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Exacerbation of ozone-induced pulmonary and systemic effects by beta2-adrenergic and/or glucocorticoid receptor agonist/s
Citation:
Henriquez, A., S. Snow, M. Schladweiler, C. Miller, J. Dye, A. Ledbetter, M. Hargrove, J. Richards, AND U. Kodavanti. Exacerbation of ozone-induced pulmonary and systemic effects by beta2-adrenergic and/or glucocorticoid receptor agonist/s. Scientific Reports. Nature Publishing Group, London, Uk, 9(1):17925, (2019). https://doi.org/10.1038/s41598-019-54269-w
Impact/Purpose:
This study was done to determine how agonists of adrenergic and glucocorticoid receptors that are widely used for treatment of chronic lung diseases including asthma can exacerbate ozone-induced lung injury and inflammation. The study shows that ozone through activation of release of glucocorticoids and adrenaline in the circulation induces lung injury and inflammation. when these agonists are combined with ozone exposure the lung injury and inflammation are exacerbated due to similar mechanisms of action.
Description:
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 0.02mg/kg), or DEX (0.02 or 0.1mg/kg). Since dual therapy is commonly used, in the second study, rats received either saline or combined CLEN+DEX (each at 0.005 or 0.02mg/kg) one day prior to and on both days of exposure (air or 0.8ppm ozone, 4hr/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-allpha and decreased circulating lymphocytes, increased FFA, glucose, and glucose intolerance. The ozone-induced 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.
URLs/Downloads:
DOI: Exacerbation of ozone-induced pulmonary and systemic effects by beta2-adrenergic and/or glucocorticoid receptor agonist/s