Adrenergic and Glucocorticoid Receptors in the Pulmonary Health Effects of Air Pollution

Hodge, Myles; Henriquez, Andres R.; Kodavanti, Urmila P.

doi:10.3390/toxics9060132

Cited by 8 publications

(5 citation statements)

References 148 publications

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“…Ligand-activated GR and GPCR are two of the most transcriptionally active nuclear signaling receptors across the genome and are highly responsive to environmental stressors ( Alhosaini et al, 2021 ; Frigo et al, 2021 ). Although adrenergic receptors (AR) and GR likely play a key role in mediating pulmonary health effects of various pollutants ( Hodge et al, 2021 ), their involvement in nasal effects of acrolein is not established. The factors involved in acrolein stress, such as AP-1 and NFκB, are often co-regulated with GRE ( Reddy et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Differential transcriptomic alterations in nasal versus lung tissue of acrolein-exposed rats

Alewel,

Jackson,

Rentschler

et al. 2023

Front. Toxicol.

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Introduction: Acrolein is a significant component of anthropogenic and wildfire emissions, as well as cigarette smoke. Although acrolein primarily deposits in the upper respiratory tract upon inhalation, patterns of site-specific injury in nasal versus pulmonary tissues are not well characterized. This assessment is critical in the design of in vitro and in vivo studies performed for assessing health risk of irritant air pollutants.Methods: In this study, male and female Wistar-Kyoto rats were exposed nose-only to air or acrolein. Rats in the acrolein exposure group were exposed to incremental concentrations of acrolein (0, 0.1, 0.316, 1 ppm) for the first 30 min, followed by a 3.5 h exposure at 3.16 ppm. In the first cohort of male and female rats, nasal and bronchoalveolar lavage fluids were analyzed for markers of inflammation, and in a second cohort of males, nasal airway and left lung tissues were used for mRNA sequencing.Results: Protein leakage in nasal airways of acrolein-exposed rats was similar in both sexes; however, inflammatory cells and cytokine increases were more pronounced in males when compared to females. No consistent changes were noted in bronchoalveolar lavage fluid of males or females except for increases in total cells and IL-6. Acrolein-exposed male rats had 452 differentially expressed genes (DEGs) in nasal tissue versus only 95 in the lung. Pathway analysis of DEGs in the nose indicated acute phase response signaling, Nrf2-mediated oxidative stress, unfolded protein response, and other inflammatory pathways, whereas in the lung, xenobiotic metabolism pathways were changed. Genes associated with glucocorticoid and GPCR signaling were also changed in the nose but not in the lung.Discussion: These data provide insights into inhaled acrolein-mediated sex-specific injury/inflammation in the nasal and pulmonary airways. The transcriptional response in the nose reflects acrolein-induced acute oxidative and cytokine signaling changes, which might have implications for upper airway inflammatory disease susceptibility.

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Section: Discussionmentioning

confidence: 99%

Differential transcriptomic alterations in nasal versus lung tissue of acrolein-exposed rats

Alewel,

Jackson,

Rentschler

et al. 2023

Front. Toxicol.

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“…Glucocorticoids are released into circulation following a single ozone exposure in a dynamic manner along with catecholamines (Henriquez, Snow, Jackson, House, Motsinger-Reif, et al, 2022) and therefore, we assessed if circulating glucocorticoids and/or catecholamines mediate tissue-speci c changes in the lung and in other tissues. There are cell-and tissue-speci c distributions of GRs and adrenergic GPCRs (Barnes, 2004;Hodge et al, 2021), which could underlie how ozone might induce cellular changes through activation of these receptors. Receptor binding activates transcriptional machinery with a variety of chaperone proteins and can cause transcriptional repression and/or enhancement (Oakley & Cidlowski, 2013;Xavier et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats

