Journal of Toxicology and Environmental Health
ISSN: 0098-4108 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/uteh19
Immunomodulating effects of ozone on macrophage functions important for tumor surveillance and host defense Judith T. Zelikoff , Guat‐Lian Kraemer , Marie Claire Vogel & Richard B. Schlesinger To cite this article: Judith T. Zelikoff , Guat‐Lian Kraemer , Marie Claire Vogel & Richard B. Schlesinger (1991) Immunomodulating effects of ozone on macrophage functions important for tumor surveillance and host defense, Journal of Toxicology and Environmental Health, 34:4, 449-467, DOI: 10.1080/15287399109531582 To link to this article: http://dx.doi.org/10.1080/15287399109531582
Published online: 20 Oct 2009.
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Date: 06 November 2015, At: 18:00
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IMMUNOMODULATING EFFECTS OF OZONE ON MACROPHAGE FUNCTIONS IMPORTANT FOR TUMOR SURVEILLANCE AND HOST DEFENSE Judith T. Zelikoff, Guat-Lian Kraemer, Marie Claire Vogel, Richard B. Schlesinger Institute of Environmental Medicine, New York University Medical Center, New York, New York
Ozone (O3) is a toxic gaseous pollutant that has been implicated in laboratory studies as a potential lung carcinogen or cocarcinogen in mice. To begin to assess the role of altered macrophage (Mø) responses as a possible mechanism by which O3 may influence carcinogenesis, we examined the effects of repeated in vivo O3 exposure on pulmonary Mø functional and biochemical activities deemed important in tumor surveillance, and host defense in general. Rabbits were exposed by inhalation to 1 ppm O3 for 3 d (2 h/d) and the lungs were lavaged immediately (t0) and 24 h (t24) after exposure. Results demonstrate that O3 reduced Mø viability and increased the number of neutrophils collected immediately after exposure. Effects of O3 on Mø movement were as follows: random migration was depressed immediately after the final exposure and chemotactic migration increased after 24 h. Mø-mediated cytotoxicity toward xenogeneic tumor cells in vitro was significantly depressed, compared to control, immediately and 24 h after O3 exposure. Release of cytotoxic factors deemed important for mediating tumor cell destruction was also assessed. Spontaneous and stimulated production of tumor necrosis factor, as measured by cytotoxicity toward LM cells (a clone of L-929 mouse fibrobtasts), was unaffected by exposure to O3. Zymosan-stimulated production of superoxide anion radical (·O-2) was depressed at t0 and increased at t24; however, no significant effects on H2O2 production by resting or zymosan-stimulated Mø were observed at either time interval. Inhaled toxicants such as O3, which can compromise Mø functions important in tumor surveillance, could potentially alter host susceptibility to pulmonary cancer. Results of this study have important implications for human health, and demonstrate the need for further studies examining the carcinogenic/cocarcinogenic potential of O3.
INTRODUCTION Ozone (O3), one of the most toxicologically significant air pollutants and a major constituent of photochemical smog (National Research Council, 1977), poses a threat to human health (Stockinger, 1965; Mehlman and Borek, 1987). In laboratory studies, exposure to O3 at concentrations as low as 0.12 ppm [the National Ambient Air Quality Standard (U.S. EPA, 1978)] may cause inflammation (Guth et al., 1986), cell This research was supported by NIEHS grant ES04627, and is part of a Center Program supported by NIEHS (ES00260). Requests for reprints should be sent to Judith T. Zelikoff, Institute of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016.
449 Journal of Toxicology and Environmental Health, 34:449-467, 1991 Copyright © 1991 by Hemisphere Publishing Corporation
Downloaded by [NUS National University of Singapore] at 18:00 06 November 2015
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J. T. ZELIKOFF ET AL.
