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Biomedical subjects

P Coyle

Publications and source records attributed to P Coyle.

At least 37 records · Page 2Linked to original sources
PubMed1997

Rat strain and vendor differences in collateral anastomoses.

Recently we observed inter- and intrastrain differences in cortical infarct volumes after middle cerebral artery (MCA) occlusion. Variations in the anastomoses providing collateral blood supply could account for different lesion sizes. Our objectives were to compare number and internal diameters of the MCA-anterior cerebral artery (MCA-ACA) anastomoses and to determine if the lesion extended beyond branches of the MCA territory into the field of the ACA in the rat strains/lines. Sprague-Dawley rats and Wistar rats from Simonsen Laboratories (SLSD and SLWIS) and Sprague-Dawley rats from Taconic Laboratories (TLSD) and Charles River Laboratories (CRSD) were anesthetized and injected with papaverine and Vultex (white latex) for arterial visualization. Some rats were also subjected to MCA occlusion. Significantly fewer anastomoses were present in SLSD and SLWIS than in CRSD and TLSD (p < 0.05). The mean internal diameters of the anastomoses were not significantly different between the strains/lines (p < 0.05). After MCA occlusion, significantly more (p < 0.05) TLSD and CRSD than SLSD had lesions extending from the MCA field beneath the anastomoses and into the region supplied by the ACA. Neither the number, luminal diameter, nor density of MCA-ACA anastomoses appears to be the limiting factor that differentiates lesion size following MCA occlusion in these particular rat strains/lines. Therefore, factors other than anatomical variations probably account for different lesion sizes.

Animals↗
PubMed1996

Trace metal, acute phase and metabolic response to endotoxin in metallothionein-null mice.

Accumulation of hepatic zinc via metallothionein (MT) induction during infection/inflammation is postulated to benefit a range of metabolic processes. The metabolic consequences of two doses of endotoxin (LPS) (1 and 5 mg/kg, intraperitoneally) were examined in normal (MT+/+) and MT-null (MT-/-) mice (all results means =/- S.E.M., n=6). At 16 h after 1 mg/kg LPS, hypozincaemia was pronounced in the MT+/+ mice (4.4+/-0.2 microM), concomitant with a 36% increase in hepatic Zn and a > 10-fold increase in hepatic MT. Plasma Zn (16.6+/-0.7 microM) and total hepatic Zn were unchanged in MT -/- mice, confirming the importance of MT in altering plasma and hepatic Zn during inflammation. Plasma iron was lower in LPS-treated MT-/- mice, whereas plasma copper increased to a similar extent in both groups of mice. Plasma fibrinogen more than doubled, and was similar in both groups of mice, which questions the importance of MT in acute-phase protein synthesis. Blood and liver glucose concentrations were not significantly different between groups before or after LPS, whereas blood and liver lactate concentrations were significantly lower (31% and 24% respectively) in MT-/- mice after LPS. At 16 h after 5 mg/kg LPS, plasma Zn was decreased even further in MT+/+ mice (2.6+/-0.3 microM), but remained unchanged in MT-/- mice at concentrations significantly above those in 16-h fasted MT-/- mice (15.8+/-0.5 versus 11.3+/-0.3 microM). Total liver Zn was 17% lower than fasting values in MT-/- mice, in contrast with 32% higher in MT+/+ mice. Synthesis of MT (in MT+/+ mice) and fibrinogen in all mice was not further enhanced by the higher LPS dose. Blood glucose was significantly decreased by 18% in MT+/+ mice and by 38% in MT-/- mice after 5 mg/kg LPS. There was a marked 44% decrease in liver glucose in MT-/- mice; that in MT+/+ mice was unchanged from fasting levels, implying a deficit in hepatic gluconeogenesis in LPS-treated MT-/- mice. In the absence of any indication of major hepatotoxicity, the results of this study indicate that energy production, and not acute-phase protein synthesis, may be most influenced by Zn supply during endotoxaemia, suggesting that MT has a role in maintaining hepatic and blood glucose in this metabolic setting.

Animals↗
PubMed1995

Hepatic zinc in metallothionein-null mice following zinc challenge: in vivo and in vitro studies.

