Dorsal third ventricle infusions of the alpha 2 adrenergic receptor antagonist, mianserin- which increases brain concentrations of dopamine, serotonin, and acetylcholine, or the glucocorticoid receptor antagonist, mifepristone, were performed in male WKY rats prior to acute ozone exposure at 0.8 ppm for 4 hours. This experiment was designed to target hippocampal and hypothalamic neuromodulation to determine the role of indoleamines, monoamines, and glucocorticoids in mediating the systemic and pulmonary effects to ozone exposure.

We have previously shown that neuroendocrine activation leading to increased circulating stress hormones was necessary for mediating ozone-induced lung injury and inflammation since adrenalectomy rats were protected from these ozone effects. Because adrenalectomy is invasive and also eliminates circulating mineralocorticoids along with stress hormones, one cannot rule out their contribution in diminution of ozone-induced lung effects. The goal of this study was to evaluate if agonists of stress hormone receptors β2 adrenergic receptors and glucocorticoid receptors were able to restore ozone-induced lung injury, inflammation and innate immune cell trafficking in adrenalectomy rats, and exacerbate these effects in control rats with sham surgery. Here, we reconfirmed that the pulmonary and systemic effects of ozone inhalation, characterized by vascular leakage, neutrophilic inflammation, cytokine release in the lungs and peripheral vascular lymphopenia, were significantly diminished by adrenlectomy. The treatment with a combination of β2 adrenergic receptor and glucocorticoid receptor agonists (Clenbuterol and dexamethasone) was able to restore these ozone effects in AD rats, and further exacerbate ozone-induced lung protein leakage, inflammation and lymphopenia in sham surgery rats. It was also noted that clenbuterol plus dexamethasone itself caused injury and cytokine increases in the lung. Although a variety of β2 adrenergic receptor and glucocorticoid agonists have been widely used for the treatment of chronic lung diseases, β2 adrenergic receptor agonists have been shown to exacerbate lung inflammation in asthmatics and epidemiological studies have indicated exacerbation of lung inflammation in asthmatics during increased air pollution episodes. Even though high concentrations of agonists were used, our study provides a potential causal mechanistic link between activation of stress hormone receptors in mediation of air pollution health effects, and how these effects might be exacerbated in those receiving asthma therapy. This dataset is associated with the following publication: Henriquez, A., S. Snow, M. Schladweiler, C. Miller, J. Dye, A. Ledbetter, J. Richards, M. Hargrove, W. Williams, and U. Kodavanti. Beta-2 adrenergic and glucocorticoid receptor agonists modulate ozone-induced pulmonary protein leakage and inflammation in healthy and adrenalectomized rats. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 166(2): 288-305, (2018).

This study was performed to determine the role of adrenal-derived stress hormones in mediating brain effects after ozone exposure. Sham and adrenalectomized rats were exposed to air or ozone for 4 hours and within 2 hours after exposure brain regions, hypothalamus and brainstem were isolated and circulating pituitary hormones were analyzed. Global gene expression was analysed in these two brain regions using Illumina mRNA sequencing platform and data were analyzed using various bioinformatics platforms. The resulting data are included in this manuscript. This dataset is associated with the following publication: Henriquez, A., J. House, S. Snow, C. Miller, M. Schladweiler, A. Astriab Fisher, H. Ren, M. Valdez, P. Kodavanti, and U. Kodavanti. Ozone-induced dysregulation of neuroendocrine axes requires adrenal-derived stress hormones. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 172(1): 38-50, (2019).

This dataset includes data for the manuscript in progress, Intracerebroventricular kynurenic acid modulation differentially regulates the immune and neuroendocrine stress response to acute ozone exposure. This study employed the use of kynurenic acid or the kynurenic acid synthesis inhibitor, PF-04859989 infused into the dorsal third ventricle of the brain in male WKY rats, prior to acute ozone exposure at 0.8 ppm, to evaluate the role of kynurenic acid in modulating the neuroendocrine stress response to ozone. Our results indicate that kynurenic acid may have a protective role in the brain, in attenuating the pulmonary and systemic effects of ozone exposure, perhaps through multiple mechanisms. This dataset is associated with the following publication: Rentschler, K., M.C. Schladweiler, R. Grindstaff, W. Williams, P.R. Kodavanti, D. Freeborn, L. Klein, G. Jung, D. Herr, P. Evansky, J. McKee, S. Gavett, and U. Kodavanti. Differential Effects of Intracerebroventricular Kynurenic Acid Regulation on the Inflammatory and Neuroendocrine Response to Acute Ozone Exposure. Presented at Society of Toxicology, Orlando, FL, USA, 03/16/2025 - 03/20/2025.

