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Biomedical subjects

C R Stevens

Publications and source records attributed to C R Stevens.

34 records · Page 2Linked to original sources
PubMed1995

The joint, a redox sensitive microenvironment?--an hypothesis.

Antioxidant depletion in a normal adult increases the risk of developing rheumatoid arthritis (1). We discuss how redox processes "control" the inflammatory reaction and suggest that the synovium is a peculiarly "redox-sensitive" microenvironment. This discussion will be illustrated by a zonal model of tissue injury to represent the diseased synovium.

Animals↗
PubMed1992

Stimulation of osteoclastic bone resorption by hydrogen peroxide.

The molecular mechanisms underlying the pathophysiology of bone destruction still remain poorly understood. We have found that hydrogen peroxide (H2O2), a reactive oxygen species (ROS), is a potent stimulator of osteoclastic bone resorption and cell motility. A marked enhancement of bone resorption was noted when rat osteoclasts, cultured on devitalised bovine cortical bone, were exposed to 10 nM [H2O2]. Apart from exposing osteoclasts to a low extracellular pH, which is known to enhance osteoclastic bone resorption, we provide first evidence for a molecule that stimulates osteoclastic bone resorption in osteoclast cultures that do not respond to parathyroid hormone and 1, 25 dihydroxyvitamin D3. We envisage that both basic biological and practical clinical implications may eventually follow from these studies.

Animals↗
PubMed1992

Isolation and culture of synovial microvascular endothelial cells. Characterization and assessment of adhesion molecule expression.

OBJECTIVE: In vitro studies investigating the role of the synovial endothelium in the pathogenesis of rheumatoid arthritis (RA) have, until recently, been performed using cultured endothelial cells of nonsynovial macrovascular origin. In an attempt to more correctly model in vivo conditions, a method for the isolation and culture of synovial microvascular endothelial cells (SMEC) has been developed. METHODS: SMEC were isolated, primarily, by the use of lectin-coated (Ulex europaeus agglutinin type I), magnetizable polystyrene beads. RESULTS: Isolated cells exhibit classic endothelial "cobblestone" morphology, express von Willebrand factor, metabolize acetylated low-density lipoprotein, and exhibit a cytokine (interleukin-1)-mediated expression of endothelial leukocyte adhesion molecule type 1 (ELAM-1) and intercellular adhesion molecule type 1 (ICAM-1). ELAM-1 levels were significantly elevated in SMEC, compared with human umbilical vein endothelial cells, over a range of interleukin-1 concentrations. CONCLUSION: This increased expression of ELAM-1 by SMEC may be a potentiating step in the pathogenesis of RA.

Cell Adhesion↗
PubMed1992

Exercise induced release of von Willebrand factor: evidence for hypoxic reperfusion microvascular injury in rheumatoid arthritis.

Experimental evidence suggests that rheumatoid synovitis may be perpetuated by the generation of reactive oxygen species during hypoxic reperfusion injury. The latter occurs because increased intra-articular pressure during exercise exceeds synovial capillary perfusion pressure, impairing blood flow. The object of this study was to establish a marker for and the mechanism of synovial hypoxic reperfusion injury. Von Willebrand factor (vWF) is only released from endothelial cells and platelets and is an in vivo and in vitro marker of endothelial injury. In vivo exercise induced changes in plasma vWF were therefore investigated in patients with rheumatoid arthritis (RA) compared with controls and in vitro vWF release by human umbilical vein endothelial cells subjected to hypoxia reperfusion. Pre-exercise plasma vWF levels were 1001 and 817 IU/l, increasing after exercise to 1658 and 845 IU/l in patients with RA and controls respectively. Von Willebrand factor release from human umbilical vein endothelial cells followed a biphasic pattern, occurring during both hypoxia and reperfusion. Hypoxia reperfusion induced vWF release by human umbilical vein endothelial cells in vitro suggests that exercise induced vWF release in patients with RA is best explained by synovial hypoxic reperfusion injury. This study supports evidence that generation of reactive oxygen species plays a principal part in synovial hypoxic reperfusion injury and suggests vWF as a useful marker of this phenomenon.

Adult↗
PubMed1992

Application of methionine as a detector molecule for the assessment of oxygen radical generation by human neutrophils and endothelial cells.

Diverse cell types can generate reactive oxygen species (ROS) which are implicated in many disease processes and are ascribed both beneficial and deleterious roles. In vitro studies of this phenomenon indicate that properties of the microenvironment in culture influence the cells' behaviour with regard to ROS generation in vivo. To date, however, the assessment of cellular ROS generation has been limited to techniques which are invasive of the culture environment, or require cells to be in suspension. This study describes the application of NMR spectroscopy to the detection of ROS generation, a technique which is non-invasive of the cell culturing environment.

Cell Division↗
PubMed1992

Hypoxia-induced von Willebrand factor release is blocked by verapamil.

