Adrenergic receptor subtypes differentially influence acrolein-induced ventilatory, vascular leakage, and inflammatory responses

Adrenergic receptors (AR) are manipulated therapeutically for the treatment of pulmonary and cardiovascular diseases; however, their role in air pollutant-induced respiratory effects is poorly understood. We examined the contribution of AR-subtypes in acrolein-induced respiratory effects through selective receptor inhibition. We pre-treated 12-week-old male Wistar-Kyoto rats intraperitoneally daily for 9-days with subtype-specific AR antagonists prazosin (PRZ, α1-AR antagonist; 2-mg/kg-day), yohimbine (YOH, α2-AR antagonist; 5-mg/kg-day), or propranolol (PROP, β-AR antagonist; 10-mg/kg-day). On day-8 and day-9 of treatment, rats were exposed nose-only to air or acrolein (1.6 or 3.2 ppm), ~4 hours/day. Head-out plethysmography during exposure on Day-9 revealed overall acrolein-related reduced ventilatory capacity, which was exacerbated in PRZ- and YOH-treated animals. Nasal (NALF) and bronchoalveolar lavage fluid (BALF), and blood samples were collected on day-9. Plasma epinephrine levels did not change; however, corticosterone decreased in YOH- and PROP-treated air-exposed animals. Adrenal and spleen weights were higher in PRZ-treated animals. Acrolein depleted circulating lymphocytes in saline-treated and increased neutrophils in PRZ- and YOH-treated animals. NALF and BALF analysis indicated robust acrolein-induced neutrophilic and lymphocytic inflammation (NALF>BALF), which was exacerbated in lung of PRZ- and YOH-treated rats and slightly dampened in PROP-treated rats. However, acrolein-induced vascular protein leakage and increases in inflammatory cytokines in NALF were reduced by PROP-treatment. In conclusion, this study highlights sympathetically-mediated adrenoreceptor influence on acrolein-indued respiratory health effects, and AR subtype-specific modulation of breathing, hemodynamic, and inflammatory responses. These results have broader translational implications, as those receiving adrenergic agonistic/antagonistic therapies might experience variable air pollution-related respiratory health effects.

Impact/Purpose

Acrolein is a high priority hazardous chemical regulated by EPA. Our data highlight the specific roles of adrenergic receptor subtypes (a1-AR, a2-AR, and b-AR) in acrolein-induced airway injury and inflammation. Each AR-subtype antagonist inhibits acrolein-induced vascular leakage, likely via differing mechanisms on respiratory hemodynamics. We also observed distinct effects by AR-subtype on nasal and lung inflammation, where a1/2-AR antagonism appeared to worsen acrolein-induced cytotoxicity and inflammation, and b-AR antagonism improved vascular and pro-inflammatory effects of acrolein. The potential clinical ramifications of these findings are that bronchodilators (commonly used b2-AR agonists) may worsen inflammation, while non-specific AR antagonists could offer additional protection. Nonetheless, a better understanding of how drug-air pollutant interactions affect susceptibility to air pollution-induced adverse health effects is crucial. Future studies should consider the role of stress-mediated AR signaling in respiratory and immune responses to air pollutants, as well as the therapeutic potential of AR-specific treatments.

Citation

Alewel, D., S. Gavett, K. Rentschler, M. Schladweiler, C. Miller, P. Evansky, T. Jackson, W. Williams, AND U. Kodavanti. Adrenergic receptor subtypes differentially influence acrolein-induced ventilatory, vascular leakage, and inflammatory responses. Elsevier B.V., Amsterdam, NETHERLANDS, 498:117303, (2025). [DOI: 10.1016/j.taap.2025.117303]

DOI: Adrenergic receptor subtypes differentially influence acrolein-induced ventilatory, vascular leakage, and inflammatory responses