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Ozone-Induced Pulmonary Injury and Inflammation are Modulated by Adrenal-Derived Stress Hormones
Citation:
Henriquez, A., D. Miller, S. Snow, M. Schladweiler, AND U. Kodavanti. Ozone-Induced Pulmonary Injury and Inflammation are Modulated by Adrenal-Derived Stress Hormones. Society of Toxicology, New Orleans, LA, March 13 - 17, 2016.
Impact/Purpose:
Previously we have characterized systemic changes that occur immediately after acute ozone exposure and are mediated by neuro-hormonal stress response pathway. Contrary to the accepted mechanism of acute ozone-induced lung cell injury which involves direct cellular damage and oxidative modification-mediated neutrophil recruitment, we show that ozone-induced lung injury and neutrophilic inflammation involving Mip2 and Il6 require circulating epinephrine and corticosterone. Additionally, acute ozone-induced neutrophilic inflammation in SHAM (normal) rats apparently may not involve acquired immune response or Th1/Th2 mechanisms.
Description:
Ozone exposure promotes pulmonary injury and inflammation. Previously we have characterized systemic changes that occur immediately after acute ozone exposure and are mediated by neuro-hormonal stress response pathway. Both HPA axis and sympathetic tone alterations induce the release of epinephrine and corticosteroids to the blood after ozone inhalation. To understand the influence of these hormones in ozone-induced lung alterations, we eliminated their source by adrenalectomy. Male Wistar-Kyoto rats (12 week-old) underwent total bilateral adrenalectomy (ADREX), adrenal demedullation (DEMED) or sham surgery (SHAM). After 4 day of recovery, rats were exposed to air or ozone (1ppm), 4h/day for 1 or 2 days. Circulating medulla-derived adrenaline in DEMED and ADREX rats were significantly reduced relative to air-exposed SHAM. Cortex-derived corticosterone levels were decreased in DEMED rats and almost disappeared in ADREX rats. Ozone-induced lung protein/albumin leakage and neutrophilic inflammation were significantly reduced in DEMED and ADREX rats (ADREX>DMED). To characterize the influence of these hormones in ozone-induced inflammation, expression of different genes involved in inflammation were quantified in the lung by qPCR. Ozone-induced increases in Mip2 and Il6 in SHAM rats were diminished in DEMED and ADREX rats which coincided with neutrophilic inflammation. Ozone increased BALF eosinophil-like cells only in ADREX rats but not in SHAM rats. Th1/Th2 response measured by expression of specific cytokines such as Infg (Th1) and Il4 (Th2) were not significantly changed by adrenalectomy or ozone, although the expression of some secreted factors such as Il5, Il13 and Il12a tended to be higher in adrenalectomized rats regardless of exposure. However ozone exposure decreased Il13 expression in SHAM rats. Contrary to the accepted mechanism of acute ozone-induced lung cell injury, vascular leakage and inflammation which involves direct cellular damage and oxidative modification-mediated neutrophil recruitment, we show that ozone-induced lung injury and neutrophilic inflammation involving Mip2 and Il6 require circulating epinephrine and corticosterone. Additionally, acute ozone-induced neutrophilic inflammation in SHAM (normal) rats apparently may not involve acquired immune response or Th1/Th2 mechanisms. (Does not reflect EPA Policy).