Hepatic zinc uptake and accumulation were compared in freshly isolated and cultured hepatocytes prepared from control (MT+/+) and metallothionein (MT)-null (MT-/-) mice. In freshly isolated hepatocytes, rapid (10-15 min) exchange of 65Zn was proportional to the Zn concentration in the medium and occurred to the same extent in hepatocytes from MT+/+ and MT-/- mice. In 24 h culture experiments with MT+/+ and MT-/- hepatocytes it was shown that approx. 40% of newly acquired cell-associated Zn was attached to the cell surface and not internalized. In MT+/+ and MT-/- hepatocyte cultures, internalized Zn (intZn) increased in proportion to extracellular Zn. Zn accumulation in MT-/- hepatocytes was only 60% that of MT+/+ cells. Addition of 1 microM dexamethasone (Dex) and recombinant mouse interleukin-6 (IL-6; 100 units/ml) increased MT accumulation by 8.6-fold in MT+/+ hepatocytes (at 50 microM Zn) and there was an associated parallel increase in intZn. Dex and IL-6 did not increase intZn in the MT-/- hepatocytes. At 16 h after an intraperitoneal injection of 5 micrograms/g Zn, plasma and urine Zn concentrations were 69 +/- 10 microM and 86 +/- 25 microM respectively in MT-/- mice (n = 10) and 27 +/- 1 microM and 23 +/- 4 microM respectively in MT+/+ controls (n = 9) (P < 0.001, plasma; P < 0.05, urine). Hepatic cytosolic Zn concentrations doubled in MT+/+ mice and increased by a significant 15% in MT-/- mice. There was no increase in hepatic Zn (dry wt.) concentrations or in total hepatic Zn, demonstrating that the increase in cytosolic Zn in MT-/- mice was due to hepatic water loss rather than net Zn uptake. It appears that even at extreme plasma concentrations of Zn, little if any accumulates within the liver when there is no MT available for its sequestration. That this is not fully demonstrated in vitro is probably due to nature of cell culture, where organ architecture is lost and the external protein binding milieu is less complex.

Animals↗
PubMed1995

Endotoxin-induced inflammation does not cause hepatic zinc accumulation in mice lacking metallothionein gene expression.

The action of endotoxin lipopolysaccharide (LPS) on hepatic Zn uptake was examined in mice lacking expression of metallothionein (MT)-1 and MT-II genes. Hepatic Zn concentrations, which in normal control mice increased by a mean 29% (MT elevated 20-fold) 16 h post-LPS exposure, did not increase in MT-null mice. Plasma Zn fell by 68% in controls and 32% in MT-null mice. The time course of LPS action in normal mice was characterized by a rapid reduction (-74% at 4 h, -81% at 8 h) and partial recovery (-39% at 24 h) in plasma Zn, with a progressive increase over 24 h in hepatic concentrations of MT (by 36-fold) and Zn (by 40%). In contrast, the MT-null mice had a linear decrease in plasma Zn (-15% at 8 h, -41% at 24 h) and early loss of Zn from the liver. The Zn changes seen in MT-null mice were largely attributable to LPS-associated anorexia. Food deprivation (20 h) alone caused respective 14% and 30% decreases in hepatic and plasma Zn concentrations and a 27% reduction in total liver Zn reserves, whereas fasted normal mice conserved Zn with a 4-fold increase in hepatic MT. This study confirms that MT synthesis is essential for endotoxin-induced liver Zn accumulation.

Animals↗
PubMed1995

Metallothionein induction in cultured rat hepatocytes by arthritic rat serum, activated macrophages, interleukin-6, interleukin-11 and leukaemia inhibitory factor.

