Long Acting β2 Adrenergic Potentiates Ozone-Induced Lung Injury and Inflammation
Citation:
Henriquez, A., S. Snow, M. Schladweiler, J. Richards, C. Miller, J. Dye, A. Ledbetter, AND U. Kodavanti. Long Acting β2 Adrenergic Potentiates Ozone-Induced Lung Injury and Inflammation. Society of Toxicology, San Antonio, Texas, March 11 - 15, 2018.
Impact/Purpose:
This abstract shows that those receiving drug therapies which include long acting beta adrenergic agonists and/or steroids for lung diseases, such as asthma and chronic pulmonary diseases are likely to be sensitive to air pollution induced pulmonary vascular leakage and inflammation.
Description:
Ozone (O3), a ubiquitous air pollutant, disproportionately affects asthmatics. We have shown that O3-induced lung injury and inflammation are associated with increased circulating epinephrine and corticosterone, and inhibiting β adrenergic receptors (AR) and glucocorticoid receptors (GR) attenuates O3 effects. Agonists of both β2AR and GR are used to reduce asthma-associated bronchoconstriction and inflammation, respectively. We hypothesized that the treatment of healthy rats with near therapeutic dose levels of long acting β2AR agonist (LABA; Clenbuterol; CLEN) and GR agonist (dexamethasone; DEX) would increase O3-induced changes in lymphoid organs, lung vascular leakage, and pulmonary inflammation. In the first study, male 12-week old Wistar Kyoto rats were injected with saline, CLEN (0.004 [low dose] or 0.02 [high dose] mg/kg, i.p.), or DEX (0.02 [low dose] or 0.1 [high dose] mg/kg, i.p.). Since dual therapy is often instituted in patients, in the second study, rats were injected with both drugs (CLEN+DEX; both at 0.005 [low dose] or 0.02 [high dose] mg/kg, i.p.). Drug treatment began one day prior to and each day before start of air or 0.8 ppm ozone exposure, 4hr/day x 2 days. Ozone, DEX and CLEN+DEX, but not CLEN alone, reduced thymus and spleen weights and circulating white blood cells such as lymphocytes in a concentration-dependent manner, suggesting that ozone effects on circulating lymphocytes mimicked those caused by DEX. High dose of CLEN treatment exacerbated O3-induced pulmonary protein leakage and neutrophils in the bronchoalveolar lavage fluid to nearly 4-fold, however, DEX had a modest effect and CLEN+DEX produced only ~2-fold exacerbation. Drugs by themselves had no significant effect in air-exposed rats. In conclusion, our results show that regardless of O3 exposure DEX regulated extra-pulmonary immune responses in an O3-like fashion while LABA monotherapy potentiated O3-induced pulmonary protein leakage and inflammation in rats. When dual therapy was used, this potentiation was reduced to nearly half. Thus, it is likely that those receiving LABA and combination of LABA and steroids will be sensitive to air pollution induced pulmonary vascular leakage and inflammation. (Does not reflect the US EPA policy).