Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the Adverse and Therapeutic Effects ofβ₂-Adrenoceptor Agonists

3区 · 医学

Article

作者: Jamieson, Kyla C ; Mostafa, Mahmoud M ; Yan, Dong ; Joshi, Radhika ; Joshi, Taruna ; Giembycz, Mark A ; Newton, Robert ; Hamed, Omar

The contribution of gene expression changes to the adverse and therapeutic effects of β₂-adrenoceptor agonists in asthma was investigated using human airway epithelial cells as a therapeutically relevant target. Operational model-fitting established that the long-acting β₂-adrenoceptor agonists (LABA) indacaterol, salmeterol, formoterol, and picumeterol were full agonists on BEAS-2B cells transfected with a cAMP-response element reporter but differed in efficacy (indacaterol ≥ formoterol > salmeterol ≥ picumeterol). The transcriptomic signature of indacaterol in BEAS-2B cells identified 180, 368, 252, and 10 genes that were differentially expressed (>1.5- to <0.67-fold) after 1-, 2-, 6-, and 18-hour of exposure, respectively. Many upregulated genes (e.g., AREG, BDNF, CCL20, CXCL2, EDN1, IL6, IL15, IL20) encode proteins with proinflammatory activity and are annotated by several, enriched gene ontology (GO) terms, including cellular response to interleukin-1, cytokine activity, and positive regulation of neutrophil chemotaxis The general enriched GO term extracellular space was also associated with indacaterol-induced genes, and many of those, including CRISPLD2, DMBT1, GAS1, and SOCS3, have putative anti-inflammatory, antibacterial, and/or antiviral activity. Numerous indacaterol-regulated genes were also induced or repressed in BEAS-2B cells and human primary bronchial epithelial cells by the low efficacy LABA salmeterol, indicating that this genomic effect was neither unique to indacaterol nor restricted to the BEAS-2B airway epithelial cell line. Collectively, these data suggest that the consequences of inhaling a β₂-adrenoceptor agonist may be complex and involve widespread changes in gene expression. We propose that this genomic effect represents a generally unappreciated mechanism that may contribute to the adverse and therapeutic actions of β₂-adrenoceptor agonists in asthma.

1997-02-01·British Journal of Clinical Pharmacology2区 · 医学

Picumeterol: dissociation of improvement in lung function and reduction of airways hyperresponsiveness in asthmatics

2区 · 医学

Article

作者: R. A. Coleman ; D. S. Postma ; A. T. Nials ; G. H. Koëter ; E. J. M. Weersink ; Y. Man

Aims The new potent and selective β2‐adrenoceptor agonist, GR 114297A (picumeterol) is the R‐enantiomer of the racemic form, GR 63411B. Picumeterol has been shown to produce long‐lasting relaxation of airways smooth muscle both in vitro and in vivo. We assessed the intrinsic activity of picumeterol by increasing intracellular levels of c‐AMP and compared this with isoprenaline and salbutamol.Methods In human atopic asthmatics, we have investigated the duration of action and efficacy of picumeterol and GR 63411B with regard to improvement in resting lung function (i.e. FEV1 ) and airways responsiveness (i.e. PC20 ) to methacholine (MCh). The study design consists of two clinical parts each for one drug. Different asthmatics participated in the two studies, seven in the first part and eight in the second part. In human bronchial smooth muscle cells in vitro, we have investigated the intrinsic activity of picumeterol in increasing intracellular levels of cyclic AMP and compared it with isoprenaline and salbutamol.Results In vivo, both drugs caused bronchodilatation with similar potency, but, their effects were short‐lasting. Despite their bronchodilator activity, neither drug improved PC20, when compared with placebo. In vitro, picumeterol was found have intrinsic activity lower than the other β2‐adrenoceptor agonists tested.Conclusions In the clinical studies, the bronchodilator potencies of picumeterol and GR 63411B were similar. However, both drugs were short‐acting, which is at odds with their activity in vitro. Our data suggest that these compounds display dissociation between bronchodilator activity and protection against MCh‐induced bronchoconstriction. These findings may be explained by low intrinsic activity and need further conformation.

1996-06-01·General Pharmacology: The Vascular System

Some pharmacodynamic aspects on long-acting β-adrenoceptor agonists

Review

作者: Waldeck, B

1. Formoterol and salmeterol are the first members of a new generation of long-acting beta(2)-adrenoceptor agonists for inhalation. The discovery of the long effect duration of formoterol was made by chance, while the development of salmeterol appeared to follow a purposeful research strategy. 2. Preclinical evaluation predictive of the clinical duration of effect of long-acting bronchodilators is not straightforward. Experiments in vitro may give false positive results, while experiments in vivo may show false negative results. 3. Once the principle of a long duration of effect was established, a number of novel long-acting beta(2)-adrenoceptor agonists of various chemical structure have emerged. 4. There are two alternative models for the explanation of the long duration of effect: the exosite binding explaining the mode of action of salmeterol, and the more general diffusion microkinetic model applicable for both formoterol and salmeterol. 5. Long-acting beta-adrenoceptor agonists with a relatively low efficacy like salmeterol may, under certain circumstances, inhibit competitively the relaxing effect of agonists with higher efficacy like formoterol and salbutamol. 6. Like all other beta(2)-adrenoceptor agonists in current clinical use, formoterol and salmeterol comprise racemic mixtures. Only the RR- and R-enantiomers are pharmacologically active. The experimental compounds TA-2005 and picumeterol have been developed as pure RR- and R-enantiomers, respectively.

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