Pulmonary arterial hypertension (PAH) is a rare, devastating disease with no
cure. Current treatment consists of a cocktail of vasodilators which relieve
symptoms of PAH but do not treat the cause. Thus, there is a need for novel
drugs that target the underlying pathological causes of PAH.
PAH is a multi-factorial, but one key contributor is the pro-inflammatory
cytokine IL-6 which stimulates pro-inflammatory and pro-angiogenic signalling
mediated by the JAK/STAT pathway. One way in which IL-6 signalling via
JAK/STAT is inhibited is via SOCS3 in a type of negative feedback loop
whereby IL-6 induces transcription of SOCS3, which then attenuates further
JAK/STAT signalling.
SOCS3 can also be induced by cAMP. This is interesting as prostanoids, a
type of drug used in the treatment of PAH due to its vasodilator effects and the
only type to show any efficacy improving the life expectancy of PAH patients,
acts by mobilising cAMP. Thus, prostanoid stimulation of cAMP could
potentially limit IL-6 signalling via the induction of SOCS3. This is a novel
mechanism of prostanoids which has not previously been considered.
This study investigated the capability of prostanoids to limit the pro-inflammatory/pro-angiogenic effects of IL-6 that enable PAH to develop. Initial
experiments confirmed that vascular endothelial cells responded to
prostanoids which increased SOCS3 and limited IL-6 signalling activity.
Further experiments utilising SOCS3 KO endothelial cell models demonstrated
prostanoid inhibition of IL-6 signalling was due in part to SOCS3.
In conclusion, this project has confirmed that prostanoids do limit the pro-inflammatory effects induced by IL-6 and that this is in part due to SOCS3.
Although the exact mechanism is yet to be discovered, it will be beneficial in
the treatment of PAH as it provides currently unexploited drug targets which
can be considered for future PAH therapies. / British Heart Foundation
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/18665 |
| Date | January 2019 |
| Creators | Durham, Gillian A. |
| Contributors | Palmer, Timothy M., Williams, Jamie J.L., Nasim, Md. Talat, Elies, Jacobo |
| Publisher | University of Bradford, School of Pharmacy and Medical Sciences Faculty of Life Sciences |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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