Abstract:
BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease for which there is no cure. Current therapeutics are only able to slow disease progression, therefore there is a need to explore alternative, novel treatment options. There is increasing evidence that the 3', 5' cyclic adenosine monophosphate (cAMP) pathway is an important modulator in the development of fibrosis, with increasing levels of cAMP able to inhibit cellular processes associated with IPF. In this study we investigate the expression of Gs-coupled G protein-coupled receptors (GPCR) on human lung fibroblasts (HLF), and explore which can increase cAMP levels, and are most efficacious at inhibiting proliferation and differentiation. METHODS:Using TaqMan arrays we determined that fibroblasts express a range of Gs-coupled GPCR. The function of selected agonists at expressed receptors was then tested in a cAMP assay, and for their ability to inhibit fibroblast proliferation and differentiation. RESULTS:Expression analysis of GPCR showed that the prostacyclin, prostaglandin E2 (PGE2) receptor 2 and 4, melanocortin-1, β2 adrenoceptor, adenosine 2B, dopamine-1, and adenosine 2A receptors were expressed in HLF. Measuring cAMP accumulation in the presence of selected Gs-coupled receptor ligands as well as an adenylyl cyclase activator and inhibitors of phosphodiesterase showed formoterol, PGE2, treprostinil and forskolin elicited maximal cAMP responses. The agonists that fully inhibited both fibroblast proliferation and differentiation, BAY60-6583 and MRE-269, were partial agonists in the cAMP accumulation assay. CONCLUSIONS:In this study we identified a number of ligands that act at a range of GPCR that increase cAMP and inhibit fibroblast proliferation and differentiation, suggesting that they may provide novel targets to develop new IPF treatments. From these results it appears that although the cAMP response is important in driving the anti-fibrotic effects we have observed, the magnitude of the acute cAMP response is not a good predictor of the extent of the inhibitory effect. This highlights the importance of monitoring the kinetics and localisation of intracellular signals, as well as multiple pathways when profiling novel compounds, as population second messenger assays may not always predict phenotypic outcomes.
journal_name
Respir Resjournal_title
Respiratory researchauthors
Roberts MJ,Broome RE,Kent TC,Charlton SJ,Rosethorne EMdoi
10.1186/s12931-018-0759-2subject
Has Abstractpub_date
2018-04-07 00:00:00pages
56issue
1eissn
1465-9921issn
1465-993Xpii
10.1186/s12931-018-0759-2journal_volume
19pub_type
杂志文章abstract::The lung responds to a variety of insults in a remarkably consistent fashion but with inconsistent outcomes that vary from complete resolution and return to normal to the destruction of normal architecture and progressive fibrosis. Increasing evidence indicates that diffuse lung disease results from an imbalance betwe...
journal_title:Respiratory research
pub_type: 杂志文章,评审
doi:10.1186/rr177
更新日期:2002-01-01 00:00:00
abstract:BACKGROUND:Legionella pneumophila (LPN) can cause a lethal infectious disease with a marked inflammatory response in humans. However, the mechanism of this severe inflammation remains poorly understood. Since necrosis is known to induce inflammation, we investigated whether LPN induces necrosis in macrophages. We also ...
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pub_type: 杂志文章
doi:10.1186/1465-9921-11-158
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abstract::The language of science should be objective and detached and should place data in the appropriate context. The aim of this commentary was to explore the notion that recent trends in the use of language have led to a loss of objectivity in the presentation of scientific data. The relationship between the value-laden vo...
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pub_type: 社论
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abstract:BACKGROUND:CD14, a receptor for lipopolysaccharides (LPS), is found in both a membrane-bound form (mCD14) and a soluble form (sCD14). It is suggested that sCD14 is mainly released from blood monocytes by serine protease-mediated shedding. Because alpha1-antitrypsin (AAT), an inhibitor of serine proteases, has been show...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-9-34
更新日期:2008-04-21 00:00:00
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pub_type: 杂志文章
doi:10.1186/1465-9921-11-30
更新日期:2010-03-16 00:00:00
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doi:10.1186/1465-9921-7-143
更新日期:2006-12-14 00:00:00
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pub_type: 杂志文章
doi:10.1186/1465-9921-14-103
更新日期:2013-10-09 00:00:00
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journal_title:Respiratory research
pub_type: 信件
doi:10.1186/s12931-016-0441-5
更新日期:2016-10-07 00:00:00
abstract:BACKGROUND:Discrepancy exists amongst studies investigating the effect of comorbid heart failure (HF) on the morbidity and mortality of chronic obstructive pulmonary disease (COPD) patients. METHODS:MEDLINE and Embase were searched using a pre-specified search strategy for studies comparing hospitalisation, rehospital...
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pub_type: 杂志文章,meta分析
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pub_type: 杂志文章,评审
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更新日期:2001-01-01 00:00:00
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pub_type: 杂志文章,评审
doi:10.1186/rr81
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pub_type: 杂志文章,多中心研究,随机对照试验
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更新日期:2018-12-13 00:00:00
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doi:10.1186/1465-9921-8-75
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abstract:: ...
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pub_type:
doi:10.1186/s12931-018-0930-9
更新日期:2018-12-20 00:00:00
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更新日期:2015-11-16 00:00:00
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pub_type: 临床试验,杂志文章,多中心研究
doi:10.1186/s12931-019-1053-7
更新日期:2019-05-14 00:00:00
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journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-6-25
更新日期:2005-03-05 00:00:00
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pub_type: 杂志文章
doi:10.1186/1465-9921-13-89
更新日期:2012-10-03 00:00:00
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pub_type: 评论,杂志文章
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更新日期:2012-09-19 00:00:00
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journal_title:Respiratory research
pub_type: 临床试验,杂志文章
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pub_type: 杂志文章
doi:10.1186/1465-9921-10-6
更新日期:2009-01-27 00:00:00
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pub_type: 杂志文章,多中心研究
doi:10.1186/1465-9921-15-27
更新日期:2014-03-04 00:00:00
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pub_type: 杂志文章,评审
doi:10.1186/rr53
更新日期:2001-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1186/s12931-015-0229-z
更新日期:2015-06-13 00:00:00
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pub_type: 杂志文章
doi:10.1186/1465-9921-8-73
更新日期:2007-10-25 00:00:00
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pub_type: 杂志文章
doi:10.1186/1465-9921-10-99
更新日期:2009-10-26 00:00:00
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pub_type: 杂志文章
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更新日期:2011-04-27 00:00:00
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pub_type: 杂志文章
doi:10.1186/s12931-018-0933-6
更新日期:2018-11-20 00:00:00