EFFECT OF THE β2-ADRENERGIC AGONIST ALBUTEROL ON PARATHYROID HORMONE-RELATED PROTEIN SIGNALING BY PULMONARY ALVEOLAR TYPE II CELLS.

Abstract

Listen

Translate article

Background Secretogogues, including β2-adrenergic agonists, bind to receptors on alveolar type II cells (ATII) and stimulate surfactant synthesis and secretion. Our laboratory has established an essential role for parathyroid hormone-related protein (PTHrP) signaling in alveolar development and surfactant synthesis. However, the effect of β2-adrenergic agonists such as albuterol, a common treatment of acute asthma exacerbations, is unknown. We hypothesize that albuterol will up-regulate the intermediary steps in alveolar type II cells that mediate the PTHrP signaling pathway. Further, levalbuterol (R-albuterol) will positively affect the PTHrP signaling pathway, whereas S-albuterol will have an inhibitory effect. Objective To determine the effects of albuterol on ATII PTHrP signaling pathway. Methods Lung ATII (either A549 or fetal rat at embryonic day 21) cells were cultured under standard conditions. At near-confluence, the cells were treated with R-albuterol, S-albuterol, or racemic-albuterol (50:50 mixture of R- and S-albuterols) (1 × 10−9 to 1 × 10−4 M for each) for 24 hours. The molecular markers of PTHrP signaling were then analyzed at mRNA (RT-PCR) and protein (Western blot) levels. The specific markers examined included PTHrP, leptin receptor, surfactant proteins A and B, and [3H]choline uptake for surfactant phospholipid synthesis. Results In general, albuterol treatment stimulated alveolar type II cell PTHrP signaling (increased PTHrP and leptin receptor expression), which was accompanied by an increase in surfactant protein B and surfactant phospholipid synthesis. Further, R-albuterol and racemic (R + S) albuterol, in general, had a stimulatory effect on PTHrP signaling, whereas, in contrast, S-albuterol had no effect or inhibitory effects. There were no significant differences in the effects of R- versus racemic (R + S) albuterol in stimulating either PTHrP signaling or surfactant phospholipid synthesis. Conclusions The β2-adrenergic agonist albuterol stimulates PTHrP signaling in pulmonary ATII. Further, R- and racemic (R + S)-albuterol are equally efficacious in stimulating PTHrP signaling and surfactant synthesis in alveolar type II cells, whereas S-albuterol may be inhibitory. Supported by grants from Sepracor Inc. and the NIH (HL55268 and HL075405).