ETB Receptor Deficiency Amplifies Allergic Airway Inflammation and Hyperresponsiveness

Background Endothelin-1 (ET-1) is a proinflammatory mediator that plays a crucial role in regulating airway tone by activating G-protein coupled endothelin receptors A (ET A ) and B (ET B ). The endothelin system has been linked to asthma, but the impact of ET B receptor deficiency on allergic airway inflammation remains uncharted. This study explores how the endothelin system influences allergic airway inflammation and hyperresponsiveness. Methods We used rescued ET B receptor-deficient (ET B −/− ) mice to obviate lethal inherited Hirschsprung disease, prepro-ET-1 overexpressing ( pre ET tg ), and wild-type (WT) mice. Basal airway resistance and responsiveness to broncho-constrictive stimuli were assessed in isolated, perfused and ventilated lungs of naïve mice. Additionally, we analyzed the humoral immune response and airway hyperresponsiveness following induction of type 2 airway inflammation induced by systemic ovalbumin (OVA) sensitization and repeated airway challenge with aerosolized OVA. Results Naïve ET B −/− mice exhibited significantly heightened airway responsiveness compared to naïve WT mice. After OVA sensitization and challenge, ET B −/− mice displayed increased OVA-specific immunoglobulin E levels, intensified allergic airway inflammation and hyperresponsiveness compared to WT mice. Conversely, pre ET tg mice displayed reduced airway inflammation and hyperresponsiveness. Conclusion Our findings suggest ET B receptors have a protective role in asthma-associated allergic airway inflammation and hyperresponsiveness. The increased asthma phenotype in sensitized and challenged ET B −/− mice is attributed to ET B -specific immunomodulatory mechanisms, rather than to elevated levels of ET-1 resulting from impaired ET B -mediated ET-1 clearance. This conclusion is supported by the diminished asthma-phenotype observed in sensitized and challenged pre ET tg mice. Therefore, adjusting endothelin signaling could offer a promising approach to managing asthma. (250 words)