Henriquez Andres, House John, Miller Desinia B, Snow Samantha J, Fisher Anna, Ren Hongzu, Schladweiler Mette C, Ledbetter Allen D, Wright Fred, Kodavanti Urmila P
Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Bioinformatics Research Center, North Carolina State University, Raleigh, NC, United States.
Toxicol Appl Pharmacol. 2017 Aug 15;329:249-258. doi: 10.1016/j.taap.2017.06.009. Epub 2017 Jun 13.
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 Ifnγ and Il-4, the IL-4 protein and ratio of IL-4 to IFNγ (IL-4/IFNγ) 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.
臭氧诱导的全身效应是通过激活神经激素应激反应途径来调节的。肾上腺髓质切除术（DEMED）或双侧肾上腺全切除术（ADREX）可抑制急性臭氧暴露的全身和肺部效应。为了了解肾上腺衍生的应激激素在介导臭氧诱导的肺损伤/炎症中的作用，我们评估了雄性Wistar-Kyoto大鼠肺组织中的全局基因表达（mRNA测序）和选定的蛋白质，这些大鼠在暴露于空气或臭氧（1ppm）之前接受了DEMED、ADREX或假手术（SHAM），每天4小时，持续1或2天。臭氧暴露显著改变了SHAM大鼠肺中超过2300个基因的表达，而在DEMED和ADREX大鼠中这些变化明显减少。SHAM手术而非DEMED或ADREX导致多种臭氧反应途径的激活，包括糖皮质激素、急性期反应、NRF2和PI3K-AKT。测序数据预测的靶点显示，臭氧诱导的转录变化与SHAM大鼠而非ADREX大鼠中肾上腺素能和类固醇对效应的调节之间存在相似性。SHAM大鼠中臭氧诱导的肺Il6增加与中性粒细胞炎症同时发生，但在DEMED和ADREX大鼠中减弱。虽然SHAM大鼠暴露于臭氧并未显著改变Ifnγ和Il-4的mRNA表达，但IL-4蛋白以及IL-4与IFNγ蛋白的比率（IL-4/IFNγ）增加，表明有Th2反应的趋势。这在ADREX和DEMED大鼠中未发生。我们证明，臭氧诱导的肺损伤和中性粒细胞炎症需要循环中的肾上腺素和皮质酮的存在，它们转录调节参与该反应的信号机制。
