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

Abstract

We have shown that acute ozone inhalation activates sympathetic-adrenal-medullary and hypothalamus-pituitary-adrenal stress axes, and adrenalectomy (AD) inhibits ozone-induced lung injury and inflammation. Therefore, we hypothesized that stress hormone receptor agonists (β2 adrenergic-β2AR and glucocorticoid-GR) will restore the ozone injury phenotype in AD, while exacerbating effects in sham-surgery (SH) rats. Male Wistar Kyoto rats that underwent SH or AD were treated with vehicles (saline + corn oil) or β2AR agonist clenbuterol (CLEN, 0.2 mg/kg, i.p.) + GR agonist dexamethasone (DEX, 2 mg/kg, s.c.) for 1 day and immediately prior to each day of exposure to filtered air or ozone (0.8 ppm, 4 h/day for 1 or 2 days). Ozone-induced increases in PenH and peak-expiratory flow were exacerbated in CLEN+DEX-treated SH and AD rats. CLEN+DEX affected breath waveform in all rats. Ozone exposure in vehicle-treated SH rats increased bronchoalveolar lavage fluid (BALF) protein, N-acetyl glucosaminidase activity (macrophage activation), neutrophils, and lung cytokine expression while reducing circulating lymphocyte subpopulations. AD reduced these ozone effects in vehicle-treated rats. At the doses used herein, CLEN+DEX treatment reversed the protection offered by AD and exacerbated most ozone-induced lung effects while diminishing circulating lymphocytes. CLEN+DEX in air-exposed SH rats also induced marked protein leakage and reduced circulating lymphocytes but did not increase BALF neutrophils. In conclusion, circulating stress hormones and their receptors mediate ozone-induced vascular leakage and inflammatory cell trafficking to the lung. Those receiving β2AR and GR agonists for chronic pulmonary diseases, or with increased circulating stress hormones due to psychosocial stresses, might have altered sensitivity to air pollution.

Exacerbation of ozone-induced pulmonary and systemic effects by β2-adrenergic and/or glucocorticoid receptor agonist/s

“…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. Our recent findings indicate that when rats were treated with relatively high non-therapeutic doses of LABA and corticosteroids given together (several folds higher than the therapeutic doses used for humans when adjusted to body weight), ozone-induced lung injury and inflammation were exacerbated in rats 8 . Thus, although 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.…”

“…Specifically, ozone-induced vascular leakage was inhibited by each antagonist, but pulmonary neutrophilia was prevented only by βAR antagonist while lymphopenia was prevented by GR antagonist. Furthermore, when βAR and GR were activated by treating rats with high non-therapeutic doses of combined agonists, ozone-induced lung injury and inflammation were exacerbated 8 .…”

“…Given the role of AR and GR activation in acute air pollution-induced lung injury and inflammation 6–8,14 , and the use of AR and GR agonists in treatment of chronic asthma and COPD, it is conceivable that patients receiving bronchodilators and/or immunosuppressants might have differential inflammatory processes induced after acute air pollutant exposures 15–18 . For instance, it was found that asthmatic children living in Detroit have worsened responses to ozone and fine particulate matter when compared to those not receiving steroids 19 .…”

“…Thus, although 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. Moreover, 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 herein, we examined the interactive effects of ozone and the combination therapy of CLEN and DEX at therapeutically relevant doses.…”

Diesel exhaust impairs TREM2 to dysregulate neuroinflammation

“…In order to determine how air pollution exposure may impact TREM2, WKY rats were exposed to DE by whole-body inhalation. We have previously explored the neuroimmune impact of DE inhalation in WKY rats [ 37 , 38 ], and there is a wealth of physiological and toxicological information on the effects of air pollution on WKY rats, making them particularly useful in examining new effects of air pollution on health and disease [ 39 – 42 ]. Petroleum diesel fuel with ultra-low sulfur (< 15 ppm) (Red Star Oil, Raleigh, NC, USA) was used to generate diesel exhaust (DE) by a single-cylinder, air-cooled, direct injection, 320-cm 3 Yanmar L70 diesel engine (Adairville, GA, USA) ran at 5.8 hp (4.3 kW) continuous load, 3600 rpm, and Pramac E3750 generator (Marietta, GA, USA) [ 43 ].…”