damage (Last et al., 1979; Lum et al., 1983), and compromise host resistance and pulmonary defenses (Coffin et al., 1968; Ehrlich, 1980). In addition, O3 has been implicated as a possible lung carcinogen, or more likely a cocarcinogen, at inhaled concentrations similar to those encountered in moderate to severe smog episodes (Last et al., 1987). Although the carcinogenic/cocarcinogenic potential of O3 may be questionable (Witschi, 1988), evidence from a number of in vitro and in vivo laboratory studies appears to suggest that inhalation of O3 can modify tumorigenesis (Werthamer et al., 1970; Penha and Werthamer, 1974; Hassett et al., 1985; Witschi, 1985; Borek et al., 1986; Last et al., 1987). For example, Last et al. (1987) observed a significant increase in lung tumor multiplicity in mice exposed by inhalation to 0.8 ppm O3 for 18 wk. In addition, in vitro exposure to O3 (5 ppm for 5 min) induced neoplastic transformation of hamster embryo cells and mouse fibroblast cultures and, in combination with ionizing radiation, acted synergistically to enhance cell transformation (Borek et al., 1986). Although effects on free radical production have been suggested as a possible mechanism by which O3 may modify carcinogenesis (Borek et al., 1986), the exact mechanism(s) remains to be elucidated. Given the ubiquitous nature of O3 and the large number of people exposed to relatively high concentrations, a better understanding of its carcinogenic potential is clearly needed. O3 has been shown to mediate host defense mechanisms by altering the pulmonary and extrapulmonary immune responses of experimental animals (Jakab and Hmeileski, 1988; Burleson et al., 1989) and humans (Harder et al., 1990). Macrophages (Mtf>), the first line of defense in the deep lung, are compromised by in vivo and in vitro exposure to O3 (Amoruso et al., 1981; Kimura and Goldstein, 1981; Driscoll et al., 1987). Single exposure of rabbits to O3 at 0.1 ppm resulted in depressed M phagocytic activity immediately and 24 h after exposure, while, in the same study, repeated exposure decreased the numbers of phagocytically active cells (Driscoll et al., 1987). In addition, acute exposure to O3 has been shown to increase arachidonic acid metabolism by M (Zelikoff et al., 1989) and to decrease intracellular killing of inhaled infectious organisms (Coffin et al., 1968); substrate attachment (Driscoll et al., 1987); random mobility (McAllen et al., 1981); lysosomal enzyme activity (Dillard et al., 1972; Kimura and Goldstein, 1981); and superoxide anion radical (•O2~) production (Amoruso et al., 1981; Ryer-Powder et al., 1988). These previous studies have demonstrated the potential for inhaled O3 to impair M function; however, there is a paucity of information concerning the effects of repeated exposures, particularly on those M0 activities associated with tumor surveillance. To begin to evaluate the role of altered M
ISSN: 0098-4108 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/uteh19
Immunomodulating effects of ozone on macrophage functions important for tumor surveillance and host defense Judith T. Zelikoff , Guat‐Lian Kraemer , Marie Claire Vogel & Richard B. Schlesinger To cite this article: Judith T. Zelikoff , Guat‐Lian Kraemer , Marie Claire Vogel & Richard B. Schlesinger (1991) Immunomodulating effects of ozone on macrophage functions important for tumor surveillance and host defense, Journal of Toxicology and Environmental Health, 34:4, 449-467, DOI: 10.1080/15287399109531582 To link to this article: http://dx.doi.org/10.1080/15287399109531582
Published online: 20 Oct 2009.
Submit your article to this journal
Article views: 4
View related articles
Citing articles: 16 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=uteh20 Download by: [NUS National University of Singapore]
Date: 06 November 2015, At: 18:00
Downloaded by [NUS National University of Singapore] at 18:00 06 November 2015
IMMUNOMODULATING EFFECTS OF OZONE ON MACROPHAGE FUNCTIONS IMPORTANT FOR TUMOR SURVEILLANCE AND HOST DEFENSE Judith T. Zelikoff, Guat-Lian Kraemer, Marie Claire Vogel, Richard B. Schlesinger Institute of Environmental Medicine, New York University Medical Center, New York, New York
Ozone (O3) is a toxic gaseous pollutant that has been implicated in laboratory studies as a potential lung carcinogen or cocarcinogen in mice. To begin to assess the role of altered macrophage (Mø) responses as a possible mechanism by which O3 may influence carcinogenesis, we examined the effects of repeated in vivo O3 exposure on pulmonary Mø functional and biochemical activities deemed important in tumor surveillance, and host defense in general. Rabbits were exposed by inhalation to 1 ppm O3 for 3 d (2 h/d) and the lungs were lavaged immediately (t0) and 24 h (t24) after exposure. Results demonstrate that O3 reduced Mø viability and increased the number of neutrophils collected immediately after exposure. Effects of O3 on Mø movement were as follows: random migration was depressed immediately after the final exposure and chemotactic migration increased after 24 h. Mø-mediated cytotoxicity toward xenogeneic tumor cells in vitro was significantly depressed, compared to control, immediately and 24 h after O3 exposure. Release of cytotoxic factors deemed important for mediating tumor cell destruction was also assessed. Spontaneous and stimulated production of tumor necrosis factor, as measured by cytotoxicity toward LM cells (a clone of L-929 mouse fibrobtasts), was unaffected by exposure to O3. Zymosan-stimulated production of superoxide anion radical (·O-2) was depressed at t0 and increased at t24; however, no significant effects on H2O2 production by resting or zymosan-stimulated Mø were observed at either time interval. Inhaled toxicants such as O3, which can compromise Mø functions important in tumor surveillance, could potentially alter host susceptibility to pulmonary cancer. Results of this study have important implications for human health, and demonstrate the need for further studies examining the carcinogenic/cocarcinogenic potential of O3.
