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

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          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-β 2AR 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 β 2AR 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 β 2AR and GR agonists for chronic pulmonary diseases, or with increased circulating stress hormones due to psychosocial stresses, might have altered sensitivity to air pollution.

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          Author and article information

          Journal
          Toxicol Sci
          Toxicol. Sci
          toxsci
          Toxicological Sciences
          Oxford University Press
          1096-6080
          1096-0929
          December 2018
          24 August 2018
          01 December 2019
          : 166
          : 2
          : 288-305
          Affiliations
          [1 ]Curriculum in Toxicology and Environmental Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina 27599
          [2 ]Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
          [3 ]Oak Ridge Institute for Science and Education, Research Triangle Park, North Carolina 27709
          Author notes

          Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does the mention of trade names of commercial products constitute endorsement or recommendation for use.

          To whom correspondence should be addressed at Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-0026. E-mail: kodavanti.urmila@ 123456epa.gov .
          Author information
          http://orcid.org/0000-0002-1917-4153
          http://orcid.org/0000-0003-1812-8582
          Article
          PMC6659033 PMC6659033 6659033 kfy198
          10.1093/toxsci/kfy198
          6659033
          30379318
          eea45131-84cf-474c-b747-d5a45f34a42d
          Published by Oxford University Press on behalf of the Society of Toxicology 2018.

          This work is written by US Government employees and is in the public domain in the US.

          History
          Page count
          Pages: 18
          Funding
          Funded by: US EPA Intramural Research Program, the EPA UNC Center for Environmental Medicine, Asthma and Lung Biology Cooperative
          Award ID: CR83515201
          Funded by: EPA UNC Cooperative Training Agreement
          Award ID: CR 83578501
          Funded by: CONICYT 10.13039/501100002848
          Award ID: IIE 15120279
          Funded by: National Institutes of Health 10.13039/100000002
          Categories
          Beta-2 Adrenergic Signaling and Ozone-Related Pulmonary Damage

          lung edema,lung inflammation,glucocorticoid receptor agonist,ozone,adrenalectomy,adrenergic receptor agonist

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