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Biomedical subjects

R A Winchurch

Publications and source records attributed to R A Winchurch.

At least 19 recordsLinked to original sources
PubMed1992

Inhibitory effects of interleukin 6 on immunity. Possible implications in burn patients.

Certain disease states are associated with abnormal increases in the monokine interleukin 6. Increased levels of interleukin 6 have been demonstrated in serum from patients with burns and are associated with systemic increases in endotoxin levels. Using a murine in vitro experimental model, we have studied the effects of interleukin 6 on various measures of immunity. Our data indicate that levels equivalent to the concentrations found in serum of burn victims inhibit T-cell proliferation. The inhibitory effect is dose and time dependent, is specific for T cells, is not due to impairment of interleukin 2 production or of interleukin 2 receptor expression, and is dependent on macrophages. These data suggest that extraordinary increases in interleukin 6 levels may be related to impaired T-cell responses and to an increased susceptibility to infection in the patient with burns.

Animals↗
PubMed1991

Pathologic concentrations of interleukin 6 inhibit T cell responses via induction of activation of TGF-beta.

Interleukin 6 levels are increased in a variety of clinical conditions including bacterial and viral infections, HIV infection, autoimmune diseases, certain neoplasias, and traumatic injury. In general, all these conditions are characterized by suppression of one or more manifestations of the immune response. Concentrations of IL 6 comparable to those found in the sera of immunosuppressed, thermally injured patients selectively inhibit T cell proliferative responses. This suppression is independent of IL 2-mediated responses, is dependent on macrophage activity, and is reversed by antisera specific for transforming growth factor-beta (TGF-beta).

Animals↗
PubMed1991

Altered organ growth and zinc and copper distribution in endotoxin-treated neonatal mice.

Organ weights and the distribution of zinc and copper were compared in HLA/ICR mice that received intraperitoneal injections of 10 micrograms of Serratia marcescens lipopolysaccharide W or of sterile physiologic saline at 2 d of age. Between 5 and 28 d of age, body weight gains were similar in both groups. At 5 and 7 d of age, lipopolysaccharide W-treated mice had significantly lower thymus weights (p less than 0.01). At 7 d of age, liver weight was significantly increased (p less than 0.01) in lipopolysaccharide W-treated mice. Compared with tissue copper concentration in coeval saline-treated mice, lipopolysaccharide W treatment significantly increased copper concentration in thymus at 5 d of age (p less than 0.05) and significantly decreased concentration of this metal in liver at 7 d of age (p less than 0.05) and in spleen at 14 d of age (p less than 0.05). Liver zinc concentration was significantly lower (p less than 0.05) in 28-d-old mice that had received lipopolysaccharide W. When expressed on the basis of total organ burdens of zinc or copper, only the liver burden of zinc in 5-d-old lipopolysaccharide W-treated mice was significantly increased (p less than 0.05). Lipopolysaccharide W treatment consistently decreased copper concentration in liver cytosol and the amounts of zinc and copper bound to metallothionein, a transition metal-binding protein, in liver cytosol. These effects of lipopolysaccharide W on organ size and metal distribution may contribute to the adverse effects that persist after endotoxin exposure in early life.

Animals↗
PubMed1990

Increased levels of circulating interleukin 6 in burn patients.

The serum levels of interleukin 6 (IL-6) were determined in a population of burn patients. In all patients, IL-6 levels were increased over a 3-week interval with peak concentrations reached during the first week after injury. Patients receiving intravenous polymyxin B therapy according to a regimen designed to reduce endotoxemia manifested greatly reduced levels of both circulating endotoxins and IL-6. Certain patients not treated with polymyxin B showed extraordinarily large increases in IL-6 which were associated with lethal or life-threatening clinical complications. Increased IL-6 levels were also associated with decreased percentage of circulating T cells and corresponding increases in B cells. However, IL-6 did not produce any direct inhibitory effects in vitro on T cell representation or function.

Biological Factors↗
PubMed1989

Influence of age upon the metabolism of zinc in livers of C57BL/6J mice.

