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Independent roles of beta-adrenergic and glucocorticoid receptors in systemic and pulmonary effects ozone
Citation:
Kodavanti, U., S. Snow, M. Schladweiler, C. Miller, A. Ledbetter, J. Richards, AND A. Henriquez. Independent roles of beta-adrenergic and glucocorticoid receptors in systemic and pulmonary effects ozone. Society of Toxicology - Virtual, Anaheim, CA, March 15 - 19, 2020.
Impact/Purpose:
This study examines independent roles of adrenergic and glucocorticoid receptors in mediating systemic metabolic and pulmonary effects of ozone using a strategy where adrenergic receptor is inhibited when glucocorticoid receptor is activated and vice versa.
Description:
The release of catecholamines is preceded by glucocorticoids during a stress response. We have shown that ozone inhalation produces homeostatic stressor effects through adrenergic receptor (AR) and glucocorticoid receptor (GR) activation by these adrenal-derived stress hormones. In this study, we 1) inhibited beta AR (BAR) while inducing GR or 2) inhibited GR while inducing BAR to examine the role of each receptor without the interactive effects of the other following ozone exposure. The treatment with each antagonist began 7 days prior to exposure to assure complete inhibition of receptors while agonist treatment occurred only 1-day prior. Twelve-week old male Wistar-Kyoto rats were treated daily with saline or propranolol (PROP; a non-selective BAR antagonist, 10 mg/kg, i.p.) starting at day-7 and with saline or dexamethasone sulfate (DEX; GR agonist; 0.02 mg/kg) starting at day-1 and during each day of air or 0.8-ppm ozone exposure (4h/day for 2 days). In the second experiment, rats were treated with saline or mifepristone (MIFE; GR antagonist, 30 mg/kg, s.c.) starting at day-7 and with saline or clenbuterol (CLEN; BAR¿agonist; 0.02 mg/kg) starting at day-1 and during each day of air or ozone exposure (4h/day for 2 days). DEX and PROP+DEX decreased adrenal, spleen and thymus weights in all rats. Ozone increased plasma epinephrine with minimal drug-treatment effect. DEX decreased and MIFE increased corticosterone levels. Ozone-induced increases in lung injury, protein leakage, inflammation and lavage fluid IL-6 were inhibited by PROP and exacerbated by CLEN. DEX and ozone decreased circulating lymphocytes, while MIFE and MIFE+CLEN reversed this effect. DEX exacerbated, while MIFE, PROP or MIFE+CLEN inhibited, ozone-induced hyperglycemia and glucose intolerance. Ozone inhibited glucose-induced insulin release with each drug having variable effect. In summary, 1) activating BAR, even with inhibition of GR, exacerbated ozone-induced pulmonary effects and inhibiting BAR attenuated these effects; and 2) activating GR exacerbated ozone systemic effects, even when BAR was inhibited. These data provide further insights on the independent role of BAR in pulmonary effects and roles of both BAR and GR in systemic metabolic effects of ozone. (Does not reflect the US EPA policy).