Potential mediators of hepatic metallothionein (MT) synthesis in adjuvant-induced arthritis were investigated in cultured rat hepatocytes. Sera from arthritic rats (14 d post-adjuvant treatment) in the presence of Zn (50 mumol/L)+dexamethasone (Dex; 1 mumol/L) increased metallothionein (MT) accumulation by 34% above that obtained with control rat serum with Zn+Dex. Endogenous IL-6 activity in serum from arthritic rats was 93 +/- 49 U/mL and was undetectable in control rat serum. The activities of TNF, IL-1 and corticosterone concentrations were the same in control and arthritic rats. The accumulation of MT in hepatocytes in the presence of Zn (10 mumol/L)+Dex (1 mumol/L) was enhanced 29% and 49% by media from lipopolysaccharide (LPS)-stimulated peritoneal macrophage (PMM) and Kupffer cell cultures (KCM), respectively. The response with PMM and KCM was quantitatively the same as that with interleukin-6 (IL-6). Analysis of PMM and KCM showed activities of 1,000-10,000 U/mL for IL-6, 100-1000 U/mL for TNF and < 10,000 U/mL for IL-1, the latter detected only in PMM. LPS alone enhanced the accumulation of MT above Zn+Dex in a dose dependent manner. A significant LPS response was obtained at 5 mg/L with a maximal stimulation above Zn+Dex of 38% at 10 mg/L. This direct stimulation of MT by LPS was not part of the response observed with PMM and KCM where the final LPS concentration in culture was only 0.1 mg/L. Other cytokines capable of synergy with Zn+Dex on MT synthesis were investigated. Interleukin-11 (IL-11) increased the Zn+Dex induction in a dose dependent manner with maximal stimulation at 100 U/mL of 40%. A small stimulation of 12% above Zn+Dex was obtained with leukaemia inhibitory factor (LIF) at concentrations greater than 100 U/mL. No enhancement of the Zn+Dex response was obtained with interleukin-3 (1000 U/mL), interleukin-4 (10 micrograms/L), platelet activating factor (5 nmol/L) or granulocyte-colony stimulating factor (5 micrograms/L). Neither IL-11 nor LIF enhanced the response obtained with Zn+Dex+IL-6. The results demonstrate that mediators present in arthritic rat serum and in LPS-stimulated PMM and KCM cause a quantitatively similar response on MT accumulation as IL-6. IL-11 and to a lesser extent LIF, are also potential mediators of MT synthesis in inflammation.

Animals↗
PubMed1994

Measurement of zinc in hepatocytes by using a fluorescent probe, zinquin: relationship to metallothionein and intracellular zinc.

Zinquin [ethyl (2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)acetate], a new intracellular zinc fluorophore, was used to reveal and to measure Zn in cultured rat hepatocytes before and after metallothionein (MT) induction. Hepatocytes labelled with an intense extranuclear fluorescence. Culture with combinations of Zn, dexamethasone and interleukin-6, increased intracellular MT by 24-fold, Zn 3-fold, and Zinquin fluorescence by approx. 2-fold above control values. Zinquin fluorescence correlated in descending order with the total cellular Zn (r = 0.747), exchangeable Zn (r = 0.735), soluble cytosolic Zn (r = 0.669) and MT (r = 0.666). When Zinquin was incubated with a cytosolic fraction of liver proteins before Sephadex G-75 column chromatography, it fluoresced with free, MT-incorporated and protein-bound Zn. Although only a slight attenuation of fluorescence was seen with high-molecular-mass protein-bound Zn, MT was degraded by 60% in the presence of Zinquin. The undegraded Zn-MT fluoresced at about 20% of the expected intensity. Although Zinquin fluoresces with all cytosolic Zn, caution is required when comparisons are made between samples with different concentrations of MT. This limitation was demonstrated by staining liver slices from adjuvant-treated rats where MT was increased 24-fold, intracellular Zn by 77%, but Zinquin fluorescence by only 19% above controls. Nevertheless, Zinquin should prove to be a useful tool for studying the distribution of Zn in living cells.

Animals↗
PubMed1994

Effects of insulin and insulin-like growth factors on protein and energy metabolism in tumour-bearing rats.