The kinetics of accumulation and loss of zinc from the liver following subcutaneous administration of 10 mg of zinc per kg were examined in young adult (6 months old) and old (24 months old) male C57BL/6J mice. After zinc treatment, total liver zinc concentrations rose equally in both groups and returned to basal levels at 96 h post treatment. However, differences were found in the subcellular distribution of zinc in these two age groups. The concentration of zinc in the cytosolic fraction (104,000 g supernate) prepared from the livers of old mice attained its maximum at 24 h post treatment. In contrast, the concentration of zinc in the cytosolic fraction of liver from young adult mice peaked at 48 h post treatment. This difference in accumulation of zinc in the cytosol was reflected by differences in the binding of zinc to metallothionein, a cytosolic transition metal binding protein. In old mice the highest amounts of zinc bound to metallothionein were found at 24 h post treatment: in young adults the maximal zinc binding to this protein occurred at 48 h post treatment. Examination of the relationship between cytosolic zinc contents and the binding of zinc to metallothionein in young adult and old mice suggested similar regulatory processes in the two age groups. Thus, age-dependent differences in accumulation and loss of zinc from the cytosolic fraction of liver probably reflect factors other than differences in regulation of the synthesis of metallothionein by this essential metal.

Age Factors↗
PubMed1988

Activation of thymocyte responses to interleukin-1 by zinc.

In vitro proliferative responses of murine thymocytes to interleukin-1 are enhanced by supplementing the cultures with the trace nutrient zinc. Zine not only enhances the responses of cells suboptimally activated by PHA but can also prime the cells to respond to IL-1 in the absence of activation by PHA. Zinc affects the early stages of the proliferative response. The data suggest that zinc may enhance the cellular uptake of IL-1 or may facilitate enzymatic steps subsequent to IL-1 binding.

Animals↗
PubMed1988

Supplemental zinc restores antibody formation in cultures of aged spleen cells. III. Impairment of II-2-mediated responses.

The effects of zinc on interleukin-2(IL-2)-dependent T cell responses of lymphocytes from immunodepressed aged mice and from young adult animals were studied. Concentrations of zinc which have been shown to restore antibody formation in cells from aged mice and to increase the production of Il-1 and Il-4 inhibited the production of Il-2. Cells from both young adults and aged mice were inhibited similarly. Zinc also impaired the ability of aged T cells to proliferate in response to concanavalin A and exogenous Il-2, but enhanced the proliferation of similarly activated splenic cultures containing both T and B cells. Cultures of isolated B lymphocytes produced antibody to sheep red blood cells if the cells were provided with supplemental zinc and Il-1. In contrast, recombinant Il-2 with or without zinc did not activate antibody formation. The results support the premise that the restorative effects of zinc are independent of Il-2 and that Il-2 is not a necessary mediator for antibody production in the aged.

Aging↗
PubMed1988

Altered expression of lymphocyte Il-2 receptors in burned patients.

Impairment of T-cell function is a consistent observation in burned patients. Concomitant with this impairment is an increase in serum factors which inhibit interleukin-2-mediated T-cell functions. These factors are heat labile and do not behave like endotoxins. Nonetheless, treatment of burned patients with endotoxin-neutralizing regimens of polymyxin B reduces the levels of these factors, suggesting that they are generated in response to endotoxin exposure. In addition to factors which inhibit Il-2 responses burn serum contains increases of circulating soluble, cell-free Il-2 receptors. However, the level of Il-2R is not altered by polymyxin B treatment and does not appear to be a direct result of endotoxin exposure. These observations suggest that multiple causes contribute to T-cell impairment in burned patients.

Adult↗
PubMed1988

Depressed natural killer cell function in thermally injured adults: successful in vivo and in vitro immunomodulation and the role of endotoxin.

Natural killer (NK) cells mediate host defense against infections and are regulated by interleukin 2 (IL-2) and other factors. We studied NK cell function in burn patients using a 51Cr release assay with K562 target cells. We found that peripheral blood lymphocytes from burn patients had depressed NK activity (target cell lysis = 22.0 +/- 3.1% vs 39.8 +/- 3.2% in healthy volunteers, P less than 0.001) and also a lower response to IL-2 (28.9 +/- 3.8% vs 53.2 +/- 4.3%, P less than 0.001). Thirteen burn patients were randomly assigned to receive either standard therapy or 5 days of intravenous polymyxin B in addition to standard therapy. After 2 weeks, the patients not receiving polymyxin B had a significant decline in peripheral blood NK activity (P less than 0.01) and response to IL-2 (P less than 0.05), while no decline in NK cell activity was seen in patients who received polymyxin B. Sera from burn patients was found to suppress the NK activity of lymphocytes from healthy adults by 5-75%. After using affinity chromatography to remove endotoxin, the sera from burn patients no longer suppressed NK cell activity. Circulating endotoxin appears to be involved in the suppression of NK activity in burn patients.

