Endothelin-1 contributes to antigen-induced airway hyperresponsiveness

Area of Science:

• Allergy and Immunology
• Respiratory Medicine
• Pharmacology

Background:

• Endothelin A (ETA)-receptors mediate endothelin-1 (ET-1) induced contractions in ovine airway smooth muscle.
• ET-1's role in antigen-induced airway responses in allergic sheep was previously unclear.

Purpose of the Study:

• To test the hypothesis that ET-1 contributes to antigen-induced airway responses in sheep allergic to Ascaris suum.
• To investigate the role of ETA-receptors in mediating these responses using the ETA-receptor antagonist BQ-123.

Main Methods:

• Established BQ-123's protective effect against aerosolized ET-1 induced bronchoconstriction.
• Administered BQ-123 via intravenous infusion or aerosol before and after antigen challenge in allergic sheep.
• Assessed immediate and late-phase bronchoconstriction and airway hyperresponsiveness to carbachol.

Main Results:

• BQ-123 effectively blocked ET-1 induced bronchoconstriction.
• Neither intravenous nor aerosolized BQ-123 blocked immediate antigen-induced bronchoconstriction.
• Both BQ-123 administration routes significantly reduced the late-phase response by approximately 50%.
• Aerosolized BQ-123 blocked antigen-induced airway hyperresponsiveness to carbachol 24 hours post-challenge.
• ET-1 challenge induced airway hyperresponsiveness, which was blocked by BQ-123.

Conclusions:

• Aerosolized ET-1 causes bronchoconstriction via ETA-receptor stimulation in allergic sheep.
• ET-1 is released into the airways following antigen challenge.
• ET-1 contributes to allergic airway responses, likely by increasing airway smooth muscle responsiveness.