Faculty Bibliography

A symposium entitled Alterations in Cytokine Receptors by Xenobiotics was held at the 37th Annual Meeting of the Society of Toxicology (SOT) in Seattle, Washington. The symposium was sponsored by the Immunotoxicology Specialty Section of SOT and was designed to present information on the effect of several different classes of xenobiotics on various aspects of receptor function (i.e., post-receptor signal transduction of receptor expression), or the involvement of cytokine receptors in the action of the toxicant under consideration. This symposium brought together scientists in the area of receptor immunobiology whose expertise in receptor modulation encompassed those major signaling agents involved in the normal immune response, i.e., proinflammatory cytokines, chemokines, interleukins, and interferons. The following is a summary of each of the individual presentations

Soluble and insoluble hexavalent chromium (Cr6+) agents are concomitantly released with ozone (O3) during welding. Although pulmonary/immunologic implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate immunomodulatory effects of inhaled Cr6+, F-344 rats were exposed for 5 h/day, 5 days/week for 2 or 4 weeks to atmospheres containing soluble potassium chromate (K2CrO4) or insoluble barium chromate (BaCrO4), each alone at 360 micrograms Cr/m3 or in combination with 0.3 ppm O3. One day after the final exposure, rats were euthanized, their lungs were lavaged, and pulmonary macrophages (PAM) were recovered for assessment of basal and inducible functions. Rats inhaling K2CrO4-containing atmospheres had greater levels of total recoverable cells, neutrophils, and monocytes in bronchopulmonary lavage compared to rats exposed to insoluble Cr6+ atmospheres, O3 alone, or air; these rats also had a reduced percentage of PAM, although total PAM levels remained unaffected. Although Cr exposure-related changes in PAM functionality were evident, any dependence upon Cr solubility was variable. K2CrO4-containing atmospheres modulated PAM-inducible interleukins-1 and -6, and tumor necrosis factor-alpha production to a greater degree than those containing BaCrO4. Conversely, BaCrO4-containing atmospheres affected PAM basal nitric oxide production and interferon-gamma-primed/zymosan-stimulated reactive oxygen intermediate production to a greater extent than did those containing K2CrO4. In none of the PAM assays did co-inhalation of O3 result in a modulation of the effects obtained with either Cr6+ compound itself. The results indicate that, while immunomodulatory effects of inhaled Cr6+ upon PAM are related to particle solubility, the co-inhalation of O3 apparently does not cause further modifications of the metal-induced effects.

Soluble and insoluble chromium (Cr) agents are concomitantly released with ozone (O-3) during welding. Although pulmonary implications from exposure to each agent individually have been investigated, the effects from simultaneous exposure, as occurs under actual working conditions, are unclear. To investigate the retention/distribution of inhaled Cr, male F-344 rats were exposed nose-only to atmospheres containing soluble potassium chromate (K2CrO4) or O-3, either alone or in combination, at 360 mu g Cr/m(3) and 0.3 ppm O-3. In a second phase of the study, insoluble barium chromate (BaCrO4) was used in place of K2CrO4. Rats were exposed for 5 h/day, 5 days/wk for 2 or 4 wk. One day after the final exposure, rats were euthanized and their lungs either removed intact or lavaged for quantitation of tissue-, lavaged cell-, and acellular lavage fluid-associated Cr. In general, rats inhaling insoluble Cr had greater total lung Cr burdens than did rats exposed to soluble Cr. Simultaneous inhalation of O-3 and K2CrO4 led to reduced lung Cr levels compared to those in rats receiving K2CrO4 only; with BaCrO4 coexposure to O-3 resulted in increased lung BaCrO, levels compared to BaCrO3 alone. Particle solubility also affected Cr levels in lavageable cells, with those from rats inhaling BaCrO, alone or BaCrO4 + O-3 consistently having greater burdens than their K2CrO4 counterparts; the presence of O-3 itself had no effect upon cell Cr levels when either compound was used. Solubility-dependent differences were also apparent in acellular lavage fluid, with Cr levels initially being greater in fluids from rats inhaling K2CrO4 alone; as exposures continued, these burdens became greater in the rats inhaling BaCrO4 alone. Although inhalation of either Cr/O-3 mixture yielded significant differences in fluid Cr levels, the presence of 4 did lead to reductions in levels compared to those in rats inhaling either Cr agent alone. In postlavage lung tissue, there were time-dependent increases in Cr levels in rats from all exposure groups; however, the most dramatic increase occurred with rats exposed to BaCrO4 + O-3. Lastly, while significant solubility-dependent differences in the relative distribution of Cr among the three pulmonary compartments were discerned, a specific effect attributable to O-3 itself was not evident. The results of this study indicate that Cr retention and distribution within the lungs, as well as any effect from coexposure to O-3, are modulated by the solubility of the inhaled Cr particles

Hosts exposed to vanadium (V) display a subsequent decrease in their resistance to infectious microorganisms. Our earlier studies with rats inhaling occupationally relevant levels of V (as, ammonium metavanadate, NH4VO3) indicated that several nascent/inducible functions of pulmonary macrophages (PAM) were reduced. In the present study, V-exposed rats were examined to determine whether some of the same effects might also occur in situ. Rats were exposed nose-only to air or 2 mg V/m3 (as NH4VO3) for 8 h/d for 4 d, followed, 24 h later, by intratracheal (it) instillation of polyinosinic:polycytidilic acid (polyl:C) or saline. Analysis of lavaged lung cells/fluids after polyl:C instillation indicated that total lavageable cell/neutrophil numbers and protein levels, while significantly elevated in both exposure groups (as well as in saline-treated V-exposed rats), were always greater in V-exposed hosts. Exposure to V also affected the inducible production of interleukin 6 (IL-6) and interferon gamma (IFN gamma), but apparently not that of tumor necrosis factor-alpha (TNF alpha) or IL-1. Although polyl:C induced significant increases in lavage fluid IL-6 and IFN gamma levels in both exposure groups, levels were greater in V-exposed rats. If calculated with respect to total lavaged protein, however, V-exposed rats produced significantly less cytokine. Following polyl:C instillation, there were no marked exposure-related differences in basal or stimulated superoxide anion production by pooled lavaged cells or PAM specifically. With V-exposed rats, pooled cells recovered 24 h after saline instillation displayed reduced production (in both cases) compared to the air control cells; PAM-specific production was affected only after stimulation. In both exposure groups, polyl:C caused decreased superoxide production in recovered cells. Though less apparent with pooled cells, there was a time post polyl:C instillation-dependent decrease in stimulated PAM-specific superoxide production; this effect was greater in PAM from V-exposed rats than in PAM from air controls. Phagocytic activity of PAM from rats in both exposure groups was significantly increased by polyl:C instillation, although total activity in cells obtained from V-exposed rats was always significantly lower compared to air control cells. Our results indicate that short-term, repeated inhalation of occupationally relevant levels of V by rats modulates pulmonary immunocompetence. Modified cytokine production and PAM functionality in response to biological response modifiers (such as lipopolysaccharide, IFN gamma, or polyl:C) may be, at least in part, responsible for the increases in bronchopulmonary disease in humans occupationally exposed to V