Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects Are Diminished in Adrenalectomized Rats

Abstract

Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals. We hypothesized that the increase of adrenal-derived stress hormones is necessary for both ozone-induced metabolic effects and lung injury. Male Wistar-Kyoto rats underwent bilateral adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1 ppm), 4 h/day for 1 or 2 days and responses assessed immediately postexposure. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to SHAM. Corticosterone tended to be low in DEMED rats and dropped to nearly zero in ADREX rats. Adrenalectomy in air-exposed rats caused modest changes in metabolites and lung toxicity parameters. Ozone-induced hyperglycemia and glucose intolerance were markedly attenuated in DEMED rats with nearly complete reversal in ADREX rats. Ozone increased circulating epinephrine and corticosterone in SHAM but not in DEMED or ADREX rats. Free fatty acids (P = .15) and branched-chain amino acids increased after ozone exposure in SHAM but not in DEMED or ADREX rats. Lung minute volume was not affected by surgery or ozone but ozone-induced labored breathing was less pronounced in ADREX rats. Ozone-induced increases in lung protein leakage and neutrophilic inflammation were markedly reduced in DEMED and ADREX rats (ADREX > DEMED). Ozone-mediated decreases in circulating white blood cells in SHAM were not observed in DEMED and ADREX rats. We demonstrate that ozone-induced peripheral metabolic effects and lung injury/inflammation are mediated through adrenal-derived stress hormones likely via the activation of stress response pathway.

Systemic metabolic derangement, pulmonary effects, and insulin insufficiency following subchronic ozone exposure in rats

“…We have previously shown that acute ozone exposure induces sympathetic and HPA-mediated systemic stress response characterized by hyperglycemia, glucose intolerance, lipidemia, and elevations in BCAA, FFA, and circulating stress hormones (Miller et al, 2015, 2016b). Humans are exposed episodically to ozone throughout their lifetime which may cause a chronic stress response activation.…”

“…Nevertheless, one could speculate that central mechanisms might be playing an important role in the ozone adaptation phenomenon. Since we have shown that catecholamines and glucocorticoids are potentially involved in these ozone-induced pulmonary and metabolic effects (Miller et al, 2016b), it is likely that adaptive mechanisms may involve altered stress response signaling during subchronic exposure. Chronic stress activation can lead to the adaptive response “habituation”, involving neural plasticity and downregulation of glucocorticoid and β-adrenergic receptors in the central nervous system and in the periphery leading to reduced stress-mediated responses (Herman, 2013).…”

“…MI) at 2 g/10 ml/kg body weight. Glucose levels were measured at 30, 60, 90, and 120 min post glucose injection as reported in our previous studies (Miller et al, 2015, 2016b). GTT was conducted in cohort 1 animals during the 1st wk of exposure immediately following day 1 (1 wk-D1) or day 3 (1 wk-D3) of exposure, and during the 12th wk.…”

“…The increases in circulating lipid metabolites and stress hormones were also noted in humans after an acute ozone exposure (Miller et al, 2016a). Interestingly, adrenalectomy prior to ozone exposure resulted in diminution of not only metabolic but also pulmonary effects in rats (Miller et al, 2016b). However, no insulin resistance was observed during an acute ozone exposure in our rat or human studies.…”

Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice

“…It has been reported that acute exposure to O 3 elevated fasting blood glucose level in rats (Miller et al 2015; Miller et al 2016). In our study, however, there was a similar fasting blood glucose level in FA- and O 3 -exposed KK mice.…”