PMID- 28623178 OWN - NLM STAT- MEDLINE DCOM- 20170731 LR - 20200225 IS - 1096-0333 (Electronic) IS - 0041-008X (Print) IS - 0041-008X (Linking) VI - 329 DP - 2017 Aug 15 TI - Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation. PG - 249-258 LID - S0041-008X(17)30265-X [pii] LID - 10.1016/j.taap.2017.06.009 [doi] AB - 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 effects 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 (1ppm), 4h/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 PI3K-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 Il6 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 Ifngamma and Il-4, the IL-4 protein and ratio of IL-4 to IFNgamma (IL-4/IFNgamma) 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. CI - Published by Elsevier Inc. FAU - Henriquez, Andres AU - Henriquez A AD - Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - House, John AU - House J AD - Bioinformatics Research Center, North Carolina State University, Raleigh, NC, United States. FAU - Miller, Desinia B AU - Miller DB AD - Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States. FAU - Snow, Samantha J AU - Snow SJ AD - Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. FAU - Fisher, Anna AU - Fisher A AD - Research Cores Unit, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. FAU - Ren, Hongzu AU - Ren H AD - Research Cores Unit, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. FAU - Schladweiler, Mette C AU - Schladweiler MC AD - Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. FAU - Ledbetter, Allen D AU - Ledbetter AD AD - Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. FAU - Wright, Fred AU - Wright F AD - Bioinformatics Research Center, North Carolina State University, Raleigh, NC, United States. FAU - Kodavanti, Urmila P AU - Kodavanti UP AD - Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States. Electronic address: kodavanti.urmila@epa.gov. LA - eng GR - EPA999999/Intramural EPA/United States GR - T32 ES007126/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20170613 PL - United States TA - Toxicol Appl Pharmacol JT - Toxicology and applied pharmacology JID - 0416575 RN - 0 (Cytokines) RN - 0 (Inflammation Mediators) RN - 0 (RNA, Messenger) RN - 66H7ZZK23N (Ozone) RN - W980KJ009P (Corticosterone) RN - YKH834O4BH (Epinephrine) SB - IM MH - Adrenal Cortex/*metabolism/surgery MH - Adrenal Medulla/*metabolism/surgery MH - Adrenalectomy MH - Animals MH - Corticosterone/*blood MH - Cytokines/metabolism MH - Disease Models, Animal MH - Epinephrine/*blood MH - Gene Expression Regulation MH - Inflammation Mediators/metabolism MH - Lung/*metabolism/pathology MH - Lung Injury/blood/*chemically induced/genetics/prevention & control MH - Male MH - Neutrophils/metabolism MH - Oxidative Stress MH - *Ozone MH - Pneumonia/blood/*chemically induced/genetics/pathology/prevention & control MH - RNA, Messenger/genetics/metabolism MH - Rats, Inbred WKY MH - Signal Transduction MH - *Stress, Physiological/genetics MH - Transcription, Genetic PMC - PMC6757346 MID - NIHMS1503394 OTO - NOTNLM OT - Adrenalectomy OT - Lung OT - Ozone OT - RNAseq OT - Stress hormones EDAT- 2017/06/18 06:00 MHDA- 2017/08/02 06:00 PMCR- 2019/09/24 CRDT- 2017/06/18 06:00 PHST- 2017/02/09 00:00 [received] PHST- 2017/05/19 00:00 [revised] PHST- 2017/06/11 00:00 [accepted] PHST- 2017/06/18 06:00 [pubmed] PHST- 2017/08/02 06:00 [medline] PHST- 2017/06/18 06:00 [entrez] PHST- 2019/09/24 00:00 [pmc-release] AID - S0041-008X(17)30265-X [pii] AID - 10.1016/j.taap.2017.06.009 [doi] PST - ppublish SO - Toxicol Appl Pharmacol. 2017 Aug 15;329:249-258. doi: 10.1016/j.taap.2017.06.009. Epub 2017 Jun 13.