Faculty Bibliography

Despite the widespread occurrence of acidic sulfur oxides in the ambient environment and their potential risks to human health, effects associated with pulmonary immune defenses have been poorly studied. The current in vivo study was designed to provide some insight into this relatively unexplored area by investigating the impact of inhaled sulfuric acid on immune defense mechanisms critical for maintaining pulmonary resistance against infectious diseases. Results of this study demonstrate that repeated inhalation of sulfuric acid reduces the uptake and intracellular killing of pathogenic bacteria by exposed pulmonary macrophages, and depresses the activity/production of important biological modifiers critical for maintaining pulmonary immunocompetence. These findings have important implications for human health, and may contribute to a better understanding of the possible mechanism(s) underlying the epidemiological evidence which suggests an association between total sulfates in the ambient air and increased incidence of acute bronchitis and lower respiratory illness in school-age children

Rabbit pulmonary macrophages were exposed in vitro to particulate lead oxide (PbO) for periods of up to 72 h and then assayed for the activity of tumor necrosis factor-alpha (TNF alpha) released after stimulation with lipopolysaccharide (LPS). The levels of TNF alpha obtained from PbO-treated cells were decreased in a dose-dependent manner as compared with metal-free control cells for each time point examined. Cells treated simultaneously with both LPS and PbO yielded less monokine than did cells receiving LPS alone. In addition, incubation of cell-free TNF alpha with PbO resulted in a diminution of cytotoxicity directed against TNF alpha-sensitive tumor target cells. Macrophage burdens of PbO particles increased with both the length of incubation and concentration of PbO used; increases in cellular lead burdens were paralleled by reductions in cell viability. Thus, under in vitro conditions, PbO affects the levels of the immunoregulatory monokine TNF alpha and also disrupts its cytotoxic properties after release from activated macrophages

Inhaled acids are associated with adverse health effects, a conclusion based largely on studies with particulate-associated acid sulfates. The acidic component of ambient air in some regions, such as California, contains nitric acid (HNO3) vapor, but there is a limited database concerning its biological effects. Furthermore, effects of HNO3 may be modulated by coexposure to other pollutants, such as ozone (O-3). Rabbits were exposed for 4 h/day, 3 days/wk for 4 wk to HNO3 vapor at 0, 50, 150, and 450 mu g/m(3) alone; 0.15 ppm 0(3) alone; or to a mixture of 50 mu g/m(3) HNO3 + 0.15 ppm 0(3). Exposure was followed by assays of biochemical markers in lavage fluid pulmonary macrophage function, and in vitro bronchial responsivity to smooth muscle constrictor challenge. Nitric acid had no effect on viability or numbers of cells recovered, nor on lactate dehydrogenase or total protein in lavage. All acid concentrations reduced both basal levels and stimulated production of superoxide anion by macrophages, while the release/activity of tumor necrosis factor by stimulated macrophages was reduced following exposure to greater than or equal to 150 mu g/m(3) HNO3. Bronchi from rabbits exposed to greater than or equal to 150 mu g/m(3) HNO3 exhibited reduced smooth muscle responsivity in vitro compared to control. Although exposure to the HNO3/O-3 mixture resulted in no interaction for most end points, antagonism was noted for stimulated superoxide production, while synergism was noted for spontaneous superoxide production and bronchial responsivity. Exposure to the mixture resulted in a total abrogation of response to spasmogens in most bronchi examined and a marked attenuation in others. These results indicate that HNO3, when inhaled in vapor phase, may adversely impact upon pulmonary health by affecting target sites throughout the lungs, and that inhalation of an HNO3/O-3 mixture can produce synergistic interaction in affecting some biological parameters

The immune defence mechanisms of fish seem to be related and similarly competent to those of mammals. Because of this, there is an increased interest in the immune responses of fish as models for higher vertebrates in immunological/immunotoxicological studies. Macrophages (M phi), phagocytic cells of the mammalian and teleost immune system which reside in tissues, represent a quiescent population of cells. However, upon stimulation, alterations in the physiology of these resident M phi occur which can be defined in terms of activation. This study was undertaken to determine whether biological markers used to assess mammalian M phi activation are applicable for use with fish M phi. Cells were recovered from the peritoneal cavity of non-injected and Aeromonas salmonicida-injected fish, and differences between resident and elicited M phi were evaluated with respect to protein content, phagocytic competence, enzyme activities and hydrogen peroxide production. Results demonstrate that biological markers used to assess mammalian M phi activation, with the exception of acid phosphatase activity, can be used to characterize the activation state of trout M phi, and that the activation process in both fish and mammals may occur by similar mechanism(s)

