Liver fibrosis has a range of aetiologies and is a global cause of mortality. A critical effect of liver fibrosis which also increases mortality is portal hypertension. The hepatic stellate cell is accepted as a major progenitor of liver myofibroblasts, which have been shown to be a major source of collagen and extracellular matrix proteins that disrupt liver architecture and function. Relaxin is a hormone involved in remodelling of extracellular matrix in the uterus and cervix and is known to increase renal blood flow in pregnancy. It has been implicated in the regulation of fibrosis in animal models and to modify the cell biology of hepatic stellate cells in vitro. I have demonstrated the profile of expression of relaxin receptors in primary human stellate cells (HSC), showing them to express RXFP-1, 3 and 4. Using a cAMP assay I confirm these receptors to be functional, with RXFP-1 positively and RXFP-3 and 4 negatively coupling to cAMP. The expression of RXFP-1 is coupled with the level of activation, demonstrating a possible role for H2-relaxin in the regulation of HSC. I have established a dynamic regulation of fibrotic mediators and HSC activation markers, including a reduction in α-SMA, TIMP-1 and TGF-β with increases in MMP-1 and MMP-2, consistent with H2-relaxin having potentially therapeutic antifibrotic effects by increasing the fibrolytic phenotype. In addition through the use of gel contraction assays I demonstrate that H2-relaxin reduces serum or endothelin-1 induced HSC contraction. Through the use of siRNA I have confirmed that H2-relaxin mediates its regulation of fibrotic mediators and HSC activation markers as well as the inhibition of gel contraction through the relaxin receptor RXFP-1. I have evidence to suggest that the inhibition of contraction may in part be via nitric oxide release in HSC. In conclusion I propose that RXFP-1 is a potential therapeutic target in end stage human liver disease, targeting fibrosis and portal blood hypertension via both resolution of the phenotypic collagen deposition and vascular constriction associated with the human hepatic stellate cell.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:503139 |
| Date | January 2009 |
| Creators | Hayden, Annette Louise |
| Contributors | Collins, Jane ; Princivalle, M. ; Iredale, J. P. |
| Publisher | University of Southampton |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://eprints.soton.ac.uk/67633/ |
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