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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. NC SOT, RTP, NC, October 22, 2016.
Impact/Purpose:
While ozone effects in the lung have been extensively studied, the contribution of central nervous system -mediated hormonal stress response has not been examined. Our results demonstrate that hypothalamus-pituitary-adrenal-axis-mediated stress response and the resultant increases in circulating stress hormones work as circulatory mediators contributing to lung injury and inflammation following acute ozone inhalation, thus adding a new perspective to the dynamics by which air pollutants act at both the systemic and pulmonary level.
Description:
Ozone, a major component of smog generated through the interaction of light and anthropogenic emissions, induces adverse pulmonary, cardiovascular, and systemic health effects upon inhalation. It is generally accepted that ozone-induced lung injury is mediated by its interaction with lung lining components causing local oxidative changes, which then leads to cell damage and recruitment of inflammatory cells. It is postulated that the spillover of reactive intermediates and pro-inflammatory molecules from lung to systemic circulation mediates extra-pulmonary effects. However, recent work from our laboratory supports an alternative hypothesis that circulating stress hormones, such as epinephrine and corticosterone/cortisol, are involved in mediating ozone pulmonary effects. We have shown in rats and humans that ozone increases the levels of circulating stress hormones through activation of the hypothalamus- pituitary-adrenal (HPA) axis before any measurable effects are observed in the lung. The surgical removal of adrenals diminishes circulating stress hormones and at the same time, the pulmonary effects of ozone suggesting a significant contribution of these hormones in ozone-induced lung injury and inflammation. While ozone effects in the lung have been extensively studied, the contribution of central nervous system -mediated hormonal stress response has not been examined. In order to understand the signaling pathways that might be involved in ozone-induced lung injury/inflammation and the reversal of ozone effects in adrenalectomized rats, we retrospectively performed lung tissue mRNA sequencing after air or ozone exposure in rats which had undergone SHAM (control) surgery, adrenal demedullation (DEMED) or total adrenalectomy (ADREX). We observed that corticosterone-responsive genes are increased after ozone exposure in the lungs of SHAM but not ADREX and DEMED rats. By assessing ozone-induced up- or down-regulated genes using Ingenuity Pathway Analysis, we observed that the pathways known to be induced by ozone such as acute phase response, NRF2-mediated oxidative stress and PI3-AKT were induced in SHAM rats. The upregulation of the afore-mentioned pathways were prevented in DEMED or ADREX rats. In addition, key inflammatory mediator genes such as IL-6 and MIP-2, neutrophilic inflammation, and vascular protein leakage that were increased in the lungs of SHAM rats after ozone exposure were diminished in ADREX and DEMED rats, suggesting the contribution of adrenal-derived stress hormones. In a follow up study, to avoid the interference of nonspecific effects induced by the invasive surgical removal of adrenal glands, we pretreated rats with drugs antagonizing the activity of both epinephrine and corticosterone, individually or in combination, and then exposed to air or ozone. Pretreatment of rats with propranolol (an α and β adrenergic receptor antagonist) and mifespristone (a glucocorticoid receptor antagonist) markedly reduced ozone-induced neutrophilia and vascular leakage in the lungs, as well as systemic responses, similar to of the findings in ADREX rats. In conclusion, our results demonstrate that HPA-mediated stress response and the resultant increases in circulating stress hormones work as circulatory mediators contributing to lung injury and inflammation following acute ozone inhalation, thus adding a new perspective to the dynamics by which air pollutants act at both the systemic and pulmonary level. (This abstract does not reflect the views and the policy of the US EPA).