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Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation
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, 329:249-258, (2017).
Ozone is a ubiquitous gaseous air pollutant and one of the major components of smog in urban areas. The goal of this study was to elucidate potential mechanisms and roles of hormones in ozone-induced lung injury and inflammation. This work provides a possible mechanism by which ozone may exert its effect on the airways and helps inform the Ozone Integrated Science Assessment.
Ozone-induced systemic effects are modulated through activation of the neuro-hormonal stress response pathway. Adrenal demedullation (DEMED)or bilateral total adrenalectomy (ADREX) inhibits systemic and pulmonary effect of acute ozone exposure. To understand the influence of adrenal-derived stress hormones in mediating ozone-induced lung injury/inflammation, we assessed global gene expression (mRNA sequencing) and selected proteins in lung tissues from male Wistar-Kyoto rats that underwent DEMED, ADREX, or sham surgery (SHAM)prior to their exposure to air or ozone (1 ppm),4 h/day for 1 or 2days. Ozone exposure significantly changed the expression of over 2300 genes in lungs of SHAM rats, and these changes were markedly reduced in DEMED and ADREX rats. SHAM surgery but not DEMED or ADREX resulted in activation of multiple ozone-responsive pathways, including glucocorticoid, acute phase response, NRF2, and Pl3K-AKT.Predicted targets from sequencing data showed a similarity between transcriptional changes induced by ozone and adrenergic and steroidal modulation of effects in SHAM but not ADREX rats. Ozone-induced Increases in lung 116 in SHAM rats coincided with neutrophilic Inflammation, but were diminished in DEMED and ADREX rats. Although ozone exposure in SHAM rats did not significantly alter mRNA expression of lfny and 11-4, the IL-4 protein and ratio of IL-4 to IFNy (IL-4/IFNy) proteins increased suggesting a tendency for a Th2 response. This did not occur in ADREX and DEMED rats. We demonstrate that ozone-induced lung injury and neutrophilic inflammation require the presence of circulating epinephrine and corticosterone, which transcriptionally regulates signaling mechanisms involved in this response.