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Biomedical subjects

C E Conner

Publications and source records attributed to C E Conner.

9 recordsLinked to original sources
PubMed2001

Regulation of prostaglandin availability in human fetal lung by differential localisation of prostaglandin H synthase-1 and prostaglandin dehydrogenase.

Specialisation of the respiratory portion of human fetal lung commences around 20-24 weeks gestation. In contrast, human fetal lung in vitro has the capacity to self-differentiate from 12 weeks gestation when grown in media devoid of growth factors or hormones, suggesting activation of autocrine or paracrine factors in vitro, or removal of the fetus from in utero inhibitory mechanisms. Prostaglandins play a key role during in vitro human fetal lung development and are synthesised by prostaglandin H synthase-1 (PGHS-1) and inactivated by 15-hydroxyprostaglandin dehydrogenase (PGDH) with formation of inactive 13,14-dihydro-15-keto-prostaglandins. We have used quantitative immunohistochemistry to determine expression and localisation of PGHS-1, PGDH, PGE2 and 13,14-dihydro-15-keto-PGE2 (PGEM) in human fetal lung with in situ hybridisation to localise PGHS-1 and PGDH mRNA. For the catabolic enzyme PGDH, amounts of mRNA, protein and enzyme product PGEM are increased within epithelium of distal as compared to more proximal airways. For PGHS-1, comparable amounts of mRNA, protein and enzyme product PGE2 are found in proximal and distal lung epithelium. Catabolism by PGDH is a sensitive mechanism for regulating bioavailability of prostaglandins and we propose that active catabolism of prostaglandins within human fetal lung epithelium is an inhibitory mechanism retarding epithelial differentiation in utero.

Cyclooxygenase 1↗
PubMed2001

Tumorigenic potential of extracellular matrix metalloproteinase inducer.

Extracellular matrix metalloproteinase inducer (EMMPRIN), a glycoprotein present on the cancer cell plasma membrane, enhances fibroblast synthesis of matrix metalloproteinases (MMPs). The demonstration that peritumoral fibroblasts synthesize most of the MMPs in human tumors rather than the cancer cells themselves has ignited interest in the role of EMMPRIN in tumor dissemination. In this report we have demonstrated a role for EMMPRIN in cancer progression. Human MDA-MB-436 breast cancer cells, which are tumorigenic but slow growing in vivo, were transfected with EMMPRIN cDNA and injected orthotopically into mammary tissue of female NCr nu/nu mice. Green fluorescent protein was used to visualize metastases. In three experiments, breast cancer cell clones transfected with EMMPRIN cDNA were considerably more tumorigenic and invasive than plasmid-transfected cancer cells. Increased gelatinase A and gelatinase B expression (demonstrated by in situ hybridization and gelatin substrate zymography) was demonstrated in EMMPRIN-enhanced tumors. In contrast to de novo breast cancers in humans, human tumors transplanted into mice elicited minimal stromal or inflammatory cell reactions. Based on these experimental studies and our previous demonstration that EMMPRIN is prominently displayed in human cancer tissue, we propose that EMMPRIN plays an important role in cancer progression by increasing synthesis of MMPs.

Animals↗
PubMed1998

Vascular endothelial growth factor induces tissue factor and matrix metalloproteinase production in endothelial cells: conversion of prothrombin to thrombin results in progelatinase A activation and cell proliferation.

