Adrenergic and steroid hormone modulation of ozone-induced pulmonary injury and inflammation
Henriquez, A., S. Snow, M. Schladweiler, A. Ledbetter, C. Miller, M. McGee, W. Williams, J. Richards, AND U. Kodavanti. Adrenergic and steroid hormone modulation of ozone-induced pulmonary injury and inflammation. American Thoracic Society (ATS) Meeting, Washington DC, DC, May 18 - 24, 2017.
We have recently shown that acute ozone inhalation promotes activation of the sympathetic and hypothalamus-pituitary-adrenal (HPA) axis leading to release of the stress hormones cortisol and epinephrine from adrenals. Our results demonstrate that circulating stress hormones and their respective receptors are active mediators in pulmonary vascular protein leakage and inflammatory cell trafficking to the lung during ozone exposure.
Rationale: We have shown that acute ozone inhalation promotes activation of the sympathetic and hypothalamic-pituitary-adrenal (HPA) axis leading to release of cortisol and epinephrine from the adrenals. Adrenalectomy (ADREX) inhibits ozone-induced pulmonary vascular leakage and inflammation, suggesting an essential role for these hormones in ozone induced lung injury. The β2 adrenergic receptor (β2-AR) and glucocorticoid receptor (GR) have been widely targeted for the treatment of chronic pulmonary diseases. Hence, we hypothesized that stress hormones receptor agonists will rescue ADREX phenotype restoring sensitivity to ozone-induced lung injury and inflammation while exacerbating ozone effects in sham surgery (SHAM) rats. Methods: Male Wistar Kyoto rats (12 wks) that underwent SHAM or ADREX were treated with the vehicles (saline+corn oil) or β2-AR agonist clenbuterol (CLEN, 0.2 mg/kg, i.p.) plus GR agonist dexamethasone (DEX, 2 mg/kg, s.c.). Rats were injected 24 hours prior to the day and immediately prior to exposure to ozone (0.8 ppm) or filtered air (4 hr/day for 1 or 2 days). Endpoints were assessed within 1-2 hour post-exposure. Results: ADREX in vehicle-treated air-exposed rats did not significantly affect breathing parameters or indices of lung injury and inflammation. However, CLEN+DEX in air-exposed SHAM rats caused lung injury and inflammation, and reduction in circulating lymphocytes, without affecting breathing parameters. Ozone increased PenH response, an index of labored breathing in vehicle-treated SHAM and ADREX rats (SHAM>ADREX). This effect was exacerbated by CLEN+DEX (SHAM>ADREX). Ozone in vehicle-treated SHAM rats increased pulmonary protein leakage and neutrophilic inflammation which was associated with increased N-acetyl glucosaminidase activity, an index of macrophage activation. Ozone exposure in these rats also decreased circulating white blood cells (WBC and lymphocytes). These ozone effects were prevented by ADREX in vehicle-treated rats. However, CLEN+DEX not only reversed the protection offered by ADREX but enhanced the ozone-induced effects on PenH, lung vascular leakage and inflammation. CLEN+DEX in ozone-exposed SHAM rats diminished levels of circulating lymphocytes without affecting WBC suggesting specific effects on cell extravasation to the lung. Conclusion: These results demonstrate that circulating stress hormones and their receptors are mediators in pulmonary vascular leakage and inflammatory cell trafficking to the lung during ozone exposure. (Does not reflect the US EPA policy).