Adrenergic and glucocorticoid receptor antagonists reduce ozone-induced lung injury and inflammation

Abstract

Recent studies showed that the circulating stress hormones, epinephrine and corticosterone/cortisol, are involved in mediating ozone-induced pulmonary effects through the activation of the sympathetic-adrenal-medullary (SAM) and hypothalamus-pituitary-adrenal (HPA) axes. Hence, we examined the role of adrenergic and glucocorticoid receptor inhibition in ozone-induced pulmonary injury and inflammation. Male 12-week old Wistar-Kyoto rats were pretreated daily for 7days with propranolol (PROP; a non-selective β adrenergic receptor [AR] antagonist, 10mg/kg, i.p.), mifepristone (MIFE; a glucocorticoid receptor [GR] antagonist, 30mg/kg, s.c.), both drugs (PROP+MIFE), or respective vehicles, and then exposed to air or ozone (0.8ppm), 4h/d for 1 or 2 consecutive days while continuing drug treatment. Ozone exposure alone led to increased peak expiratory flow rates and enhanced pause (Penh); with greater increases by day 2. Receptors blockade minimally affected ventilation in either air- or ozone-exposed rats. Ozone exposure alone was also associated with marked increases in pulmonary vascular leakage, macrophage activation, neutrophilic inflammation and lymphopenia. Notably, PROP, MIFE and PROP+MIFE pretreatments significantly reduced ozone-induced pulmonary vascular leakage; whereas PROP or PROP+MIFE reduced neutrophilic inflammation. PROP also reduced ozone-induced increases in bronchoalveolar lavage fluid (BALF) IL-6 and TNF-α proteins and/or lung Il6 and Tnfα mRNA. MIFE and PROP+MIFE pretreatments reduced ozone-induced increases in BALF N-acetyl glucosaminidase activity, and lymphopenia. We conclude that stress hormones released after ozone exposure modulate pulmonary injury and inflammatory effects through AR and GR in a receptor-specific manner. Individuals with pulmonary diseases receiving AR and GR-related therapy might experience changed sensitivity to air pollution.

Beta-2 Adrenergic and Glucocorticoid Receptor Agonists Modulate Ozone-Induced Pulmonary Protein Leakage and Inflammation in Healthy and Adrenalectomized Rats

“…Effects of ozone inhalation are not limited to the respiratory system. Our results support the previous observation that ozone exposure reduces circulating WBC, especially lymphocytes, while increasing circulating epinephrine and corticosterone in rats (Henriquez et al, 2018;Miller et al, 2016b). Since CLENþDEX also produces a substantial reduction in circulating lymphocytes (likely due to the immunosuppressive dose of DEX) while increasing BALF neutrophils, it is likely that these effects of ozone are modulated by stress hormones in a dynamic and cellspecific manner (Dhabhar et al, 2012).…”

“…As we have noted in previous publications (Henriquez et al, 2018), ozone exposure was also associated with BALF NAG activity (a marker of macrophage activation) increases in vehicletreated SH rats at D þ 2. AD diminished this ozone effect at D þ 2 ( Figure 5F).…”

“…We have recently demonstrated that total bilateral adrenalectomy (AD), which diminishes circulating epinephrine and corticosterone in rats, inhibits ozone-induced metabolic changes as well as lung injury, protein leakage, and inflammation (Miller et al, 2016b;Henriquez et al, 2017). Pharmacological inhibition of AR and GR also led to suppression of ozoneinduced vascular leakage and neutrophil inflammation, suggesting a proinflammatory role of endogenously released epinephrine and corticosterone (Henriquez et al, 2018). Although glucocorticoids have been shown to suppress immune response and inhibit lymphocyte function in rats, the proinflammatory effect of newly released epinephrine and corticosterone has also been reported after an acute restraint stress (Dhabhar et al, 2012) and after a treatment with exogenous epinephrine and glucocorticoids (Dhabhar, 2014).…”

Air Pollution, Stress, and Allostatic Load: Linking Systemic and Central Nervous System Impacts

“…1C, D), confirming a role for the HPA axis in mediating and modifying local and systemic effects of ozone exposure [54]. More recently, evidence of adrenal stress hormone involvement was further substantiated in a study that showed that administration of adrenergic and glucocorticoid receptor antagonists prior to and concurrent with exposure modified the pulmonary response to ozone [55]. The relevance of these observations to humans was confirmed in a panel study that showed that controlled exposure to 0.2 ppm ozone increased plasma stress hormone levels [56].…”

Characterization of low‐dose ozone‐induced murine acute lung injury

“…These molecules mediate platelet, neutrophil, and mononuclear infiltration into the lungs (Berman & Muller, 1950;Grommes et al, 2012;Schenkel, Chew, Chlipala, Harbord, & Muller, 2006). Animal models have also helped characterize potential mechanisms of pulmonary (Dowell, Lohrbauer, Hurst, & Lee, 1970;Michaudel, Fauconnier, Jule, & Ryffel, 2018) Bhattacharya & Westphalen, 2016) as well as multiple organ injury (Bouthillier et al, 1998;Erickson et al, 2017;Henriquez et al, 2018;Kasahara et al, 2014;Thomson, Pilon, Guenette, Williams, & Holloway, 2018) resulting from O 3 exposure. These studies show that a 3-6 hr exposure to 0.8 or 2 ppm O 3 induces recruitment and accumulation of lung monocytes and neutrophils at 24 hr (Francis et al, 2017;Tighe et al, 1950).…”