Hypoxia-induced stimulation of the rate of von Willebrand factor (vWF) release from human umbilical vein endothelial cells in culture, and the influence of the calcium antagonist verapamil, was studied using a system in which a pO2 of 20 mm Hg was achieved over 60 min. The mean +/- SEM rate of vWF release over 60 min in normoxia was 0.42 +/- 0.07% pooled plasma standard. The addition of verapamil did not alter the basal rate of vWF release, but after 60 min of hypoxia, the rate was increased to 0.71 +/- 0.03% plasma standard (p < 0.01). Verapamil at a concentration of 0.1 microgram/ml of media had no influence on the stimulated rate of release (0.78 +/- 0.07%), but increasing concentrations of verapamil up to a maximum of 1 microgram/ml attenuated the hypoxia induced stimulation (0.48 +/- 0.07%; p = 0.04 vs. hypoxic control). Thus, verapamil at this concentration completely blocked the hypoxia-induced stimulation.

Calcimycin↗
PubMed1991

A comparative study by morphometry of the microvasculature in normal and rheumatoid synovium.

Vascularity is said to be increased (subjectively) in rheumatoid arthritis, yet synovial fluid is hypoxic and acidotic. Morphometry by image analysis was used to quantify vascularity in normal and rheumatoid synovium from the knee joint. Capillaries were distributed more deeply in the rheumatoid synovium (93.3 microns, compared with 32.5 microns in normal synovium) and were significantly less densely arranged (80.2/mm2 rheumatoid, 241.5/mm2 normal). The blood volume fraction fell from 2.9% in normal knee synovium to 1.2% in rheumatoid synovium. These results imply that there is impairment of O2 transfer, which contributes to the intraarticular hypoxia, in rheumatoid arthritis.

Adult↗
PubMed1991

Influence of disodium aurothiomalate on the activities of xanthine dehydrogenase and xanthine oxidase in endothelial cells.

The effect of aurothiomalate in modulating the conversion of xanthine dehydrogenase to its superoxide producing oxidase form in rat and human liver cytosolic preparations has been investigated. Low concentrations (10(-8)-10(-5) mol.dm-3) of this second-line agent were found to inhibit the conversion of the dehydrogenase to its corresponding oxidase form. High concentrations (10(-4) mol.dm-3), however, accelerated this conversion. It is possible that the influence of aurothiomalate on the relative proportions of xanthine dehydrogenase and xanthine oxidase is a reflection of the gold(I) blockage of critical thiol(ate) or sulphido ligands present in this enzymatic system. These effects may form the basis of aurothiomalate's anti-proliferative action on endothelial cells.

Animals↗
PubMed1991

Localisation of xanthine oxidase to synovial endothelium.

The presence of the xanthine oxidase enzyme system has been demonstrated in the rheumatoid synovium. This supplies a reactive oxygen species generating system to synovium that is subjected to hypoxic-reperfusion cycles (cf inflamed rheumatoid synovium). An antibody to bovine milk xanthine oxidase has been used to localise the enzyme by immunohistochemistry to synovial endothelium. This implicates the endothelial cell as playing a major part in exacerbations of synovitis, induced by radicals.

Antigens↗
PubMed1990

A monoclonal antibody (Mab 67) marks type B synoviocytes.

The functionally important lining cells of the synovium (types A and B synoviocytes) are the subjects of much study but have presented problems with their characterization and microscopical identification, particularly at the light level. Type A (macrophage-like) synoviocytes, however are more easily localized than the type B (fibroblast-like) variety because of the greater availability of antimacrophage antisera. We describe, using light and electron microscopy, a monoclonal antibody which in the synovial intimal layer is specific for type B synoviocytes.

Antibodies, Monoclonal↗
PubMed1988

Lactosylceramide in inflammatory bowel disease: a biochemical study.

A simple technique for isolating lipids from small pieces of tissue was applied to mucosal biopsies and samples of resected intestine from patients with inflammatory bowel disease. Scanning densitometry of two dimensional chromatograms showed increased concentrations of the membrane associated glycosphingolipid lactosylceramide in Crohn's disease, on comparison with ulcerative colitis (p less than 0.01), or controls (p less than 0.01). This indicates either that normal glycosphingolipid metabolism is altered, or that a novel source of lactosylceramide is present in the inflamed mucosa of patients with Crohn's disease.

Adolescent↗
PubMed1988

Mechanisms of persistent synovitis.

Rheumatoid arthritis is characterised by persistent and symmetrical synovitis. In this article we propose two linked hypotheses to explain these observations. A mechanism to explain symmetry of synovitis is described whereby fine afferent nerve fibres from joints become bilaterally sensitized to movement with resultant release of neuropeptides promoting an inflammatory response. Clinical and experimental evidence is reviewed and shows that movement and resulting hypoxic reperfusion injury leads to a persistent synovitis.

Animals↗