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The inhibition of human lung fibroblast proliferation and differentiation by Gs-coupled receptors is not predicted by the magnitude of cAMP response

Overview of attention for article published in Respiratory Research, April 2018
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4 tweeters

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Title
The inhibition of human lung fibroblast proliferation and differentiation by Gs-coupled receptors is not predicted by the magnitude of cAMP response
Published in
Respiratory Research, April 2018
DOI 10.1186/s12931-018-0759-2
Pubmed ID
Authors

Maxine J. Roberts, Rebecca E. Broome, Toby C. Kent, Steven J. Charlton, Elizabeth M. Rosethorne

Abstract

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. 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. Expression analysis of GPCR showed that the prostacyclin, prostaglandin E2(PGE2) receptor 2 and 4, melanocortin-1, β2adrenoceptor, 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. 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.

Twitter Demographics

The data shown below were collected from the profiles of 4 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 23 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 23 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 6 26%
Student > Ph. D. Student 3 13%
Student > Bachelor 3 13%
Student > Doctoral Student 3 13%
Other 2 9%
Other 5 22%
Unknown 1 4%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 9 39%
Pharmacology, Toxicology and Pharmaceutical Science 5 22%
Agricultural and Biological Sciences 3 13%
Medicine and Dentistry 2 9%
Nursing and Health Professions 1 4%
Other 0 0%
Unknown 3 13%

Attention Score in Context

This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 12 April 2018.
All research outputs
#7,758,547
of 13,793,900 outputs
Outputs from Respiratory Research
#970
of 1,694 outputs
Outputs of similar age
#134,840
of 274,124 outputs
Outputs of similar age from Respiratory Research
#1
of 2 outputs
Altmetric has tracked 13,793,900 research outputs across all sources so far. This one is in the 42nd percentile – i.e., 42% of other outputs scored the same or lower than it.
So far Altmetric has tracked 1,694 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 5.2. This one is in the 38th percentile – i.e., 38% of its peers scored the same or lower than it.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 274,124 tracked outputs that were published within six weeks on either side of this one in any source. This one is in the 48th percentile – i.e., 48% of its contemporaries scored the same or lower than it.
We're also able to compare this research output to 2 others from the same source and published within six weeks on either side of this one. This one has scored higher than all of them