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The β2-subtype of adrenoceptors mediates inhibition of pro-fibrotic events in human lung fibroblasts

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Abstract

Fibrosis is part of airway remodelling observed in bronchial asthma and COPD. Pro-fibrotic activity of lung fibroblasts may be suppressed by β-adrenoceptor activation. We aimed, first, to characterise the expression pattern of β-adrenoceptor subtypes in human lung fibroblasts and, second, to probe β-adrenoceptor signalling with an emphasis on anti-fibrotic actions. Using reverse transcription PCR, messenger RNA (mRNA) encoding β2-adrenoceptors was detected in MRC-5, HEL-299 and primary human lung fibroblasts, whereas transcripts for β1- and β3-adrenoceptors were not found. Real-time measurement of dynamic mass redistribution in MRC-5 cells revealed β-agonist-induced Gs-signalling. Proliferation of MRC-5 cells (determined by [3H]-thymidine incorporation) was significantly inhibited by β-agonists including the β2-selective agonist formoterol (−logIC50, 10.2) and olodaterol (−logIC50, 10.6). Formoterol’s effect was insensitive to β1-antagonism (GCP 20712, 3 μM), but sensitive to β2-antagonism (ICI 118,551; apparent, pA 2, 9.6). Collagen synthesis in MRC-5 cells (determined by [3H]-proline incorporation) was inhibited by β-agonists including formoterol (−logIC50, 10.0) and olodaterol (−logIC50, 10.3) in a β2-blocker-sensitive manner. α-Smooth muscle actin, a marker of myo-fibroblast differentiation, was down-regulated at the mRNA and the protein level by about 50% following 24 and 48 h exposure to 1 nM formoterol, a maximally active concentration. In conclusion, human lung fibroblasts exclusively express β2-adrenoceptors and these mediate inhibition of various markers of pro-fibrotic cellular activity. Under clinical conditions, anti-fibrotic actions may accompany the therapeutic effect of long-term β2-agonist treatment of bronchial asthma and COPD.

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Acknowledgement

This work was supported by Research Grants from AstraZeneca, Boehringer Ingelheim and Bonfor, University of Bonn. The paper contains part of the Ph.D. thesis of FL and ASA. We thank M. Fuhrmann for excellent technical assistance. W.K.S. was supported by the NRW International Graduate Research School BIOTECH-PHARMA.

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Authors and Affiliations

  1. Institute of Pharmacology & Toxicology, University of Bonn, Bonn, Germany

    F. Lamyel, M. Warnken-Uhlich, A. S. Ahmedat, M. Smit & Kurt Racké

  2. Pharmacology & Toxicology Section, Institute of Pharmacy, University of Bonn, Bonn, Germany

    W. K. Seemann & K. Mohr

  3. Institute of Pharmaceutical Biology, University of Bonn, Bonn, Germany

    E. Kostenis

  4. Department of Molecular Pharmacology, University of Groningen, Groningen, The Netherlands

    M. Smit, R. Gosens & H. Meurs

  5. Clinical Pharmacology & DMPK, AstraZeneca R&D, Lund, Sweden

    A. Miller-Larsson

  6. Institute of Pharmacology & Toxicology, Biomedical Center, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Kurt Racké

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  1. F. Lamyel
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Correspondence to Kurt Racké.

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F. Lamyel and M. Warnken-Uhlich contributed equally to this work.

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Lamyel, F., Warnken-Uhlich, M., Seemann, W.K. et al. The β2-subtype of adrenoceptors mediates inhibition of pro-fibrotic events in human lung fibroblasts. Naunyn-Schmiedeberg's Arch Pharmacol 384, 133–145 (2011). https://doi.org/10.1007/s00210-011-0655-5

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