Production of vascular endothelial growth factor (VEGF) by cancer cells at invasive and metastatic sites is an important aspect of tumor angiogenesis. Although known primarily as a mitogen and a vascular permeability factor (VPF) for endothelial cells, VEGF/VPF has been proposed to induce the expression of procoagulant factors in endothelial cells. In this study, we have explored the ramifications of VEGF induction of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) and subsequent activation of progelatinase A. Within 3 hr of incubation with VEGF/VPF, endothelial cells accelerate TF generation as measured using chromogenic substrate assays for coagulation factors Xa and thrombin. Incubation of VEGF/VPF-pre-treated cells with prothrombin and factors X, Va, and VIIa at 37 degrees C and subsequent generation of thrombin resulted in activation of secreted endothelial progelatinase A as demonstrated by gelatin zymography. Anti-thrombin III or antibodies to TF inhibited thrombin generation and progelatinase A activation. VEGF/VPF also directly increased HUVEC secretion of interstitial collagenase, tissue inhibitor of metalloproteinases (TIMP-1) and, to a lesser extent, gelatinase A. The effect of thrombin on endothelial proliferation in serum-free media was examined. Thrombin was a growth factor for HUVECs at a lower dose than that required for progelatinase A activation. Whereas TIMP-2 abrogated thrombin-induced progelatinase A activation, it had no significant effect on thrombin-induced endothelial cell growth. We propose that an early step in tumor angiogenesis involves VEGF-induced thrombin generation and increased MMP production with subsequent activation of endothelial progelatinase A and degradation of the underlying basement membrane.

Cell Division↗
PubMed1996

Reduced Na+/K+ adenosine triphosphatase activity and motor nerve conduction velocity in L-fucose-fed rats is reversible after dietary normalization.

Development of early defects in diabetic neuropathy has been linked to metabolic abnormalities and is considered reversible. To further address some of the questions concerning the contribution by metabolic derangements to the development of neural defects and reversibility, we have developed an animal model, by feeding rats a diet containing 20% L-fucose, that develops neural defects similar to those that occur in streptozotocin-induced diabetic rats. After 6 weeks on a 20% L-fucose diet, myo-inositol content and Na+/K+ adenosine triphosphatase (ATPase) activity of the sciatic nerve were significantly reduced, as was the motor nerve conduction velocity (MNCV). L-Fucose is a monosaccharide that occurs in low concentrations in normal serum but is increased in diabetic patients. In cultured cells, L-fucose, at concentrations that occur in diabetic circulation, is a competitive inhibitor of myo-inositol uptake. The purpose of the present study was to compare the sequential pattern of the reversibility of the slowing of MNCV with ouabain-inhibited sciatic nerve Na+/K+ ATPase activity and myo-inositol content in rats fed a diet containing 20% L-fucose for a period of 6 weeks followed by a normal diet lasting up to 2 weeks. Unbound L-fucose levels in the serum returned to normal in less than 24 hours of the rats being placed on the normal diet. Normalization of slowed MNCV after removing L-fucose-fed rats from the L-fucose diet followed a pattern of recovery similar to the recovery of sciatic nerve ouabain-inhibited Na+/K+ ATPase activity, with complete recovery occurring within 7 days of the rats being placed on the normal diet. In contrast, myo-inositol content of the sciatic nerve remained decreased following 3 days on the normal diet, and required 14 days for complete normalization. Results from these studies suggest that a causal relationship may exist for reduced Na+/K+ ATPase activity and MNCV in L-fucose-fed rats, and that a measurable decrease in myo-inositol content may not be necessary for the development of these defects in the sciatic nerve.

Animals↗
PubMed1996

Osmotic regulation of Na-myo-inositol cotransporter mRNA level and activity in endothelial and neural cells.

Myo-inositol (MI) is an important factor in the synthesis of phosphoinositides, and as an osmolyte, MI contributes to the regulation of cell volume. In cells of renal origin, hypertonicity causes an increase in sodium-dependent MI transporter (SMIT) mRNA levels and MI transport. However, it is unknown whether changes in osmolarity regulate transport of MI in neural or endothelial cells. IN these studies, neural and endothelial cells were exposed to hyperosmotic medium for up to 48 h, and the effect on MI transport was determined. Transport of MI was maximally increased by exposing the cells to hyperosmotic medium for 24 h. Kinetic analysis of high-affinity MI transport demonstrated an increase in the apparent maximal velocity with no significant change in the apparent Km. The hyperosmotic induction of MI transport was blocked by the addition of cycloheximide, indicating a requirement for protein synthesis, and was associated with increased levels of SMIT mRNA. In contrast to the effect of hypertonicity, exposure of neural and endothelial cells to hypotonic conditions caused a decrease in SMIT mRNA levels and MI transport in endothelial cells. These studies demonstrate that, in extrarenal cell types, changes in osmolarity also regulate SMIT activity and mRNA levels.