The effects of insulin-like growth factor-1 (IGF-I), and a more potent variant LR3-IGF-I, which binds poorly to IGF-binding proteins, were investigated in rats bearing a mammary adenocarcinoma. The effect of insulin, either alone or in combination with LR3-IGF-I, was also investigated. Peptides were infused via osmotic minipumps for 6-7 days after tumour size reached 5% of body weight. Infusion of IGFs alone at either 200 or 500 microgram/day significantly decreased food intakes as well as circulating levels of insulin and glucose, and consequently failed to promote muscle protein accretion in the host. Tumour growth was increased by the IGFs, especially by LR3-IGF-I, even though these peptides did not promote growth of the adenocarcinoma in cell culture. Infusion of LR3-IGF-I, and to a lesser extent IGF-I, led to decreased rates of muscle protein synthesis and increased muscle protein breakdown, but each of these measures was closely related to the final tumour burden (r2 = 0.454 and 0.810 respectively; P < 0.01) and possibly resulted from a decrease in substrate supply to the host tissues. Insulin infusion (100 micrograms/day) increased food consumption by more than 50% and significantly decreased tumour growth. Insulin and LR3-IGF-I had a synergistic effect on host weight, which increased by 19.1 +/- 1.9, -1.1 +/- 4.7 and 37.9 +/- 1.5 g for insulin, LR3-IGF-I and combined treatments respectively. Carcass protein was increased by more than 10% with insulin treatment, due to increased rates of synthesis and decreased rates of muscle protein breakdown, but LR3-IGF-I had no positive effect on carcass protein accretion, either alone or in combination with insulin. Similarly, the amount of carcass fat was increased almost 2-fold by insulin treatment, whereas it was decreased by 30% by LR3-IGF-I. These changes may have arisen either from direct hormone effects on metabolism or from the indirect effects of food intake, or both. Our results suggest that IGF administration may exacerbate an insulin insufficiency associated with the tumour-bearing state and further decrease metabolic substrate supply to the host. This can be overcome by co-infusion of insulin.

Adenocarcinoma↗
PubMed1994

Wasting in adjuvant-induced arthritis and its relationship to plasma zinc, copper and liver metallothionein.

The appearance of joint inflammation (JI) 14 days after the injection of adjuvant (AJ) in the tail of rats is associated with a cachectic syndrome which is characterised by marked weight loss (WL). The degree of weight loss was examined in relation to the extent of change in other markers of inflammation including increased plasma copper (pCu), decreased plasma zinc (pZn) and increased hepatic metallothionein (hMT). At 14 days post-AJ injection, arthritic rats showed the following changes, relative to the controls: body weight, 12% decrease, pZn, 50% decrease; pCu, 90% increase and hMT, 11-fold increase (all p < 0.001). Significant relationships were observed between JI, WL, pZn and hMT. The following coefficients of determination (r2) were observed; JI and WL, -0.530, JI and pZn, -0.485; JI and hMT, 0.286; WL and hMT, -0.510 (all p < 0.007). There was a strong relationship between the decreased pZn and increased hMT; r2 = 0.456 (p < 0.001). While increased pCu was clearly associated with AJ-arthritis in these rats, there was no quantitative relationship between the extent of change in pCu and the other parameters measured (r2 all < 0.01). The highest correlation observed was between pZn and WL (r2 = 0.637, p < 0.001). While the initial depression of pZn may be the result of increased hepatic hMT levels, longer term reductions in pZn levels are linked to systemic inflammation, the degree of arthritis and associated weight loss.

Animals↗
PubMed1994

Metallothionein and zinc homeostasis during tumor progression. Effect of methotrexate treatment.

Zinc homeostasis was studied during the induction, growth, and methotrexate (MTX) treatment of Dark Agouti rat mammary adenocarcinomas (DAMA). A progressive fall in plasma Zn concentration (pZn), significant at a tumor burden of less than 1% body weight (bw), was sustained during tumor enlargement to give a 54% reduction in pZn at 16.3% bw (n = 6/group). The hypozincemia was attributed to the increasing Zn demand for tumor growth. Zn content of the 16.3% bw tumors equaled that of muscle (normally 60% of total body Zn). Tumor metallothionein (tMT) was sufficient to bind < 3% of total tumor Zn, and hepatic MT (hMT) remained at basal concentrations during early tumor growth, doubling only in the presence of significant necrosis in large tumors. Methotrexate (MTX, 0.5 mg/Kg im x 2 d) at respective tumor burdens of 5 and 10% bw (n = 9, 10/group) gave 2 therapeutic effects, dependent on tumor size: 1.5% bw tumors in 7 rats remained close to their original size until experiment end when pZn, hMT, and tMT were typical of 5% bw untreated tumors. 2. Tumors in 5 rats given MTX at 10% bw had marked subcapsular necrosis and regression to a size similar to those in group 1; pZn returned toward normal, whereas hMT was 6 times its 5% bw counterpart. Host weight loss was significantly reduced, as were tumor-associated changes in plasma glucose and calcium. In summary, neither tMT nor hMT appears to play a role in the hypozincemia that follows DAMA Zn sequestration and growth. Critically timed MTX can result in tumor regression and return of plasma Zn, Ca, and glucose toward normal. This is associated with an increase in hMT and reduction in host weight loss, suggesting a flow of Zn from the resorbing tumor to the host, enabling the synthesis of hMT and retention of host structural proteins.

