Late Breaking Abstract - β2-Adrenoceptor Dysfunction in Severe Asthma

<bold>Rationale:</bold> Impaired β2-AR function in airway smooth muscle (ASM) cells is a possible mechanism for poor efficacy of β2-agonist therapy in severe asthma. <bold>Methods:</bold> ASM cell responsiveness to β2-agonists in healthy and severe asthmatic subjects was investigated by their ability to inhibit chemokine production & induce STC-1 induction, promote collagen gel relaxation, produce cAMP accumulation, induce phosphorylation of VASP, and modulate transcriptome response using RNA-seq. Also, altering β2-AR expression was assessed to determine if it rescued β2-AR function in severe asthma. <bold>Results:</bold> Healthy ASM cells with albuterol dose-dependently inhibited CCL5, PTX3, and CXCL-10 production induced by TNFα, respectively. In contrast, albuterol failed to inhibit chemokine production in severe asthma ASM cells treated with TNFα. Albuterol-induced STC-1 production was significantly reduced in ASM cells from severe asthmatics when compared to healthy ASM cells. Albuterol reduced the spontaneous contraction of healthy cell-embedded collagen gels by 50.1%, while no effect was seen in severe asthmatic cell-embedded collagen gels. In addition, β2-agonists-induced cAMP production and VASP phosphorylation at ser157 or ser239 were reduced in ASM cells from severe asthmatics when compared to cells from healthy subjects. The RNA-Seq analysis uncovered a profound difference in the transcriptomic response associated with β2-AR activation in ASM cells in severe asthma compared to healthy controls, with a number of genes and associated different pathways being absent or reduced in severe asthma. Interestingly, overexpressing β2-AR in severe asthmatic ASM cells rescued their responsiveness to β2-agonists to inhibit chemokine production and induce cAMP production.