Animals↗
PubMed1995

L-fucose reduces collagen and noncollagen protein production in cultured cerebral microvessel endothelial cells.

L-fucose is a monosaccharide which is present in low concentrations in normal serum but is increased in diabetes, cancer, and inflammatory diseases. The contribution that abnormal L-fucose levels make to the progression of these disorders is unknown. In a previous study we showed that increased L-fucose concentration reduced proliferation and proteoglycan production by cultured cerebral microvessel endothelial cells. In the present study we show that exposing cerebral microvessel endothelial cells for 2 weeks to medium containing an increased concentration of L-fucose causes a significant decrease in collagen and to a lesser extent noncollagen protein production. The effect of L-fucose on collagen and noncollagen protein production is concentration-dependent: 1 mM L-fucose causes a significant decrease in collagen production but has no effect on noncollagen protein production; a 5 mM L-fucose concentration causes a maximum decrease in both collagen and noncollagen protein production. This defect is unrelated to the reduction in myo-inositol uptake caused by L-fucose and is not prevented by aminoguanidine. Collagen production can be improved by restoring L-fucose-conditioned cells to normal medium. Culturing cells for 2 weeks in medium containing 10 mM L-fucose resulted in a 50% decrease in collagen production, which was restored to 75% of control after cells were transferred to normal medium for 7 days. In contrast, noncollagen protein production was totally restored after 3 days in normal medium. Increasing levels of L-fucose in serum of rats also resulted in a decrease in collagen production. Collagenase digestible incorporation of L-[2,3,4,5-3H]proline into protein of the articular cartilage from rats fed a diet containing 20% L-fucose for 3 weeks was reduced by about 40% compared to rats fed a normal diet. The decrease in collagen production in L-fucose fed rats was less than the reduction that occurred in streptozotocin-induced diabetic rats. These data suggest that changes in L-fucose concentration itself may be a factor in the regulation of collagen production.

Animals↗
PubMed1993

Reduced motor nerve conduction velocity and Na(+)-K(+)-ATPase activity in rats maintained on L-fucose diet. Reversal by myo-inositol supplementation.

L-Fucose is a monosaccharide that occurs in low concentrations in normal serum but has been shown to be increased in diabetic individuals. In cultured mammalian cells, L-fucose is a potent competitive inhibitor of myo-inositol transport. Abnormal myo-inositol metabolism has been proposed to be a factor in the development of diabetic complications. To test the hypothesis that myo-inositol deficiency may be responsible for the electrophysiological and biological defects in diabetic neuropathy, rats were fed a diet containing 10 or 20% L-fucose for a period of 6 wk. After 3 wk, the L-fucose diets in two groups of rats were supplemented with 1% myo-inositol. At the end of the study protocol, motor nerve conduction velocity, sciatic nerve tissue Na(+)-K(+)-ATPase activity, and myo-inositol content were determined. These results were compared with those of STZ-induced diabetic rats fed either a normal diet or a diet containing 1% myo-inositol or with those given 450 mg/kg body wt of sorbinil. Serum L-fucose levels were significantly increased in rats fed a diet containing 10 or 20% L-fucose. In comparison, the serum L-fucose levels in the diabetic rats were increased to a lesser extent. Motor nerve conduction velocity was significantly slower in rats fed a 10 or 20% L-fucose diet. Sciatic nerve composite and ouabain-sensitive Na(+)-K(+)-ATPase activity and myo-inositol content was also significantly decreased. Supplementation of 1% myo-inositol to the L-fucose-containing diet restored nerve myo-inositol levels and significantly improved Na(+)-K(+)-ATPase activity and motor nerve conduction velocity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