Adenocarcinoma↗
PubMed1994

Metabolic consequences of methotrexate therapy in tumour-bearing rats.

The metabolic response of the tumour-bearing host to methotrexate (MTX) therapy was investigated with particular attention to effects resulting from MTX-induced anorexia. Biochemical changes in female Dark Agouti rats bearing mammary adenocarcinomas and treated with MTX (0.5 mg/kg, 2 i.m. injections, 24 h apart) were compared with untreated (CON) tumour-bearing rats, and tumour-bearing rats pair-fed (PF) to the MTX group. MTX treatment halted progression of the tumour (tumour 6% of bodyweight) while the tumour burden doubled in the CON and PF groups. A number of biochemical and haematological changes were specific to MTX treatment and did not result from decreased food intake. MTX treatment was associated with significantly decreased plasma calcium, bilirubin, alkaline phosphatase, aspartate aminotransferase and the total white cell count. Decreases in plasma albumin and total protein concentrations were observed in both MTX and PF rats. Other parameters commonly used to assess renal and liver function were not significantly affected by MTX. MTX reversed the hypoglycaemia, hyperketonaemia and hypertriglyceridaemia induced by tumour-bearing. In contrast, PF rats had an even more pronounced hypoglycaemia and hyperketonaemia than the CON rats. Measurement of glucose uptake in vivo with 2-deoxy[U-14C]-glucose showed that MTX treatment halved the glucose requirement of the tumour (8.2% of bodyweight compared to 12.2% in the control). It is concluded that the potentially adverse effects of MTX treatment on host metabolism are outweighed by the beneficial effects of a reduced metabolic demand resulting from inhibition of tumour progression.

Adenocarcinoma↗
PubMed1994

A community outbreak of echovirus infection associated with an outdoor swimming pool.

Forty-six people became ill with vomiting, diarrhoea and headache within days of an outdoor swimming pool opening for the summer season in a small seaside village. During the weekend of the outbreak, 185 tickets to the pool had been sold. It was found that 34 bathers were ill, and one subject had vomited into the pool. All other cases arose after this incident. The risk of infection was greatest among those who swallowed pool water (24/28 versus 10/17, p = 0.07). Echovirus 30 was isolated from the case who vomited into the pool and from six other cases. Normal chlorine levels had not been adequate to contain the infection risk from vomitus, and, in future, pool attendants witnessing such incidents should consider closing the pool to the public and seeking advice on superchlorination.

Adolescent↗
PubMed1993

Influence of season, age, and sex on renal stone formation in South Australia.

OBJECTIVE: To investigate trends in renal stone formation in the South Australian population, between 1977 and 1991 (3634 stones), with respect to age, sex and seasonal variation. RESULTS: The frequency of the different stone types was: calcium oxalate (with or without phosphate), 68%; uric acid, 17%; infection stones (magnesium ammonium phosphate), 12%; and pure calcium phosphate, 3%. No significant seasonal variation was observed with calcium oxalate or calcium phosphate stones. The incidence of uric acid stones increased significantly during summer and autumn (P < 0.001 and P < 0.01 respectively), and that of infection stones decreased significantly during spring and summer (P < 0.05 and P < 0.01 respectively). Calcium oxalate, uric acid and calcium phosphate stones were more frequent in male subjects; male to female ratio 2.8:1, 3.7:1 and 1.4:1 respectively. However, there was an increased frequency of calcium oxalate stones in women 20 to 25 years of age; male to female ratio 0.7:1. Infection stones were more common in female subjects; male to female ratio 0.7:1. CONCLUSIONS: This study demonstrates significant seasonal variation in uric acid and infection stones. Men are at a higher risk of forming stones than women, with the exception of infection stones. Additionally, with calcium oxalate stones, women may have distinct periods of higher risk. This study confirms that calcium oxalate stones are the most common stone type, which is in accordance with studies from other industrialised countries.

Adult↗
PubMed1993

Metallothionein induction in freshly isolated rat hepatocytes.

