Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • Circulating adrenal derived stress hormones epinephrine

    2023-01-24

    Circulating adrenal-derived stress hormones, epinephrine and corticosterone mediate their tissue effects through adrenergic (AR; α and β) and glucocorticoid (GR) receptors. AR are widely distributed throughout the body and although epinephrine is a prototypical agonist for all types of AR, the selective activation of specific AR subtypes determines the physiological organ-specific response. β1AR are mainly expressed in the cardiac tissue and are central in maintaining cardiac output and contractility of cardiac muscle (Kurz et al., 1991), hence βAR blockers are widely used to reduce blood pressure. On the other hand, β2AR are primarily distributed in the smooth muscles of bronchi and blood vessels (Molinoff, 1984). Airway smooth muscle relaxation by β2AR agonists is a common pharmacological intervention used for bronchodilation in Doxorubicin and chronic obstructive pulmonary disease (Cazzola et al., 2013). Propranolol (PROP) is a non-selective βAR antagonist capable of blocking both β1AR and β2AR and, unlike epinephrine, it readily crosses the blood brain barrier (Olesen et al., 1978). Circulating cortisol/corticosterone binds to GR that are present in virtually all cells in the body. Nuclear translocation of these receptors up-regulates a variety of genes involved in homeostatic response(s) (Oakley and Cidlowski, 2013). Non-genomic actions of glucocorticoids on GR have also been identified (Duque and Munhoz, 2016). Although the anti-inflammatory and immunosuppressive actions of glucocorticoids are not completely understood, potent GR agonists are commonly used to treat inflammatory conditions (Petta et al., 2016). By contrast, other studies have shown pro-inflammatory actions of GR activation (Cruz-Topete and Cidlowski, 2015). Mifepristone (MIFE) is a GR antagonist used to examine cellular effects of GR (Kakade and Kulkarni, 2014). Based on the previous observation that circulating stress hormones are likely involved in mediating pulmonary effects of ozone (Miller et al., 2016b), the goal of this study was to examine the role of stress hormone receptors, βAR and GR in ozone-induced local lung injury and inflammation using a pharmacological approach. PROP, a non-selective βAR antagonist, was used to antagonize the activity of epinephrine while MIFE, a GR antagonist, was used to antagonize the activity of corticosterone. We hypothesized that the blocking of βAR and/or GR would produce selective inhibition of lung injury and/or inflammation and associated signaling events caused by exposure to ozone in rats.
    Materials and methods
    Results
    Discussion In this study, we blocked the activity of stress hormone receptors βAR and GR, individually or together, to better understand and define the role of stress hormones in ozone-induced pulmonary effects. The experimental design was developed to separately account for the effects likely to be mediated via epinephrine, corticosterone, or both, by pretreating rats with PROP, MIFE or PROP+MIFE, respectively (Fig. 8). We hypothesized that βAR and GR blockade would prevent ozone-mediated activation of these receptors by stress hormones, and also downstream signaling events in the lung, leading to reduction in ozone-induced pulmonary effects. Since only PROP+MIFE but not other individual pretreatments reduced minute volume and PEF in ozone-exposed rats, the degree of ozone-induced lung edema or neutrophilic inflammation in the PROP and/or MIFE-pretreated rats were likely not influenced by the possibility of reduction in lung ozone dose. Nevertheless, PROP, MIFE or PROP+MIFE (inhibition of βAR and/or GR) were sufficient to attenuate ozone-induced pulmonary protein leakage; however, only PROP and PROP+MIFE (inhibition of βAR or βAR+GR) reduced ozone-induced lung neutrophilic inflammation, and pro-inflammatory cytokine increases. On the other hand, only MIFE (inhibition of GR) pretreatment reversed ozone-induced lymphopenia and increases in BALF NAG activity which reflects macrophage activation (Fig.8). These data suggest that βAR and GR have distinct roles in mediating inflammatory cell-specific responses induced by ozone. It is noteworthy that the pretreatment of animals with PROP, MIFE or PROP+MIFE themselves, had very little if any pulmonary and systemic effect in air-exposed animals, highlighting the role of βAR and GR as specific modulators of ozone–induced pulmonary vascular leakage and innate immune responses. Since βAR and GR have been widely manipulated in cardiopulmonary diseases, those receiving βAR and GR-related treatments might have altered susceptibility to high levels of ozone or other pulmonary irritants.