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Published on: May 5, 2011
Adrenergic receptor subtypes differentially influence acrolein-induced ventilatory, vascular leakage, and
Devin I Alewel1, Stephen H Gavett2, Katherine M Rentschler3
1Existing Chemicals Risk Assessment Division, Office of Chemical Safety and Pollution Prevention, U.S. Environmental Protection Agency, Research Triangle Park, NC, United States of America.
Abstract:
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 h/day. Head-out plethysmography during exposure on Day-9 revealed overall concentration-dependent 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, 3.2-ppm depleted circulating lymphocytes in saline-treated and increased neutrophils in PRZ- and YOH-treated animals. NALF and BALF analysis indicated 3.2-ppm 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.
Insights
Adrenergic receptors (AR) influence respiratory responses to acrolein exposure. Blocking alpha-AR subtypes worsened breathing issues, while beta-AR blockers offered some protection against inflammation and vascular leakage from air pollutants.
Area of Science:
- Environmental Toxicology
- Respiratory Pharmacology
- Adrenergic Receptor Signaling
Background:
- Adrenergic receptors (AR) are crucial for cardiovascular and pulmonary functions.
- The specific role of AR subtypes in air pollutant-induced respiratory damage remains unclear.
- Acrolein is a common air pollutant with known respiratory irritant properties.
Purpose of the Study:
- To investigate the contribution of specific adrenergic receptor subtypes (α1-AR, α2-AR, β-AR) in acrolein-induced respiratory effects.
- To determine how selective AR antagonists modulate breathing, inflammation, and vascular responses to acrolein exposure.
Main Methods:
- Wistar-Kyoto rats were treated daily for 9 days with subtype-specific AR antagonists: prazosin (α1-AR), yohimbine (α2-AR), or propranolol (β-AR).
- Rats were exposed to air or acrolein (1.6 or 3.2 ppm) for 4 hours/day on days 8 and 9.
- Respiratory function (plethysmography), bronchoalveolar lavage fluid (BALF), nasal lavage fluid (NALF), and blood parameters were analyzed.
Main Results:
- Acrolein exposure reduced ventilatory capacity, an effect worsened by prazosin and yohimbine treatment.
- Acrolein-induced neutrophilic and lymphocytic inflammation in NALF and BALF was exacerbated by prazosin and yohimbine but dampened by propranolol.
- Propranolol treatment reduced acrolein-induced vascular protein leakage and inflammatory cytokine levels in NALF.
Conclusions:
- Sympathetic nervous system-mediated adrenergic receptor signaling significantly influences respiratory health effects from acrolein exposure.
- Specific AR subtypes differentially modulate breathing, hemodynamic, and inflammatory responses to air pollutants.
- These findings suggest that individuals on adrenergic therapies may experience variable respiratory health outcomes when exposed to air pollution.
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