This data set shows high throughput gene expression assessment using RNAseq to examine how ozone-induced transcriptional changes in the lung are influenced by adrenalectomy or adrenal demedullation in rats. We have previously observed that lung injury and inflammation are diminished in adrenalectomized rats and this study was planned to understand if circulating stress hormones influence ozone transcriptional effects and what ozone-induced pathway changes might be impacted by removal of adrenal glands. This dataset is associated with the following publication: Henriquez, A., J. House, D. Miller, S. Snow, A. Fisher, H. Ren, M. Schladweiler, A. Ledbetter, F. Wright, and U. Kodavanti. Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, USA, 329: 249-258, (2017).

A manuscript describing the independent roles of beta adrenergic and glucocorticoid receptors in mediating ozone-induced pulmonary and systemic effects. This dataset is associated with the following publication: Henriquez, A., S. Snow, M.C. Schladweiler, C. Miller, and U. Kodavanti. Independent roles of beta-adrenergic and glucocorticoid receptors in systemic and pulmonary effects of ozone. INHALATION TOXICOLOGY. Taylor & Francis, Inc., Philadelphia, PA, USA, 32(4): 155-169, (2020).

A manuscript describing the independent roles of beta adrenergic and glucocorticoid receptors in mediating ozone-induced pulmonary and systemic effects. This dataset is associated with the following publication: Henriquez, A., S. Snow, M.C. Schladweiler, C. Miller, and U. Kodavanti. Independent roles of beta-adrenergic and glucocorticoid receptors in systemic and pulmonary effects of ozone. INHALATION TOXICOLOGY. Taylor & Francis, Inc., Philadelphia, PA, USA, 32(4): 155-169, (2020).

Ozone exposure induces neuroendocrine stress response, which causes lymphopenia. We hypothesized that ozone-induced increases in stress hormones will temporally follow changes in circulating granulocytes, monocytes and lymphocyte subpopulations. The goal of this study was to chronicle the changes in circulating stress hormones, cytokines, and leukocyte trafficking during 4-hour exposure to ozone. Male Wistar Kyoto rats were exposed to air or ozone (0.4 or 0.8 ppm) for 0.5, 1, 2, or 4 hours. After each time point, we assessed, circulating stress hormones and cytokines, lung gene expression, and live and apoptotic granulocytes, monocytes (classical and non-classical), and lymphocytes (B, Th and Tc) in blood, thymus and spleen using flow cytometry. This dataset is associated with the following publication: Henriquez, A., W. Williams, S. Snow, M.C. Schladweiler, C. Fisher, M. Hargrove, D. Alewel, C. Colonna, S. Gavett, C. Miller, and U. Kodavanti. The Dynamicity of Acute Ozone-Induced Systemic Leukocyte Trafficking and Adrenal-Derived Stress Hormones. TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 458(152823): 1, (2021).

Ozone exposure induces neuroendocrine stress response, which causes lymphopenia. We hypothesized that ozone-induced increases in stress hormones will temporally follow changes in circulating granulocytes, monocytes and lymphocyte subpopulations. The goal of this study was to chronicle the changes in circulating stress hormones, cytokines, and leukocyte trafficking during 4-hour exposure to ozone. Male Wistar Kyoto rats were exposed to air or ozone (0.4 or 0.8 ppm) for 0.5, 1, 2, or 4 hours. After each time point, we assessed, circulating stress hormones and cytokines, lung gene expression, and live and apoptotic granulocytes, monocytes (classical and non-classical), and lymphocytes (B, Th and Tc) in blood, thymus and spleen using flow cytometry. This dataset is associated with the following publication: Henriquez, A., W. Williams, S. Snow, M.C. Schladweiler, C. Fisher, M. Hargrove, D. Alewel, C. Colonna, S. Gavett, C. Miller, and U. Kodavanti. The Dynamicity of Acute Ozone-Induced Systemic Leukocyte Trafficking and Adrenal-Derived Stress Hormones. TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 458(152823): 1, (2021).

we hypothesized that ozone-adaptation is linked to diminution of neuroendocrine stress-axes activation and glucocorticoid levels. Male Wistar-Kyoto-rats (12-week-old) were injected with vehicle or a therapeutically-relevant dexamethasone dose (0.01-mg/kg/day; intraperitoneal) for 1-month to determine if suppression of glucocorticoid signaling was linked to adaptation. Vehicle- and dexamethasone-treated rats were exposed to air or 0.8-ppm ozone, 4 hours/dayx2 or 4 days to assess the impacts of acute exposure and adaptation, respectively. This dataset is associated with the following publication: Heinriquez, A., S. Snow, J. Dye, M.C. Schladweiler, D. Alewel, C. Miller, and U. Kodavanti. The contribution of the neuroendocrine system to adaption after repeated daily ozone exposure in rats. TOXICOLOGY AND APPLIED PHARMACOLOGY. Academic Press Incorporated, Orlando, FL, USA, 447(116085): 1, (2022).