Treatment of cultured mouse macrophages with either of two different vanadium compounds was shown to affect the production/release of two major immunoregulatory cytokines. The pentavalent vanadium compound ammonium metavanadate was shown previously to disrupt cell-mediated immunity at the earliest stages of an in vivo anti-Listerial response, in that mice treated with vanadium displayed decreased accessory cell recruitment and numbers of activated macrophages at infection sites. To determine whether these effects were due to vanadium-induced alterations in the production of biologically-active mediators, mouse macrophage-like WEHI-3 cells were treated in vitro with ammonium metavanadate or vanadium pentoxide prior to stimulation with lipopolysaccharide endotoxin (LPS). After stimulation, monokine (tumor necrosis factor-alpha and interleukin-1) and prostaglandin E2 (PGE2) activities were assessed. Both vanadium compounds decreased recovered monokine activities; measured TNF alpha concentrations were also reduced. Spontaneous release of the IL-1/TNF-regulating prostanoid PGE2 was significantly increased by the highest concentration of vanadate tested, although LPS-stimulated PGE2 production was unaffected by either compound. These results indicate that, in vitro, pentavalent vanadium can interfere with immunoregulatory mediators critical for maintaining host immunocompetence

Lead, an immunomodulator and potential human carcinogen, is a major airborne pollutant in industrial environments which poses a serious threat to human health. Despite the wide-spread occurrence of respirable lead particles in the air, and the potential human health risks, effects associated with inhalation of particulate lead on the the lung have been poorly studied. This study was performed to determine whether inhalation of particulate lead oxide (PbO), at a concentration below the currently acceptable air lead standard for occupational exposure, disrupts macrophage (M phi) functions important for maintaining pulmonary immunocompetence. These functions include phagocytosis, production of reactive oxygen intermediates, and the biological activity of tumor necrosis factor-alpha (TNF-alpha). Rabbits exposed to PbO at 30 micrograms/m3 for 4 days (3 hr/day) were sacrificed and their lungs lavaged immediately, 24 hr, and 72 hr after the final exposure. Lactate dehydrogenase (a marker of lung cell damage) and lysozyme activity (a marker of lysosome permeability), measured in the lavage fluid, were significantly increased 24 and 72 hr after exposure. PbO produced neutrophil infiltration nor effects on M phi viability or total numbers. Effects on M phi functions were as follows. Phagocytic uptake of latex particles was reduced with increasing post-exposure time reaching a maximum inhibition at 72 hr. Inhalation of PbO enhanced hydrogen peroxide (H2O2) and superoxide anion radical (O2-) production in a time-dependent manner; effects on H2O2 began at 24 hr and were persistent up to 72 hr. Effects on TNF-alpha release/activity appeared earliest and were persistent up to 72 hr. Immediately and 24 hr after exposure, lipopolysaccharide-stimulated activity of TNF-alpha was depressed by 62 and 50%, respectively; after 72 hr, TNF-alpha release was significantly enhanced compared to control levels. Results demonstrate that the lung is a sensitive target for the toxic effects of inhaled lead. This study provides the first evidence that inhalation of particulate lead, at an occupationally relevant concentration, and in the absence of elevated blood lead levels, alters pulmonary M phi functions critical for lung defense against inhaled antigens. Our findings may have important implications for human health and should be considered when evaluating the health risks associated with inhaled lead

There is considerable interest in the potential health effects resulting from inhalation of acidic aerosols. However, except for well documented irritant effects and acid-induced changes in lung clearance function, other potential health effects have not been well defined. This study was designed to provide further insight regarding the relationship of sulfuric acid aerosol to the pathogenesis of respiratory disease by describing the effects of inhaled acid on the release and/or activity of biologically active mediators critical for maintaining pulmonary immunocompetence and resistance against infectious diseases. Results of this study demonstrated that a single inhalation exposure of rabbits to environmentally relevant and higher concentrations of sulfuric acid depresses the release/activity of lipopolysaccharide-stimulated tumor necrosis factor-alpha and also reduces the ability of pulmonary macrophages to produce superoxide anion radical in response to opsonised zymosan. These findings should be considered when evaluating the health risks associated with sulfuric acid exposure