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Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats#
Citation:
Miller, D., S. Snow, M. Schladweiler, J. Richards, Andy Ghio, A. Ledbetter, AND U. Kodavanti. Acute Ozone-Induced Pulmonary and Systemic Metabolic Effects are Diminished in Adrenalectomized Rats#. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 150(2):312-22, (2016).
Impact/Purpose:
This paper provides the evidence that neurohormonal activation of stress response pathway and release of stress hormones are necessary for systemic metabolic effects, pulmonary injury and inflammation after acute ozone exposure. An unique approach of surgical removal of adrenals or adrenal medulla are used to provide conclusive evidence.
Description:
Acute ozone exposure increases circulating stress hormones and induces metabolic alterations in animals and humans. 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 adrenal demedullation (DEMED), total bilateral adrenalectomy (ADREX), or sham surgery (SHAM). After a 4 day recovery, rats were exposed to air or ozone (1ppm), 4h/day for 1 or 2 days. Circulating adrenaline levels dropped to nearly zero in DEMED and ADREX rats relative to air-exposed SHAM. Corticosterone levels 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=0.15) 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>DMED). 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 as a result of activation of the stress response pathway.