Adult↗
PubMed1987

Ontogenic variation in acute lethality of cadmium in C57BL/6J mice.

Susceptibility of C57BL/6J mice to the lethal effects of parenterally administered Cd declined as a function of age at exposure. The 7-day LD50 increased from 1.65 mg Cd/kg body wt in 7-day-old mice to 4.08 mg/kg in adult mice. Survival time following treatment with Cd also increased as a function of age. High constitutive concentrations of metallothionein, a transition metal-binding protein, in livers of young mice did not protect against the lethality of Cd. These results suggest that, in the mouse, the interaction between Cd and this metal-binding protein may be affected by age at exposure to this toxic metal.

Aging↗
PubMed1987

Supplemental zinc (Zn2+) restores antibody formation in cultures of aged spleen cells. II. Effects on mediator production.

In vitro antibody production to T-dependent erythrocyte antigens is depressed as a function of age. Supplementation of antibody-forming cultures with the essential trace element zinc restores the capacity of cells from immunodepressed, aged mice to generate an antibody response. Zn2+ produces maximal enhancement of immune function when it is added to the cultures within the first 24 h. Supernatants obtained from cultures supplemented with zinc from 0-24 h contain soluble, nondialyzable factors which support enhanced antibody production in fresh cultures of cells from aged mice. Interleukin 2 levels in the supernatants from Zn2+-supplemented cultures were not increased. However, the levels of interleukin 1 were increased approximately 300% over nonsupplemented controls and these increases corresponded with the ability of the supernatants to support antibody formation. Further studies showed that, in addition to enhancing the production of interleukin 1, Zn2+ enhanced the ability of concanavalin A-activated T cells from aged mice to produce B cell stimulatory factor-1.

Aging↗
PubMed1987

Endotoxemia in burn patients: levels of circulating endotoxins are related to burn size.

With use of a quantitative limulus assay, the levels of circulating endotoxins were examined in a population of burn patients with injuries covering 1% to 88% of the total body surface area (TBSA). In cases in which the injury was less than 20% TBSA, the increases in endotoxins were only 35% as compared with those of normal controls. As the extent of injury increased, the levels of endotoxins also increased: burns between 21% and 40% TBSA showed average increases of over 350% and burns in excess of 40% showed increases of 500%. The relationship between burn size and total endotoxin burden was significant (p = less than 0.01). Time-course studies indicated that in most cases, peak endotoxin levels occurred 3 to 4 days after injury. The data also showed that there was no relationship between the age of the patient and the extent of the endotoxin increase.

Adult↗
PubMed1986

Reversal of postburn immunosuppression with low-dose polymyxin B.

In a randomized study of 28 patients with thermal injury, polymyxin B was administered intravenously in small doses to attempt to block the immunosuppressive effects of endotoxin. When compared with controls, treated patients showed a reduction in septic complications and death, but this reduction is not statistically significant at this time. In vitro measurements of lymphocyte function, however, indicate a statistically significant improvement in the T helper to suppressor ratio, and in the lymphocyte responsiveness to a number of bacterial antigens.

Adult↗
PubMed1985

Burns. Infection and immunology.

The burn wound is successively colonized by gram-positive then gram-negative flora. The reduction of mortality from sepsis in burns depends on our understanding of the chain of events leading to microbial invasion of the burn wound and the host response that follows. These are outlined in this article, together with the current attempts to improve this response in the host.

Adjuvants, Immunologic↗
PubMed1979

Ribonuclease activity of preparations of human lymphoblastoid interferon.

Crude human lymphoblastoid interferon has less ribonuclease activity than equivalent primary leukocyte interferon and ribonuclease was eliminated when it was purified. The methods used differed from those that had failed to eliminate similar activity from leukocyte interferon. This result makes it unlikely that exogenous ribonuclease plays a major role in the antiviral action of interferon preparations.

Burkitt Lymphoma↗
PubMed1977

RNase activity in human interferon preparations.

The level of RNase activity in human interferon preparations was examined. Although sequential purification of interferon resulted in nearly a 300-fold increase in specific activity, RNase-specific activity remained more or less constant. The implications of this finding for the analyses of the mode of action of interferon are discussed.

Humans↗