevertheless provide the basis for further investigation. The co-administration of other agents, the use of surgery and/or radiation, and elimination of the MMPIs-induced adverse effects, as well as the use of antisense technology, might be the tools by which the natural and synthetic MMPIs could find their place in everyday clinical practice for the management of CNS malignancies.

Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases

Matrix metalloproteinases (MMPs) have outgrown the field of extracellular-matrix biology and have progressed towards being important regulatory molecules in cancer and inflammation. This rise in status was accompanied by the development of various classes of inhibitors. Although clinical trials with synthetic inhibitors for the treatment of cancer were disappointing, recent data indicate that the use of selective inhibitors might lead to new therapies for acute and chronic inflammatory and vascular diseases. In this Review, we compare the major classes of MMP inhibitors and advocate that future drug discovery should be based on crucial insights into the differential roles of specific MMPs in pathophysiology obtained with animal models, including knockout studies.

New therapeutic options in congestive heart failure: Part II.

The second part of this review deals with newer, nonneurohumoral, pharmacological approaches to congestive heart failure (CHF) and nonpharmacological interventions in heart failure patients with low left ventricular ejection fraction (LVEF) as well as potential treatments for CHF with preserved LV systolic function. An algorithm summarizing current, evidence-based therapy is also provided. Cytokines, such as tumor necrosis factor, are produced in increased amounts in a variety of tissues in patients with CHF.1 Higher plasma cytokine concentrations are associated with a worse prognosis.1 Experimentally, cytokines depress myocardial contractility, cause myocyte death, and induce heart failure.1 There is some evidence that anticytokine interventions improve ventricular function and clinical status in CHF.2,3⇓ Two parallel trials (Randomized Etanercept North American Strategy to Study Antagonism of Cytokines [RENAISSANCE] and Research into Etanercept Cytokine Antagonism in Ventricular Dysfunction Trial [RECOVER], pooled as the Randomized Etanercept Worldwide Evaluation [RENEWAL] program) examining the effect of the anti–tumor necrosis factor agent etanercept on morbidity and mortality in CHF, however, were recently discontinued because of futility (Table). Even more recently, a placebo-controlled phase II trial with an alternative anti–tumor necrosis factor chimeric monoclonal antibody, infliximab, was stopped early because of higher rates of mortality and hospitalization in the active-therapy group. Whether this means that the cytokine hypothesis is invalid, that etanercept and infliximab were the wrong drugs to use (or were used incorrectly), that inappropriate patients were chosen, or that the study designs were flawed is unknown. View this table: Table 1107874. Ongoing and Planned Trials of Pharmacological Agents in CHF The constitution of the cardiac extracellular matrix depends on the balance in activity of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases.4,5⇓ End-stage heart failure is associated with increased collagenase activity (increased expression of MMP-1 and MMP-9) and reduced expression of tissue inhibitors of metalloproteinases.5 Experimentally, …

Matrix metalloproteinases in pathophysiology and treatment of heart failure

The structural integrity of the heart is dependent on an extensive network of fibrillar collagens. First recognised in skeletal muscle by Holmgren in 1907, 1 Holmgren E Ueber die Trophospongien der quergestreiften Muskelfasern, nebst Bemerkungen uber den allgemeinen Bau dieser Fasern. Arch Mikrosk Anat. 1907; 71: 165-201 Crossref Scopus (21) Google Scholar these collagen fibres are grouped in weaves that surround myocytes, struts that interconnect adjacent myocytes, small fibrils that attach the plasma membrane to the encircling basal lamina, long tendon-like bundles that link adjacent weaves, and collagen struts that connect the myocytes to adjacent capillaries. 2 Borg TK Caulfield JB The collagen matrix of the heart. Fed Proc. 1981; 40: 2037-2041 PubMed Google Scholar This complex scaffolding facilitates the transmission of force between neighbouring myocytes, maintains capillary patency during ventricular contractions, maintains lateral cell-to-cell alignment, and precludes cell slippage and ventricular-cavity dilatation during diastole. 3 Weber KT Cardiac interstitium in health and disease: the Fibrillar Collagen Network. J Am Coll Cardiol. 1989; 13: 1637-1652 Summary Full Text PDF PubMed Scopus (841) Google Scholar In addition, collagen cross-linking is an important determinant of systolic and diastolic performance. In the cardiac extracellular matrix, collagens are produced by fibroblasts, the most common collagen subtypes in the myocardium being types I and III. 3 Weber KT Cardiac interstitium in health and disease: the Fibrillar Collagen Network. J Am Coll Cardiol. 1989; 13: 1637-1652 Summary Full Text PDF PubMed Scopus (841) Google Scholar Type I, which predominates in the heart, has a higher tensile strength than type III, which provides greater distensibility. To what extent is research into their metabolism contributing to the development of therapies for heart failure?