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 (ETA) and B (ETB). The endothelin system has been linked to asthma, but the impact of ETB 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 ETB receptor-deficient (ETB -/-) mice to obviate lethal inherited Hirschsprung disease, prepro-ET-1 overexpressing (preETtg), 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.

RESULTS

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

CONCLUSION

Our findings suggest ETB receptors have a protective role in asthma-associated allergic airway inflammation and hyperresponsiveness. The increased asthma phenotype in sensitised and challenged ETB -/- mice is attributed to ETB-specific immunomodulatory mechanisms, rather than to elevated levels of ET-1 resulting from impaired ETB-mediated ET-1 clearance. This conclusion is supported by the diminished asthma-phenotype observed in sensitised and challenged preETtg mice. Therefore, adjusting endothelin signalling could offer a promising approach to managing asthma.