JOURNAL ARTICLE
RESEARCH SUPPORT, N.I.H., EXTRAMURAL
RESEARCH SUPPORT, NON-U.S. GOV'T
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β 2 -Adrenoceptor signaling in airway epithelial cells promotes eosinophilic inflammation, mucous metaplasia, and airway contractility.

The mostly widely used bronchodilators in asthma therapy are β2 -adrenoreceptor (β2 AR) agonists, but their chronic use causes paradoxical adverse effects. We have previously determined that β2 AR activation is required for expression of the asthma phenotype in mice, but the cell types involved are unknown. We now demonstrate that β2 AR signaling in the airway epithelium is sufficient to mediate key features of the asthmatic responses to IL-13 in murine models. Our data show that inhibition of β2 AR signaling with an aerosolized antagonist attenuates airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus-production responses to IL-13, whereas treatment with an aerosolized agonist worsens these phenotypes, suggesting that β2 AR signaling on resident lung cells modulates the asthma phenotype. Labeling with a fluorescent β2 AR ligand shows the receptors are highly expressed in airway epithelium. In β2 AR-/- mice, transgenic expression of β2 ARs only in airway epithelium is sufficient to rescue IL-13-induced AHR, inflammation, and mucus production, and transgenic overexpression in WT mice exacerbates these phenotypes. Knockout of β-arrestin-2 (βarr-2-/- ) attenuates the asthma phenotype as in β2 AR-/- mice. In contrast to eosinophilic inflammation, neutrophilic inflammation was not promoted by β2 AR signaling. Together, these results suggest β2 ARs on airway epithelial cells promote the asthma phenotype and that the proinflammatory pathway downstream of the β2 AR involves βarr-2. These results identify β2 AR signaling in the airway epithelium as capable of controlling integrated responses to IL-13 and affecting the function of other cell types such as airway smooth muscle cells.

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