The beta2-subtype of adrenoceptors mediates inhibition of pro-fibrotic events in human lung fibroblasts.
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Lamyel F, Warnken-Uhlich M, Seemann WK, Mohr K, Kostenis E, Ahmedat AS, Smit M, Gosens R, Meurs H, Miller-Larsson A, Racke K
The beta2-subtype of adrenoceptors mediates inhibition of pro-fibrotic events in human lung fibroblasts.
Naunyn Schmiedebergs Arch Pharmacol. 2011 Aug;384(2):133-45. doi: 10.1007/s00210-011-0655-5. Epub 2011 May 21.
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- 21603974 [ View in PubMed]
- Abstract
Fibrosis is part of airway remodelling observed in bronchial asthma and COPD. Pro-fibrotic activity of lung fibroblasts may be suppressed by beta-adrenoceptor activation. We aimed, first, to characterise the expression pattern of beta-adrenoceptor subtypes in human lung fibroblasts and, second, to probe beta-adrenoceptor signalling with an emphasis on anti-fibrotic actions. Using reverse transcription PCR, messenger RNA (mRNA) encoding beta(2)-adrenoceptors was detected in MRC-5, HEL-299 and primary human lung fibroblasts, whereas transcripts for beta(1)- and beta(3)-adrenoceptors were not found. Real-time measurement of dynamic mass redistribution in MRC-5 cells revealed beta-agonist-induced G(s)-signalling. Proliferation of MRC-5 cells (determined by [(3)H]-thymidine incorporation) was significantly inhibited by beta-agonists including the beta(2)-selective agonist formoterol (-logIC(50), 10.2) and olodaterol (-logIC(50), 10.6). Formoterol's effect was insensitive to beta(1)-antagonism (GCP 20712, 3 muM), but sensitive to beta(2)-antagonism (ICI 118,551; apparent, pA (2), 9.6). Collagen synthesis in MRC-5 cells (determined by [(3)H]-proline incorporation) was inhibited by beta-agonists including formoterol (-logIC(50), 10.0) and olodaterol (-logIC(50), 10.3) in a beta(2)-blocker-sensitive manner. alpha-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 beta(2)-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 beta(2)-agonist treatment of bronchial asthma and COPD.