The control of metallothionein (MT) synthesis was investigated in freshly prepared rat hepatocytes in experiments of short-term duration. Viability and metabolic function were maintained in incubations of 6-h duration. MT synthesis was measurable in hepatocytes from fed rats at Zn concentrations down to 1 microM. Zn and dexamethasone induced concentration-dependent increases in the synthesis of MT with maximal increases above the 5-h control of 3.2- and 2.5-fold, respectively. Zn induction of MT was first measurable at 2 h and was inhibited by actinomycin C. Although initial (0 h) MT concentrations in hepatocytes from fasted rats were double those from fed rats, after 6-h incubation in the presence of 50 microM Zn, the fasted rat hepatocytes showed only half the MT concentrations of the fed rat hepatocytes. Glucagon and interleukin-6 (IL-6) were less effective inducers and increased MT synthesis by 28 and 17%, respectively. IL-6 (100 U/mL) was found to have an additive effect on MT synthesis above that of Zn alone (1-50 microM) or Zn plus dexamethasone (1 microM). A supernatant from LPS-stimulated macrophages increased MT synthesis by 40%. The basal MT synthesis was not increased by either tumor necrosis factor-alpha (TNF-alpha) or interleukin-1 (IL-1). All incubations were carried out in the presence of RPMI 1640 medium with Hepes (20 mM), bicarbonate (24 mM), and fatty acid-free albumin (FAFA; 0.5% w/v). MT synthesis was also seen using Krebs bicarbonate buffer with glucose (10 mM), Hepes (20 mM), and FAFA (0.5% w/v), and although the level of MT synthesis was less than in RPMI, the increases in concentrations of MT at 5 h were 225, 139, 36 and 20% for Zn, dexamethasone, glucagon, and control, respectively. It is concluded that MT synthesis occurs in freshly prepared hepatocytes and that these cells are responsive to some of the established inducers of MT. This system enables the study of MT synthesis in individual rats in various metabolic and pathological states.

Animals↗
PubMed1993

The effects of hypercholesterolaemia, simvastatin and dietary fat on the low density lipoprotein receptor of unstimulated mononuclear cells.

The in vivo expression and regulation of the LDL receptor of circulating mononuclear cells was studied using a sensitive spectrophotometric assay with low density lipoproteins conjugated to colloidal gold (LDL-gold). The high plasma cholesterol of familial hypercholesterolemic subjects was shown to be related to a low in vivo LDL receptor activity; cells from a homozygote had virtually no activity and those from 24 heterozygotes expressed 45% of the activity of cells from 35 normals. The average receptor activity of cells from 18 polygenic hypercholesterolemic (PH) subjects was not significantly different from normal but a low expression may have been a factor in six of these subjects. Simvastatin increased the LDL receptor activity of cells from the PH subjects by 70% while lowering their plasma cholesterol by 26%, but reducing the fat intake from 38% to 20% of energy and cholesterol from 239 to 96 mg/day had no effect on the receptor despite a 10% reduction in plasma cholesterol. Upregulation of the LDL receptor may therefore have been involved in the lowering of plasma cholesterol by simvastatin but not by the reduction in dietary fat and cholesterol.

Anticholesteremic Agents↗
PubMed1993

Prevention and treatment of Staphylococcus aureus infections with recombinant cytokines.

Antibiotic therapy is only moderately efficacious for bovine Staphylococcus aureus mastitis. We have used recombinant bovine cytokines to activate the natural host defenses, to prevent and treat bovine mastitis. Uninfected mammary glands infused with GM-CSF or IL-2 increased the percentage of phagocytic cells in the milk by 2-3 fold. IL-1 increased the number of polymorphonuclear cells in the milk, enhanced their inducible oxygen radical formation, and had no effect on phagocytosis. Treatment with IL-2 increased the number of polymorphonuclear cells in the milk, enhanced their inducible oxygen radical formation, and enhanced their phagocytosis. GM-CSF had no effect on the number polymorphonuclear cells in the milk but enhanced their inducible oxygen radical formation, and enhanced their phagocytosis. All cytokines were effective in preventing S. aureus infections (20-100%). 52% of all chronically infected mammary gland quarters treated with three doses of IL-2 responded to therapy and 32% of the treated quarters remained cured. 75% of all mammary glands treated with three doses of IL-1 beta responded to therapy by clearing the infection and 22% of the treated glands remained cured. These studies demonstrate that recombinant bovine cytokines can be used effectively to prevent infections as well as treat established chronic infection.