Jackson¹,

House

Henriquez

et al. 2023

Preprint

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Air pollutant exposures have been linked to systemic disease; however, the underlying mechanisms between responses of the target tissue and systemic effects are poorly understood. A prototypic inducer of stress, ozone causes respiratory and systemic multiorgan effects through activation of a neuroendocrine stress response. The goal of this study was to assess transcriptomic signatures of multiple tissues and serum metabolomics to understand how neuroendocrine and adrenal-derived stress hormones contribute to multiorgan health outcomes. Male Wistar Kyoto rats (12–13 weeks old) were exposed to filtered air or 0.8 ppm ozone for 4-hours, and blood/tissues were collected immediately post-exposure. Each tissue had distinct expression profiles at baseline. Ozone changed 1,640 genes in lung, 274 in hypothalamus, 2,516 in adrenals, 1,333 in liver, 1,242 in adipose, and 5,102 in muscle (adjusted p-value < .1, absolute fold-change > 50%). Serum metabolomic analysis identified 863 metabolites, of which 447 were significantly altered in ozone-exposed rats (adjusted p-value < .1, absolute fold change > 20%). A total of 6 genes were differentially expressed in all 6 tissues. Glucocorticoid signaling, hypoxia, and GPCR signaling were commonly changed, but ozone induced tissue-specific changes in oxidative stress, immune processes, and metabolic pathways. Genes upregulated by TNF-mediated NFkB signaling were differentially expressed in all ozone-exposed tissues, but those defining inflammatory response were tissue-specific. Upstream predictor analysis identified common mediators of effects including glucocorticoids, although the specific genes responsible for these predictors varied by tissue. Metabolomic analysis showed major changes in lipids, amino acids, and metabolites linked to the gut microbiome, concordant with transcriptional changes identified through pathway analysis within liver, muscle, and adipose tissues. The distribution of receptors and transcriptional mechanisms underlying the ozone-induced stress response are tissue-specific and involve induction of unique gene networks and metabolic phenotypes, but the shared initiating triggers converge into shared pathway-level responses. This multi-tissue transcriptomic analysis, combined with circulating metabolomic assessment, allows characterization of the systemic inhaled pollutant-induced stress response.

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“…Additionally, inhalation of O 3 leads to oxidative damage due to the generation of reactive oxygen species (ROS), resulting in excessive mitochondrial oxidative stress [44]. O 3 can also activate adrenergic and glucocorticoid receptors, causing the release of epinephrine and corticosterone into the circulation, thereby exacerbating O 3 -induced pulmonary damage and inflammation [45]. Transcriptomics studies also suggest the dysregulation of numerous pathways after O 3 exposure, such as mitochondrial dysfunction and glucocorticoid receptor signaling [46].…”

Section: O 3 Exposure and Respiratory Diseasesmentioning

confidence: 99%

Effects of Ambient O3 on Respiratory Mortality, Especially the Combined Effects of PM2.5 and O3

Deng,

Wang,

Sun

et al. 2023

Toxics

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Background: In China, the increasing concentration of ozone (O3) has emerged as a significant air pollution issue, leading to adverse effects on public health, particularly the respiratory system. Despite the progress made in managing air pollution in China, it is crucial to address the problem of environmental O3 pollution at present. Methods: The connection between O3 exposure and respiratory mortality in Shenyang, China, from 2014 to 2018 was analyzed by a time-series generalized additive regression model (GAM) with quasi-Poisson regression. Additionally, the potential combined effects of fine particulate matter (PM2.5) and O3 were investigated using the synergy index (SI). Results: Our findings indicate that each 10 μg/m3 increase in O3 at lag 2 days was associated with a maximum relative risk (RR) of 1.0150 (95% CI: 1.0098–1.0202) for respiratory mortality in the total population. For individuals aged ≥55 years, unmarried individuals, those engaged in indoor occupations, and those with low educational attainment, each 10 μg/m3 increase in O3 at lag 07 days was linked to RR values of 1.0301 (95% CI: 1.0187–1.0417), 1.0437 (95% CI: 1.0266–1.0610), 1.0317 (95% CI: 1.0186–1.0450), and 1.0346 (95% CI: 1.0222–1.0471), respectively. Importantly, we discovered a synergistic effect of PM2.5 and O3, resulting in an SI of 2.372 on the occurrence of respiratory mortality. Conclusions: This study confirmed a positive association between O3 exposure and respiratory mortality. Furthermore, it highlighted the interaction between O3 and PM2.5 in exacerbating respiratory deaths.

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Adrenergic and Glucocorticoid Receptors in the Pulmonary Health Effects of Air Pollution

Cited by 8 publications

References 148 publications

Differential transcriptomic alterations in nasal versus lung tissue of acrolein-exposed rats

Differential transcriptomic alterations in nasal versus lung tissue of acrolein-exposed rats

Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats

Effects of Ambient O3 on Respiratory Mortality, Especially the Combined Effects of PM2.5 and O3

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