ET_B receptor deficiency amplifies allergic airway inflammation and hyperresponsiveness

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.

We used rescued ET_B receptor-deficient (ET_B ^-/-) mice to obviate lethal inherited Hirschsprung disease, prepro-ET-1 overexpressing (_preET^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 analysed the humoral immune response and airway hyperresponsiveness following induction of type 2 airway inflammation induced by systemic ovalbumin (OVA) sensitisation and repeated airway challenge with aerosolised OVA.

Naïve ET_B ^-/- mice exhibited significantly heightened airway responsiveness compared to naïve WT mice. After OVA sensitisation and challenge, ET_B ^-/- mice displayed increased OVA-specific immunoglobulin E levels, intensified allergic airway inflammation and hyperresponsiveness compared to WT mice. Conversely, _preET^tg mice displayed reduced immunoglobulin E levels, airway inflammation and hyperresponsiveness.

Our findings suggest ET_B receptors have a protective role in asthma-associated allergic airway inflammation and hyperresponsiveness. The increased asthma phenotype in sensitised 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 sensitised and challenged _preET^tg mice. Therefore, adjusting endothelin signalling could offer a promising approach to managing asthma.