Pulmonary fibroblasts, an emerging target for anti-obstructive drugs

Racké, Kurt; Haag, Susanne; Bahulayan, Amit; Warnken, Mareille

doi:10.1007/s00210-008-0264-0

Cited by 24 publications

(20 citation statements)

References 83 publications

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“…Furthermore, AChE also attenuated the CSE-reduced cAMP, which indicates the involvement of the non-neuronal cholinergic system. This may be explained by the fact that the main muscarinic receptor expressed on lung fibroblasts is M2 [32], which is coupled to G i protein, so stimulation of M2 by means of a nonneuronal cholinergic system could also promote the inhibition of adenylate cyclase/cAMP pathway and, therefore, myofibroblast transition.…”

Section: Discussionmentioning

confidence: 99%

Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition

Milara

Serrano

Peiró³

et al. 2012

Eur Respir J

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Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of this remodelling, peribronchiolar fibrosis is observed in the small airways of COPD patients and contributes to airway obstruction. Fibroblast-to-myofibroblast transition is a key step in peribronchiolar fibrosis formation.This in vitro study examined the effect of cigarette smoke on bronchial fibroblast-tomyofibroblast transition, and whether aclidinium bromide inhibits this process. Human bronchial fibroblasts were incubated with aclidinium bromide (10 -9 -10 -7 M) and exposed to cigarette smoke extract. Collagen type I and a-smooth muscle actin (a-SMA) expression were measured by realtime PCR and Western blotting, as myofibroblast markers. Intracellular reactive oxygen species, cyclic AMP (cAMP), extracellular signal-regulated kinase (ERK)1/2 and choline acetyltransferase were measured as intracellular signalling mediators. Cigarette smoke-induced collagen type I and a-SMA was mediated by the production of reactive oxygen species, the depletion of intracellular cAMP and the increase of ERK1/2 phosphorylation and choline acetyltransferase. These effects could be reversed by treatment with the anticholinergic aclidinium bromide, by silencing the mRNA of muscarinic receptors M1, M2 or M3, or by the depletion of extracellular acetylcholine by treatment with acetylcholinesterase.A non-neuronal cholinergic system is implicated in cigarette smoke-induced bronchial fibroblast-to-myofibroblast transition, which is inhibited by aclidinium bromide.

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Section: Discussionmentioning

confidence: 99%

Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition

Milara

Serrano

Peiró³

et al. 2012

Eur Respir J

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“…Since fibrotic alterations are crucial in airway remodelling and fibroblasts represent one of the cell populations of particular significance for structural changes, we recently started to analyse effects of classical anti-obstructive drugs on pulmonary fibroblasts (Racké et al 2008). We demonstrated expression of muscarinic receptors in pulmonary fibroblasts (Matthiesen et al 2006;Haag et al 2008a) and showed that muscarinic receptors mediate stimulatory effects on proliferation and collagen synthesis (Matthiesen et al 2006(Matthiesen et al , 2007Haag et al 2008a).…”

Section: Introductionmentioning

confidence: 95%

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

Lamyel

Warnken-Uhlich

Seemann

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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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 β 2 -adrenoceptors was detected in MRC-5, HEL-299 and primary human lung fibroblasts, whereas transcripts for β 1 -and β 3 -adrenoceptors were not found. Real-time measurement of dynamic mass redistribution in MRC-5 cells revealed β-agonistinduced G s -signalling. Proliferation of MRC-5 cells (determined by [ 3 H]-thymidine incorporation) was significantly inhibited by β-agonists including the β 2 -selective agonist formoterol (−logIC 50 , 10.2) and olodaterol (−logIC 50 , 10.6). Formoterol's effect was insensitive to β 1 -antagonism (GCP 20712, 3 μM), but sensitive to β 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 β-agonists including formoterol (−logIC 50 , 10.0) and olodaterol (−logIC 50 , 10.3) in a β 2 -blockersensitive manner. α-Smooth muscle actin, a marker of myofibroblast 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 β 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 β 2 -agonist treatment of bronchial asthma and COPD.

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“…226: 1970-1980, 2011. ß 2010 Fibrotic alterations in the lung are a pathological feature of pulmonary diseases like asthma, idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD). Although, in contrast to IPF, fibrosis may not be the dominant aspect in asthma and COPD, it is assumed that progression of such structural changes have a strong impact on long-term outcome of these diseases (Racké et al, 2008). In asthma and COPD the activation of fibroblasts leads to an excessive deposition of extracellular matrix proteins that modulate the development of subepithelial fibrosis that affects the large and small airways of the lung (Du et al, 1999;Fahy et al, 2000).…”

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confidence: 98%

The differential impact of PDE4 subtypes in human lung fibroblasts on cytokine‐induced proliferation and myofibroblast conversion

Selige¹,

Hatzelmann²,

Dunkern³

2011

Journal Cellular Physiology

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Lung fibroblast proliferation and differentiation into myofibroblasts are pathological key events during development of lung fibrosis. Cyclic nucleotide signaling is described as a negative modulator of these cellular processes, and cyclic nucleotide degrading type 4 phosphodiesterases (PDE4) are important regulators of these pathways. In this study, we elucidated expression and the role of individual subtypes of PDE4 in primary normal human lung fibroblast (NHLF) in controlling cytokines-induced proliferation and conversion to myofibroblasts by short-interfering RNAs (siRNAs) induced knockdown. We verified the expression of PDE4A, B, and D, while PDE4C was only minor or even not expressed in NHLF. An efficient liposome-mediated transfection method for mRNA silencing and a knockdown of the expressed PDE4 subtypes was achieved in these cells. This knockdown was further validated by PDE4 protein expression analysis and PDE4 activity measurements. Functionally, the knockdown of PDE4A and PDE4B inhibited proliferation induced by the cytokine combination of bFGF and IL-1β, whereas knockdown of PDE4D was ineffective. In contrast, TGF-β induced differentiation into myofibroblasts was affected by knockdown of PDE4B and PDE4D, but not by PDE4A knockdown. In summary, our data allow to assign different PDE4 subtypes to distinct functions of human lung fibroblasts and highlight the predominant role of PDE4B in controlling pathophysiological processes of human lung fibroblasts. This provides a scientific rationale for focused therapeutic targeting of PDE4B to treat respiratory diseases with fibrotic lesions in the lung.

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Pulmonary fibroblasts, an emerging target for anti-obstructive drugs

Cited by 24 publications

References 83 publications

Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition

Aclidinium inhibits cigarette smoke-induced lung fibroblast-to-myofibroblast transition

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

The differential impact of PDE4 subtypes in human lung fibroblasts on cytokine‐induced proliferation and myofibroblast conversion

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