Free fatty acid receptors, FFAR1 and FFAR4, are novel bronchodilator targets in mouse and human precision-cut lung slices

Abstract

Background: Alternative dilator targets need to be identified for severe asthma, as excessive use of β2-adrenoceptor agonists causes desensitization and loss of efficacy. Free fatty acid receptors, FFAR1 and FFAR4, are highly expressed in mouse and human airways but their role in the regulation of contraction is unclear. Aims: To assess FFAR1/FFAR4 agonists as bronchodilators. Methods: Precision cut lung slices (PCLS) containing small airways (100-300 μm diam) were prepared to visualise changes in area in response to the dual FFAR1/FFAR4 agonists TUG891 (FFAR4-biased), GW9508 (FFAR1-biased) or salbutamol. Immunohistochemistry for FFARs was performed in airways from saline- and ovalbumin-challenged mice and from non-asthmatic and asthmatic subjects. Results: TUG891 and GW8508 caused slower relaxation than salbutamol but with greater efficacy in both mouse and human PCLS. β2-mediated relaxation was abolished with increasing pre-contraction with MCh or by overnight incubation with salbutamol. In contrast, responses to TUG891 and GW8508 were maintained in maximally contracted airways or after incubation with the same FFAR agonist or salbutamol. Expression of FFAR1 and FFAR4 was evident in airway epithelium and smooth muscle and unchanged after allergen challenge. Conclusions: FFAR1/FFAR4 agonists elicit airway relaxation under conditions that mimic severe asthma. Their activity profile relative to β2-agonists is favourable, showing resistance to homologous or heterologous desensitization and maintained efficacy in maximally contracted airways. Expression of FFAR1 and FFAR4 in asthmatic airways supports further investigation of these novel dilator targets.