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

作者：Henriquez Andres R; Snow Samantha J; Schladweiler Mette C; Miller Colette N; Dye Janice A; Ledbetter Allen D; Richards Judy E; Mauge Lewis Kevin; McGee Marie A; Kodavanti Urmila P^*

来源：Toxicology and Applied Pharmacology, 2018, 339: 161-171.

DOI：10.1016/j.taap.2017.12.006

• Stress response
• Glucocorticoid receptor antagonist
• Adrenergic receptor antagonist
• Ozone
• Lung injury
• Lung inflammation

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 7 days with propranolol (PROP; a non-selective beta adrenergic receptor [AR] antagonist, 10 mg/kg, i.p.), mifepristone (MIFE; a glucocorticoid receptor [GR] antagonist, 30 mg/kg, s.c.), both drugs (PROP + MIFE), or respective vehicles, and then exposed to air or ozone (0.8 ppm), 4 h/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 inflanunation 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-alpha proteins and/or lung Il6 and Tnf alpha 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.

• 出版日期2018-1-15