Citation:

Henriquez, A., S. Snow, M. Schladweiler, C. Miller, J. Dye, A. Ledbetter, J. Richards, M. Hargrove, W. Williams, AND U. Kodavanti. Beta-2 adrenergic and glucocorticoid receptor agonists modulate ozone-induced pulmonary protein leakage and inflammation in healthy and adrenalectomized rats. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 166(2):288-305, (2018). https://doi.org/10.1093/toxsci/kfy198

Impact/Purpose:

The goal of the study was to understand the role of neuroendocrine axes activation and adrenergic and steroid receptors in mediation air pollution health effects. These data provide a potential mechanistic link for the epidemiological evidence that air pollution effects are exacerbated in those socioeconomically disadvantaged communities with high levels of psychosocial stresses and high levels of circulating stress hormones. Furthermore, this study may suggest that the pulmonary effects of air pollutants might be exacerbated in asthmatics patients receiving bronchodilators with or without immunosuppressant steroids, since air pollutants increase levels of circulating stress hormones.

Description:

We have shown that acute ozone inhalation activates sympathetic-adrenal-medullary and hypothalamus-pituitary-adrenal stress axes, and adrenalectomy (AD) inhibits ozone-induced lung injury and inflammation. Therefore, we hypothesized that stress hormone receptor agonists (β2 adrenergic-β2AR and glucocorticoid-GR) will restore the ozone injury phenotype in AD, while exacerbating effects in sham-surgery (SH) rats. Male Wistar Kyoto rats that underwent SH or AD were treated with vehicles (saline+corn oil) or β2AR agonist clenbuterol (CLEN, 0.2 mg/kg, i.p.) + GR agonist dexamethasone (DEX, 2 mg/kg, s.c.) for 1-day and immediately prior to each day of exposure to filtered-air or ozone (0.8 ppm, 4hr/day for 1- or 2-days). Ozone-induced increases in PenH and peak-expiratory flow were exacerbated in CLEN+DEX-treated SH and AD rats. CLEN+DEX affected breath waveform in all rats. Ozone exposure in vehicle-treated SH rats increased bronchoalveolar lavage fluid (BALF) protein, N-acetyl glucosaminidase activity (macrophage activation), neutrophils, and lung cytokine expression while reducing circulating lymphocyte subpopulations. AD reduced these ozone effects in vehicle-treated rats. At the doses used herein, CLEN+DEX treatment reversed the protection offered by AD and exacerbated most ozone-induced lung effects while diminishing circulating lymphocytes. CLEN+DEX in air-exposed SH rats also induced marked protein leakage and reduced circulating lymphocytes but did not increase BALF neutrophils. In conclusion, circulating stress hormones and their receptors mediate ozone-induced vascular leakage and inflammatory cell trafficking to the lung. Those receiving β2AR and GR agonists for chronic pulmonary diseases, or with increased circulating stress hormones due to psychosocial stresses, might have altered sensitivity to air pollution.

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