OZONE-INDUCED LUNG INJURY AND INFLAMMATION ARE MODULATED BY CIRCULATING STRESS HORMONES

Abstract

Air pollution has been associated with a wide-range of health effects. Pulmonary effects of acute ozone inhalation have been widely characterized in humans and animals. These include decrements in lung function, neutrophilic inflammation, and increased epithelial permeability. Ozone has also been shown to induce cardiovascular, neurological, metabolic and immune effects. It is believed that the “spillover” of bioactive lung-derived molecules to the circulation is responsible for extra-pulmonary effects of ozone. Our lab has recently shown that ozone, in addition to pulmonary effects, induces widespread systemic metabolic and immune effects in rats and humans. Importantly, these systemic changes are associated with increased circulating stress hormones, such as corticosterone and epinephrine, which are known to be involved in the “fight-or-flight” response. In our intervention study, we noted that extra-pulmonary but also pulmonary effects of ozone were dramatically reduced in adrenalectomized rats, indicating that circulating stress hormones contributed to all ozone effects. Since neuroendocrine stress response targets two essential survival processes, metabolic and immune, in this project we characterized in detail how pulmonary immune response and injury are influenced by the enhanced release of circulating stress hormones after ozone inhalation. In the first study, we demonstrated that the circulating stress hormones act at a transcriptional level to change gene expression after ozone exposure since global pulmonary gene changes induced by ozone exposure were attenuated in adrenalectomized rats. These ozone-induced expression changes depicted similarity to those predicted by glucocorticoid and adrenergic receptor activation, suggesting the contribution of stress hormones in mediating transcriptional effects. In our second round of studies, we demonstrated that by blocking endogenous stress hormone signaling adrenergic and glucocorticoid receptor antagonists, ozone-induced lung injury and inflammation were reduced in a receptor-specific manner (i.e. β adrenergic blocker inhibited lung neutrophilia while glucocorticoid receptor blocker caused lymphopenia). These results validated the role of stress hormones as bona fide circulating mediators acting directly on the lungs, and provided insights on the role of corticosterone versus epinephrine as individual modulators of ozone effects. In the third study, we combined surgical and pharmacological approaches, and demonstrated that the ozone-injury and inflammation phenotypes can be restored in adrenalectomized rats by providing exogenous glucocorticoid and β-adrenergic receptor agonists. These findings demonstrated unequivocally that stress hormones are the key systemic mediators of ozone-induced lung injury and innate immune effects. Thus, we show that circulating stress hormones, released from adrenal glands in response to ozone exposure, through their effects on β-adrenergic and glucocorticoid receptors, mediate most known pulmonary injury and innate immune effects. Our studies highlight the role of neuroendocrine stress response as a potential key regulator of air pollution health effects. Any perturbations in this neuroendocrine pathway and/or β-adrenergic and glucocorticoid receptor signaling through disease processes or the use of adrenergic or steroidal therapies, are likely to play a central role in susceptibility to air pollution health effects.Doctor of Philosoph