Exacerbation of ozone-induced pulmonary and systemic effects by \u03b22-adrenergic and/or glucocorticoid receptor\xa0agonist/s

Andres R Henriquez,Mette C Schladweiler,Samantha J Snow,Colette N Miller,Janice A Dye,Judy E Richards,Urmila P Kodavanti,Marie M Hargrove,Allen D Ledbetter

doi:10.1038/s41598-019-54269-w

Abstract

Agonists of β2 adrenergic receptors (β2AR) and glucocorticoid receptors (GR) are prescribed to treat pulmonary diseases. Since ozone effects are mediated through the activation of AR and GR, we hypothesized that the treatment of rats with relevant therapeutic doses of long acting β2AR agonist (LABA; clenbuterol; CLEN) and/or GR agonist (dexamethasone; DEX) would exacerbate ozone-induced pulmonary and systemic changes. In the first study, male 12-week-old Wistar-Kyoto rats were injected intraperitoneally with vehicle (saline), CLEN (0.004 or 0.02 mg/kg), or DEX (0.02 or 0.1 mg/kg). Since dual therapy is commonly used, in the second study, rats received either saline or combined CLEN + DEX (each at 0.005 or 0.02 mg/kg) one day prior to and on both days of exposure (air or 0.8ppm ozone, 4 hr/day x 2-days). In air-exposed rats CLEN, DEX or CLEN + DEX did not induce lung injury or inflammation, however DEX and CLEN + DEX decreased circulating lymphocytes, spleen and thymus weights, increased free fatty acids (FFA) and produced hyperglycemia and glucose intolerance. Ozone exposure of vehicle-treated rats increased bronchoalveolar lavage fluid protein, albumin, neutrophils, IL-6 and TNF-α. Ozone decreased circulating lymphocytes, increased FFA, and induced hypeerglycemia and glucose intolerance. Drug treatment did not reverse ozone-induced ventillatory changes, however, lung effects (protein and albumin leakage, inflammation, and IL-6 increase) were exacerbated by CLEN and CLEN + DEX pre-treatment in a dose-dependent manner (CLEN > CLEN + DEX). Systemic effects induced by DEX and CLEN + DEX but not CLEN in air-exposed rats were analogous to and more pronounced than those induced by ozone. These data suggest that adverse air pollution effects might be exacerbated in people receiving LABA or LABA plus glucocorticoids.

Highlights

IntroductionWe and others have shown that acute exposure to air pollutants, such as ozone, leads to a rapid release of stress hormones (i.e. epinephrine and cortisol/corticosterone) into the circulation through the activation of the neuroendocrine stress axes in rats[1,2,3,4] and in humans[5]
We and others have shown that acute exposure to air pollutants, such as ozone, leads to a rapid release of stress hormones into the circulation through the activation of the neuroendocrine stress axes in rats[1,2,3,4] and in humans[5]
We established the role of combined βAR and glucocorticoid receptors (GR) activation using higher doses in ozone-induced pulmonary and systemic effects, the purpose of the current study was to examine if ozone-induced lung injury, inflammation, lymphopenia and metabolic alterations were exacerbated in rats receiving more therapeutically relevant dosages of LABA or the GR agonist, dexamethasone (DEX), as separate treatments

Summary

Introduction

We and others have shown that acute exposure to air pollutants, such as ozone, leads to a rapid release of stress hormones (i.e. epinephrine and cortisol/corticosterone) into the circulation through the activation of the neuroendocrine stress axes in rats[1,2,3,4] and in humans[5]. Ritchie and collaborators[22] demonstrated that β2AR agonists may promote lung inflammation through activation of the cyclic adenosine monophosphate response element in epithelial cells, while producing bronchodilator effects in smooth muscle cells These studies suggest that single and/or dual therapies might exacerbate acute pulmonary injury/inflammation induced by air pollutants through activation of AR and GR. We established the role of combined βAR and GR activation using higher (non-therapeutic) doses in ozone-induced pulmonary and systemic effects, the purpose of the current study was to examine if ozone-induced lung injury, inflammation, lymphopenia and metabolic alterations were exacerbated in rats receiving more therapeutically relevant dosages of LABA (clenbuterol; CLEN) or the GR agonist, dexamethasone (DEX), as separate treatments. Since dual therapy involving LABA and steroids are often recommended over single therapy, and because the dosages of dual drug treatment used in prior study were in a non-therapeutic range[8], in the second study we examined the interactive effects of ozone and the combination therapy of CLEN and DEX at therapeutically relevant doses

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