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Stressed lungs: unveiling the role of circulating stress hormones in ozone-induced lung injury and inflammation
Citation:
Henriquez, A., S. Snow, D. Miller, A. Ledbetter, M. Schladweiler, J. Richards, AND U. Kodavanti. Stressed lungs: unveiling the role of circulating stress hormones in ozone-induced lung injury and inflammation. Society of Toxicology, Baltimore, MD, March 12 - 16, 2017.
Impact/Purpose:
Our recent work demonstrated that circulating stress hormones, epinephrine and corticosterone/cortisol, are involved in mediating ozone pulmonary effects through the activation of hypothalamus-pituitary-adrenal axis. In this study we show that the stress hormones released after ozone exposure modulate not only systemic but also pulmonary injury/inflammation effects through adrenergic and glucocorticoid receptors. These studies bring forth a new perspective to the mechanisms of inhaled pollutant-induced health effects.
Description:
Our recent work demonstrated that circulating stress hormones, epinephrine and corticosterone/cortisol, are involved in mediating ozone pulmonary effects through the activation of hypothalamus-pituitary-adrenal (HPA) axis. Adrenalectomy in Wistar Kyoto (WKY) rats diminished circulating stress hormones, and prevented ozone-induced glucose intolerance and respiratory effects suggesting a pivotal role of these hormones in pulmonary and systemic effects following ozone exposure. In our first experiment, we retrospectively performed mRNA sequencing of lungs from sham surgery (SHAM) and adrenalectomized (ADREX) WKY rats exposed to air or ozone (1 ppm) 4h/day for 1 or 2 days. Ozone led to upregulation of corticosterone-responsive genes and pathways known to be induced by ozone such as acute phase response, NRF2-mediated oxidative stress and PI3-AKT in SHAM but not ADREX rats. In a follow up study, we examined the role of adrenergic and steroid receptors in mediating systemic and pulmonary effects of ozone through release of stress hormones. Male 12-week old WKY rats were pretreated daily (6 days prior to and during exposure) with respective vehicles, mifepristone (MF; a glucocorticoid receptor [GR] antagonist, 30 mg/kg, s.c.), propranolol (PR; an α/β adrenergic receptor [AR] antagonist, 10 mg/kg, i.p.), or both drugs (MF+PR). After treatment, rats were exposed to air or ozone (0.8 ppm) 4h/day for 1 or 2 days. GR blocking by MF treatment resulted in the decrease of ozone-induced vascular leakage and macrophage activation in the lungs, while systemically prevented white blood cell depletion and glucose intolerance. α/β AR blocking by PR treatment promoted the reduction of ozone-induced neutrophilia and vascular leakage in the lungs as well as hyperglycemia. MF+PR prevented all of the aforementioned ozone-induced responses, suggesting that epinephrine and corticosterone release mediate specific and sometimes overlapping responses, but synergistically regulate pulmonary and systemic effects induced by ozone. In conclusion, the stress hormones released after ozone exposure modulate not only systemic but also pulmonary injury/inflammation effects through adrenergic and glucocorticoid receptors. These studies bring forth a new perspective to the mechanisms of inhaled pollutant-induced health effects. (Does not reflect the US EPA policy).