Citation:

Alewel, D., K. Rentschler, M. Schladweiler, S. Gavett, C. Miller, T. Jackson, P. Evansky, AND U. Kodavanti. Adrenergic receptor antagonists modulate acrolein-induced ventilatory changes, upper respiratory inflammation, and cytokine release. Society of Toxicology, Salt Lake City, UT, March 10 - 14, 2024.

Impact/Purpose:

Acrolein induces nasal injury and inflammation and is one of the hazardous air pollutants. This abstract shows the study results that indicate the role of adrenergic receptors in mediating nasal and systemic response to acrolein inhalation.

Description:

Background and Purpose: Adrenergic receptors (AR) are the most extensive therapeutically manipulated drug receptors in the treatment of respiratory diseases, such as asthma and chronic obstructive pulmonary disease. The airways are densely innervated by AR, which are cellular receptors crucial in maintaining breathing functions and homeostasis; however, the role of AR in mediating airway effects of inhaled air pollutants is not well understood. Acrolein, a volatile aldehyde generated from combustion and pyrolytic pollution sources, such as tobacco and wildfire smoke, is a well-characterized respiratory irritant. Acrolein inhalation induces reflexive airway constriction and initiates airway injury and inflammation that contribute to the development or exacerbation of asthma and chronic respiratory diseases. Previously, we associated acrolein-induced airway resistance and inflammatory responses with neuro-hormonal stress reactions through adrenergic GPCR-mediated mRNA expression changes, suggesting adverse initiating events of acrolein-induced airway effects are mediated through catecholamine binding with ligand-activated AR. In this study, we examined the contribution of diverse AR subtypes in mediating acute acrolein-induced ventilatory and inflammatory changes through selective pharmacological inhibition. Methods: We pre-treated 12-week-old male Wistar-Kyoto rats daily for 7 days with either vehicle (saline), prazosin (α1-AR antagonist; 2 mg/kg/day, i.p.), yohimbine (α2-AR antagonist; 5 mg/kg/day, i.p.), or propranolol (β-AR antagonist; 10 mg/kg/day, i.p.). On days 8 and 9 following respective drug injection, rats were exposed nose-only to either air (0 ppm) or acrolein (1.6 or 3.2 ppm for dose effect assessment), ~4 hours/day (two consecutive days). In-life head-out plethysmography (HOP) was performed during exposure on day 9, and then animals were necropsied immediately following end of exposure. As acrolein primarily deposits in the upper airways of rodents, especially at lower concentrations, respiratory injury and inflammation markers were analyzed in nasal lavage fluid (NALF) and bronchoalveolar lavage fluid (BALF). Results: Acrolein inhalation reduced breathing frequency, peak expiratory flow, tidal volume, and minute volume at 3.2 ppm. Propranolol pretreatment mitigated 3.2 ppm acrolein-induced changes in breathing frequency and expiration time, as well as expiratory and tidal volumes. Interestingly, prazosin changed baseline breathing parameters in rats regardless of acrolein inhalation, as evidenced by a slower respiratory rate and decreased minute volume. Further, NALF analysis indicated robust acrolein-induced increases in neutrophilic and eosinophilic inflammation in nasal airways at 3.2 but not 1.6 ppm acrolein. NALF pro-inflammatory cytokines IL-6, TNF-α, IL-1β, and CXCL1 were also increased following 3.2 ppm acrolein inhalation in rats pretreated with vehicle. Pretreatment of rats with propranolol, resulting in β-AR blockade (but not yohimbine [α2-AR blockade] or prazosin [α1-AR blockade]) significantly reduced NALF inflammatory response and also IL-6, TNF-α, and IL-1β cytokine increases in rats exposed to 3.2 ppm acrolein. Conclusions: These data demonstrate the involvement of the neuro-hormonal sympathetic stress axis in mediating acrolein-induced upper airway inflammation and pathophysiological changes through activation of β-AR. This study provides the mechanistic understanding of how those receiving bronchodilators (β-AR agonists) may experience exacerbation of air pollution effects, and conversely, those receiving non-specific βAR antagonists might have added therapeutic benefits from the harmful respiratory effects of air pollutants. The significance of ventilatory and immune response modulation by stress-mediated activation of AR needs to be considered in understanding respiratory effects of air pollutants and therapeutics. (This abstract does not reflect US EPA policy).

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