Animals↗
PubMed1993

Corticosterone enhances the zinc and interleukin-6-mediated induction of metallothionein in cultured rat hepatocytes.

The regulation of metallothionein induction in cultured rat hepatocytes was investigated with Zn, hormones, cytokines and either the synthetic glucocorticoid, dexamethasone, or the endogenous rat glucocorticoid, corticosterone. A concentration-dependent increase was seen with Zn (two- to fivefold increase in 24 h, Zn 10-50 mumol/L). Dexamethasone at 1 mumol/L increased metallothionein synthesis by fourfold that of the controls. Maximal metallothionein concentrations of 17-fold the control value were seen with 50 mumol/L Zn and 1 mumol/L dexamethasone. Interleukin-6 (1 x 10(5) U/L) alone did not induce metallothionein but increased it 35-65% with Zn+dexamethasone. Like dexamethasone, corticosterone had a dose dependent effect on metallothionein and synergy with Zn and Zn+interleukin-6. Dexamethasone was approximately 100 times more potent than corticosterone at 10-100 mumol/L. Physiological concentrations of corticosterone (1 mumol/L) when added alone, with Zn (10 mumol/L), and with Zn+interleukin-6 resulted in inductions of 2.2, 5.0 and 7.4-fold above the control cultures. Glucagon (1 mumol/L) had no independent effect but increased metallothionein by 31% and 33% with Zn(10 mumol/L)+dexamethasone (1 mumol/L) and Zn-dexamethasone+interleukin-6, respectively. There was no accumulation of metallothionein with interleukin-1 beta, tumor necrosis factor alpha or interferon gamma (1 x 10(5) U/L) alone, but interleukin-1 beta and tumor necrosis factor alpha enhanced the response obtained with Zn+dexamethasone with and without interleukin-6. Insulin (100 U/L) alone, caused metallothionein accumulation and further enhanced the response seen with Zn+dexamethasone+interleukin-6+glucagon. No additional enhancement was seen with interleukin 1 beta+tumor necrosis factor alpha+interferon. The results demonstrate that concentrations of corticosterone in rats with experimental inflammation facilitate metallothionein induction with Zn and interleukin-6.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Spatial features of focal infarction after hydralazine treatment in stroke-prone spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: Rapid occlusion of the middle cerebral artery above the rhinal fissure produces a large ischemic infarct in hypertensive rats, but this occlusion results in a minimal lesion in young normotensive rats. Our purpose was to attenuate rising blood pressure in young stroke-prone spontaneously hypertensive rats with hydralazine before the occlusion to determine if the gross infarct volume is smaller, and if it is, to determine whether length, width, depth, or surface area of the infarct changes, which could suggest a mechanism of protection. METHODS: Untreated rats (n = 6) and rats receiving hydralazine for 1.5 (n = 6) or 5 (n = 5) weeks were anesthetized, and the middle cerebral artery was rapidly occluded with a ligature. One day later the rats were killed and the brains were fixed in formalin. Fine-grain-release film that is sensitive to spectral properties of the infarct was used to photograph the tissue. Infarcted areas were traced on paper and then digitized for measurements and computations with a microcomputer. RESULTS: Compared with untreated rats, tail systolic blood pressure (120 +/- 3 versus 138 +/- 4 mm Hg), infarct volume (61 +/- 4 versus 93 +/- 6 mm3), infarct surface area (39 +/- 1 versus 54 +/- 2 mm2), infarct width (3.8 +/- 0.1 versus 4.8 +/- 0.2 mm), and infarct length (6.0 +/- 0.3 versus 8.1 +/- 0.3 mm) were less in rats receiving hydralazine for 5 weeks (p < 0.05). No change was detected in infarct depth. CONCLUSIONS: Treatment of young stroke-prone spontaneously hypertensive rats with hydralazine for 5 weeks before middle cerebral artery occlusion results in a smaller infarct. The narrower, shorter dimensions indicate increased protection against lateral enlargement of the infarct and the possibility that protection was due to increased collateral blood flow through modified blood vessels.

Animals↗