Arian Zarkower

Antioxidant effects on cell-mediated immunity.

Experiments were performed to determine the effects of dietary selenium and/or vitamin E deficiency on cell‐mediated cytotoxicity in the mouse. Natural killer cell‐mediated cytotoxicity (NKCC) was depressed after 8 wk on diets deficient in selenium and/or vitamin E. In contrast, antibody‐dependent cell‐mediated cytotoxicity (ADCC) was not affected by 8 wk of dietary deficiency of selenium and/or vitamin E. T‐lymphocyte‐mediated cytotoxicity (TCMC) was found to be depressed by combined selenium‐vitamin E deficiency after 7 weeks on diets.

The effects of ozone inhalation on the immunological response of selenium- and vitamin E-deprived rats

Deficiencies in vitamin E (E) or Se result in immune alterations, possibly due to reduction of antioxidant activity. Such reductions might greatly compromise the ability of the immune system to deal with additional oxidant stress, as encountered during exposure to air pollutants such as ozone (O3). To study possible interactions of these oxidative stresses on immune function, male Long-Evans hooded rats were maintained 5 weeks on torula yeast-based diets, with or without the addition of E or Se. Each dietary group was subdivided into O3-exposed and nonexposed groups. Two different regimens of O3 exposure were used: continuous (1.0 ppm, 8 hr/day for 7 days) or intermittent (2.0 ppm, 8 hr/day for 4 days, 2-4 days in ambient air followed by 1 day of exposure prior to sacrifice). Exposure to O3 in either regimen resulted in increased numbers of cells recovered by pulmonary lavage. With continuous exposure this increase was due to macrophage influx and, with intermittent exposure, due to influx of both macrophages and neutrophils. Combined deficiency of E and Se led to an enhanced ability of spleen and lung cells to mediate antibody-dependent cell-mediated cytotoxicity (ADCMC). In animals deficient in E, but not Se, O3 exposure depressed spleen cell ADCMC. Deficiencies of either E or Se also depressed lymphocyte response to mitogens. Although intermittent exposure to O3 caused no changes in mitogen response, in animals exposed continuously to O3 there was a significant enhancement of this response.

Murine immunological and histological changes in response to chronic silica exposure.

Abstract The relationship between immunological and histological changes was studied in mice exposed to silica dust over a period of 39 weeks. The response of these mice to Escherichia coli antigens given as an aerosol was suppressed in the spleen at all times tested, while in the mediastinal lymph nodes (MLN) an initial enhancement at 9 weeks was followed by suppression of responses at all subsequent times. The development of silica-induced lesions also was studied using histological methods. With polarized light, silica-laden aggregations of macrophages were observed in the lungs after 24, 33, 36, and 39 weeks. Using scanning electron microscopy, numerous macrophages were frequently present in respiratory airways of silica-exposed animals. Typical silicotic lesions were observed in lungs and adjacent lymph nodes after 39 weeks of exposure.

Alterations in Antibody Response Induced by Chronic Inhalation of SO2 and Carbon

Mice were exposed to low concentrations of carbon, SO2, and carbon plus SO2 In an attempt to determine the effect of chronic exposures on the immunological defense mechanism. Carbon alone or in combination with SO2 caused a progressive decrease in overall ability of the animals to form antibody. Reduction of antibody formation occurred in mice exposed to 2.00 ppm SO2 for 192 days. An enhancement of antibody production occurred in mediastinal lymph nodes after 102 and 135 days of exposure, but this effect was being reversed by 192 days. An unexpected enhancement of antibody production, especially in the spleen, occurred in mice exposed to SO2 alone for 135 days. This adjuvant activity had faded by 192 days, when an overall suppression of antibody response was seen, though not to the degree observed in the animals exposed to carbon.

Effects of inadequate vitamin E and/or selenium nutrition on the release of arachidonic acid metabolites in rat alveolar macrophages

Effects of vitamin E and/or selenium (Se) deficiency on the secretion of arachidonic acid metabolites by zymosan-stimulated pulmonary alveolar macrophages (AM) were examined using cells from male Long-Evans hooded rats fed torula-yeast based diets with or without the supplementation of vitamin E (150 IU/kg) or Se (0.5 mg/kg). Alveolar macrophages obtained by lavage were purified by adherence and cultured for 4 h in Hanks balanced salt solution containing bovine serum albumin (0.1%) and zymosan (300 micrograms/ml). The arachidonic acid metabolites present in the culture supernatant were measured by radioimmunoassay. Altered vitamin E and Se nutrition had no effect on the number of cells or cell types recovered from the pulmonary airways. Alveolar macrophages derived from animals fed on diets deficient in vitamin E or Se or both nutrients secreted higher levels of prostaglandin E2 and thromboxane B2. Levels of both 5-hydroxyeicosatetraenoic acid and leukotriene B4 were significantly increased only in the group fed the diet adequate in Se but deficient in vitamin E. Our data suggest that vitamin E and Se might play an important role to control the levels of several physiologically and pathologically important arachidonic acid metabolites.

