Neuroendocrine aspect of ozone adaptation at lung and systemic level: The influence of one-month glucocorticoid pretreatment
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Ozone-induced lung injury and inflammation dissipate despite continuation of exposure for 3 or more days; however, the mechanisms of adaptation/habituation remain unclear. We have shown that ozone-induced pulmonary and systemic effects are mediated through reversible neuroendocrine activation and adrenal release of the stress hormones corticosterone and epinephrine. Here, we hypothesized that adaptation from ozone-induced pulmonary and systemic effects is associated with diminution of neuroendocrine activation and reduced glucocorticoid activity. Male Wistar Kyoto rats (12-week old) were injected daily with vehicle (VEH, saline) or a therapeutically relevant dose of dexamethasone sulfate (DEX, 0.01 mg/kg/day; i.p.) for 1-month to induce glucocorticoid resistance and to determine if reduced glucocorticoid effectiveness is associated with diminution of ozone adaptation response. Saline or DEX-treated rats were exposed to air or 0.8 ppm ozone, 4 hours/day for 2 or 4 days (D+2 or D+4) to assess impacts of acute exposure and characterize adaptation responses, respectively. Acute ozone exposure (D+2) increased lung lavage fluid protein and neutrophils, and decreased circulating lymphocytes; effects that were not evident in D+4. Likewise, ozone-induced hyperglycemia, glucose intolerance and inhibition of beta-cell insulin release in D+2 were attenuated in D+4. This adaptation was modestly attenuated in DEX pretreated rats. Ozone-induced depletion of circulating prolactin, thyroid stimulating hormone, and luteinizing hormone after 2-day exposure were not observed at D+4 suggesting central mediation of adaptation. Genes involved in epinephrine synthesis were similarly induced in adrenals after ozone exposure at D+2 and D+4, however, those involved in glucocorticoid biosynthesis were induced only after D+2 but not D+4 exposure, suggesting involvement of reduced glucocorticoid synthesis in mediating ozone adaptation. These results suggest that ozone adaptation likely involves the lack of hypothalamic-pituitary-adrenal axis activation and glucocorticoid production. (Does not reflect US EPA policy)