Beta adrenergic pathway independent relaxation of human airway smooth muscle (870.9)

Severe acute asthma, defined as asthma that is refractory to current anti‐inflammatory agents and bronchodilators, accounts for an estimated two‐million emergency department visits annually. β 2 ‐adrenergic receptor (β 2 AR) agonists (β‐agonists) are widely used for the treatment of bronchospasm associated with acute asthma attacks, however, some patients develop refractory responses to long term usage of β –agonists. It also causes adverse effects in patients with a genetic polymorphism (Arg/Arg genotype, about a sixth of the US population) in the adrenergic receptor creating a need for additional therapeutics for managing asthma. We have shown earlier that β‐agonist induced airway smooth muscle (ASM) relaxation is associated with increases in the phosphorylation of HSP20. In this study we evaluate the effect of a transducible phosphopeptide mimetic of HSP20 protein (P20 peptide) on the relaxation of human ASM. Freshly isolated human ASM was pretreated with either a β‐agonist, isoproterenol (ISO), or the P‐20 peptide followed by a bronchoconstrictor, carbachol and force was measured in a tissue bath system. ISO blocked carbachol induced contraction in human ASM by activating the β 2 AR pathway. P‐20 peptide also blocked carbachol induced contraction of ASM, but in a β 2 AR independent manner. P20 peptide also relaxed human ASM precontracted with carbachol. These results suggest that the P20 peptide targets molecular events downstream of the β‐agonists‐cAMP pathway and that P20 peptide may be developed as a therapeutic to alleviate bronchospasm for patients who are refractory to β‐agonist, thus reducing the morbidity, mortality, and costs associated with managing asthma. Grant Funding Source : Supported by NIH RO1 70715