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Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation.

ABSTRACT: 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 Ifn? and Il-4, the IL-4 protein and ratio of IL-4 to IFN? (IL-4/IFN?) 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.

SUBMITTER: Henriquez A

PROVIDER: S-EPMC6757346 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation.

Henriquez Andres A House John J Miller Desinia B DB Snow Samantha J SJ Fisher Anna A Ren Hongzu H Schladweiler Mette C MC Ledbetter Allen D AD Wright Fred F Kodavanti Urmila P UP

Toxicology and applied pharmacology 20170613

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 DEM ...[more]

PMID: 28623178

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Project description:BackgroundAcute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are devastating clinical disorders with high mortality, and for which more effective therapies are urgently needed. FGF1, the prototype member of the FGF family, is shown to exert protective effects against injurious stimuli in multiple disease models. Here we aimed to evaluate whether FGF1 pretreatment is protective against LPS-induced ALI and elucidate the potential underlying mechanisms.MethodsFor drug-treated groups, C57B/6 mice received a single i.p. injection of FGF1 (1 mg/kg) 1 h before the LPS challenge or not. To induce the ALI model, the mice were treated by intratracheal instillation of LPS (5 mg/kg). Then, histopathological changes in lung tissues were assessed by hematoxylin and eosin staining and transmission electron microscopy. ELISA and qPCR assays were used to detect pro-inflammatory cytokine levels in BALF and lung tissues, respectively. The total number of inflammatory cells (neutrophils and macrophages) in BALF were counted using the Wright-Giemsa method. The expressions of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured using their respective kits. Western blot and immunostaining were used to evaluate the expressions of antioxidants (Nrf-2, HO-1, SOD2, GPX4, and Catalase), as well as the inflammatory and/or apoptosis-related factors (TLR4, NF-κB, and Cleaved- caspase 3).ResultsFGF1 pretreatment significantly ameliorated the LPS-induced histopathological changes, reduced lung wet/dry ratios, ROS and MDA levels, total BALF protein, inflammatory cell infiltration, proinflammatory cytokine levels, and significantly increased the expression of antioxidant proteins (Nrf-2, HO-1, Catalase, and SOD2). In addition, FGF1 pretreatment significantly reduced the expression of TLR4 and cleaved- caspase 3, inhibited NF-κB activation, and reduced LPS-induced cell apoptosis.ConclusionsAltogether, our results suggest that FGF1 pretreatment is protective against LPS-induced ALI through mediating anti-inflammatory and antioxidant effects, which may be attributed to the downregulation of TLR4 expression and inhibition of NF-κB activation, as well as promotion of antioxidant defenses. Therefore, FGF1 administration may prove beneficial in preventative strategies for ALI/ARDS.

Dataset Information

Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation.

Publications

Adrenal-derived stress hormones modulate ozone-induced lung injury and inflammation.

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