INTRODUCTION Ozone (O3), one of the most toxicologically significant air pollutants and a major constituent of photochemical smog (National Research Council, 1977), poses a threat to human health (Stockinger, 1965; Mehlman and Borek, 1987). In laboratory studies, exposure to O3 at concentrations as low as 0.12 ppm [the National Ambient Air Quality Standard (U.S. EPA, 1978)] may cause inflammation (Guth et al., 1986), cell This research was supported by NIEHS grant ES04627, and is part of a Center Program supported by NIEHS (ES00260). Requests for reprints should be sent to Judith T. Zelikoff, Institute of Environmental Medicine, New York University Medical Center, 550 First Avenue, New York, NY 10016.
449 Journal of Toxicology and Environmental Health, 34:449-467, 1991 Copyright © 1991 by Hemisphere Publishing Corporation
Downloaded by [NUS National University of Singapore] at 18:00 06 November 2015
450
J. T. ZELIKOFF ET AL.
damage (Last et al., 1979; Lum et al., 1983), and compromise host resistance and pulmonary defenses (Coffin et al., 1968; Ehrlich, 1980). In addition, O3 has been implicated as a possible lung carcinogen, or more likely a cocarcinogen, at inhaled concentrations similar to those encountered in moderate to severe smog episodes (Last et al., 1987). Although the carcinogenic/cocarcinogenic potential of O3 may be questionable (Witschi, 1988), evidence from a number of in vitro and in vivo laboratory studies appears to suggest that inhalation of O3 can modify tumorigenesis (Werthamer et al., 1970; Penha and Werthamer, 1974; Hassett et al., 1985; Witschi, 1985; Borek et al., 1986; Last et al., 1987). For example, Last et al. (1987) observed a significant increase in lung tumor multiplicity in mice exposed by inhalation to 0.8 ppm O3 for 18 wk. In addition, in vitro exposure to O3 (5 ppm for 5 min) induced neoplastic transformation of hamster embryo cells and mouse fibroblast cultures and, in combination with ionizing radiation, acted synergistically to enhance cell transformation (Borek et al., 1986). Although effects on free radical production have been suggested as a possible mechanism by which O3 may modify carcinogenesis (Borek et al., 1986), the exact mechanism(s) remains to be elucidated. Given the ubiquitous nature of O3 and the large number of people exposed to relatively high concentrations, a better understanding of its carcinogenic potential is clearly needed. O3 has been shown to mediate host defense mechanisms by altering the pulmonary and extrapulmonary immune responses of experimental animals (Jakab and Hmeileski, 1988; Burleson et al., 1989) and humans (Harder et al., 1990). Macrophages (Mtf>), the first line of defense in the deep lung, are compromised by in vivo and in vitro exposure to O3 (Amoruso et al., 1981; Kimura and Goldstein, 1981; Driscoll et al., 1987). Single exposure of rabbits to O3 at 0.1 ppm resulted in depressed M phagocytic activity immediately and 24 h after exposure, while, in the same study, repeated exposure decreased the numbers of phagocytically active cells (Driscoll et al., 1987). In addition, acute exposure to O3 has been shown to increase arachidonic acid metabolism by M (Zelikoff et al., 1989) and to decrease intracellular killing of inhaled infectious organisms (Coffin et al., 1968); substrate attachment (Driscoll et al., 1987); random mobility (McAllen et al., 1981); lysosomal enzyme activity (Dillard et al., 1972; Kimura and Goldstein, 1981); and superoxide anion radical (•O2~) production (Amoruso et al., 1981; Ryer-Powder et al., 1988). These previous studies have demonstrated the potential for inhaled O3 to impair M function; however, there is a paucity of information concerning the effects of repeated exposures, particularly on those M0 activities associated with tumor surveillance. To begin to evaluate the role of altered M
