Increased beta 2-adrenoceptor phosphorylation in airway smooth muscle in severe asthma: possible role of mast cell-derived growth factors

The purpose of this study was to investigate whether growth factors produced by activated human lung mast cells (HLMCs) impair (2)-adrenoceptor ((2)-AR) function in human airway smooth muscle (ASM) cells. Protein array analysis confirmed the presence of various growth factors, including transforming growth factor (TGF)-1, in the supernatants of high-affinity IgE receptor (Fc epsilon RI)-activated HLMCs which, when applied to ASM cells, impaired albuterol-induced cyclic adenosine monophosphate (cAMP) production, an effect that was prevented following neutralization of TGF-1. This blunted (2)-AR response was reproduced by treating ASM cells with TGF-1 or fibroblast growth factor (FGF)-2, which induced (2)-AR phosphorylation at tyrosine residues Tyr(141) and Tyr(350), and significantly reduced the maximal bronchorelaxant responses to isoproterenol in human precision cut lung slices (PCLS). Finally, ASM cells isolated from severe asthmatics displayed constitutive elevated (2)-AR phosphorylation at both Tyr(141) and Tyr(350) and a reduced relaxant response to albuterol. This study shows for the first time that abnormal (2)-AR phosphorylation/function in ASM cells that is induced rapidly by HLMC-derived growth factors, is present constitutively in cells from severe asthmatics.