Comparative pathological aspects of chronic olivine and silica inhalation in mice

A comparative study was done in mice on the effects of silica and olivine inhalation. The exposure periods in the dust chambers were for periods of 150, 300, and 570 days, with the longest time period covering a large portion of the predicted life span of the Balb/c mouse. Detailed necropsies including histology were done at the end of the exposures and at 30 and 150 days following removal of animals from the 150- and 300-day dust exposures. The results indicate that silica causes considerably more tissue damage in lungs and mediastinal lymph nodes, leading to granulomas.

Effects of prolonged inhalation of silica and olivine dusts on immune functions in the mouse

Immunologic responses were determined in Balb/c mice following intermittent silica or olivine inhalations for 150, 300, or 570 days. Animals dust-exposed for 570 days were tested immediately postexposure, while those exposed for 150 or 300 days were tested immediately or were rested for 30 or 150 days as a measure of possible recovery from effects of the dust inhalations. Silica inhalation suppressed the number of specific plaque-forming cells (PFC) in the spleen produced in response to aerosolized Escherichia coli bacteria. When tested after 570 days, silica inhalation also reduced the ability of alveolar macrophages to phagocytize Staphylococcus aureus in vitro. Olivine inhalation also suppressed splenic PFCs and alveolar macrophage phagocytosis, but to a lesser degree than silica. In animals tested after 570 days of dust exposure, it was determined that the ability to lyse allogeneic tumor cells in vitro was impaired by olivine slightly more than by silica, while antibody-dependent cell-mediated cytotoxic and mitogenic responses by splenic lymphocytes were unchanged by inhalation of either dust. The effects of increased exposure periods, and of recovery periods after exposure, were confounded by age-related immunologic changes which were present after the longer exposures.

Immunological alterations in the mouse following injection or inhalation of silica and olivine dusts

Immunologic responses were determined in mice following silica or olivine inhalations of up to 300 days, or following intravenous (iv) and intraperitoneal (ip) injections of the dusts. The comparative toxicity of iv injected silica or olivine was also studied. Silica inhalation suppressed the splenic plaque-forming cell (PFC) responses to Escherichia coli given as an aerosol, while olivine inhalation caused less severe suppression. Similar decreases in specific serum antibody levels and alveolar macrophage phagocytic indices were also seen. Few changes were found in spleen lymphocyte responses to mitogens. Injections of silica (iv or ip) caused either enhancement, or in some cases suppression, of the response to antigenic stimulation, with lower doses generally stimulating and very high doses suppressing the response. Olivine injections, in general, produced similar but less severe alterations of the responses to antigenic stimulations. Comparison of lethal dose levels by iv injection indicated a greater toxicity for silica than olivine in this respect.

Effects of fly ash inhalation on murine immune function: Changes in macrophage-mediated activities

Mice were exposed to fly ash particles (<2.1 μm diameter) by inhalation for variable amounts of time at concentrations ranging from 535 to 2221 μg/m3. This fine fraction was approximately 32% by weight of the total dust generated. The effects of these exposures were assessed on macrophage-mediated functions. Phagocytosis of bacterial cells by the alveolar macrophages was depressed in the fly ash-exposed animals as was the ability to enhance T-cell mitogenesis. Fly ash exposure failed to produce a significant change in the cellular immune response (delayed-type hypersensitivity reaction) to antigenic challenge in the lungs of sensitized animals.

Increased thromboxane A2 synthesis by rat lung neutrophils during selenium deficiency

Modulation of cellular hydroperoxide levels is considered one of the important physiological mechanisms for regulating the synthesis of prostaglandins (PGs) and leukotrienes (LTs) in mammalian cells. Both vitamin E and selenium (Se) have the potential to affect the concentration of peroxides and, thus, the biosynthesis of eicosanoids. To gain insight into some of the molecular mechanisms underlying the regulation of the arachidonic acid cascade by vitamin E and Se, we have investigated the influence of altered vitamin E and Se nutrition on the ability of polymorphonuclear leukocytes (PMNs) derived from endotoxin-challenged lung to secrete arachidonic acid metabolites. Selenium deficiency had no significant effect (p > 0.05) on lavage fluid levels of thromboxane (TX) B2, LTB4 or LTC4. Vitamin E deficiency, however, led to a significant increase in LTB4 recovered from lavage fluid while having no effect on TXB2. In contrast, Se deficiency, although producing no discernible effects on the production of LTB4, resulted in a significant increase in the release of TXB2 by PMNs. An increase in TXB2 release was seen in both in vitro-stimulated and nonstimulated PMNs. Vitamin E deficiency appeared to induce an enhancement of LTB4 release by PMNs but the increase was not statistically significant. No detectable levels of LTC4 were found in PMN cultures stimulated with either zymosan or A23187. Thus, these studies indicate that deficiencies of either Se or vitamin E lead to alterations in the metabolism of arachidonic acid in the lung.