Health implications of neuroendocrine stress responses to air pollutants: resiliency vs. disease
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The autonomic nervous system serves to recognize stressors and to rapidly and precisely direct local and peripheral biologic responses. These coordinated hypothalamic neuroendocrine stress responses serve to provide reversible systemic homeostatic adjustments as needed. Although the importance of neuroendocrine stress responses in health and disease is well established, the implications of such changes in eliciting adverse health outcomes related to air pollutant exposures remain unclear. Our studies show that, in both rodents and humans, inhalation of oxidant and irritant air pollutants produce local, peripheral, and central effects, including widespread, largely transient changes in metabolic and immunological processes. We have demonstrated that these tightly regulated responses are mediated via neuroendocrine pathways. Key mediators include release of adrenal-derived stress hormones, such as catecholamines and glucocorticoids, and subsequent activation of adrenergic and glucocorticoid receptors across multiple organs. Using interventional strategies to manipulate stress hormone responses in animal models, we have further demonstrated that organ-specific hormone receptor subtype distribution serves, in part, to explain the diverse pulmonary and extra-pulmonary effects of air pollution exposure. In addition, we have demonstrated that systemic release of adrenal-derived hormones is necessary to produce local lung injury and inflammation. With depletion of circulating adrenal hormones, the central nervous system appears unable to properly recognize stress signals and thus produce adaptive lung responses to inhaled pollutants. Moreover, we have shown that the dynamicity of the ozone-induced stress responses provides contextual evidence of causality for immune and metabolic effects. Our data further suggest that resiliency, in terms of the body’s ability to adapt to repeated exposure to ozone, is established in part through the glucocorticoid stress response pathway. Proteins that regulate glucocorticoid activity seem to play critical roles in the plasticity; conversely, the lack thereof may promote disease states. Evidence of the importance of efficient and plastic stress responses are provided by animal models of psychosocial stress, insulin resistance/diabetes, and cellular senescence – all of which demonstrate that rigidity or weakness in stress responses may contribute to organ-specific pathologies. Collectively, our studies: (1) reveal that the neuroendocrine system is an integral contributor to the observed health effects of air pollutants and (2) provide biological plausibility for the diverse systemic health effects associated with air pollution exposure. Such data are needed to better understand and address human resiliency vs. susceptibility variations to environmental exposures. Our ongoing research seeks to address the role of integrated stress responses towards psychosocial and toxicant stressors including increasing ambient temperatures. (This abstract does not reflect the U.S. EPA policy).