Peritoneal fibrosis is a significant problem for peritoneal dialysis patients resulting in a loss in membrane dialysing capacity ultimately leading to technique failure. The development of peritoneal fibrosis is attributed to recurrent peritonitis infections and bio-incompatible dialysate fluid, both of which contribute to a chronic inflammatory state within the peritoneum. Transforming growth factor beta 1 (TGF-β1) is a cytokine with a central role in peritoneal fibrosis. However, this cytokine has multiple key roles, including development, wound healing cell proliferation and differentiation and regulation of the immune response. Cellular response to TGF-β1 can vary depending on cellular context and phenotype. Factors governing responses to TGF-β1 within the peritoneum are poorly characterised. Previous research through a murine model representing inflammation driven fibrosis has identified Interferon gamma (IFN-γ) having a central role in inflammation driven fibrosis. Therefore examination of the interaction between TGFβ1 and IFN-γ were undertaken in both murine samples and primary human peritoneal cells (HPMC). Within the SES murine model differences in TGF-β1 responses were observed between WT and IL6KO mice, with WT mice displaying significant increase in expression of TGF-β1 and matrix genes. There was increased expression of matrix metalloproteinases 3 and 10 (MMP3 and MMP10) in 116K0 mice, suggesting that these mice are protected against scarring and fibrosis through enhanced tissue remodelling. Similar findings were observed in HPMC treated with TGF-β1 alone resulting in significant increased MMP3 expression, which was inhibited in the presence of IFN-γ. IFN-γ did not affect any other TGF-β1 induced responses thus suggesting a specific fibrotic effect of IFN-γ within this system by inhibiting matrix degradation. Analysis of the mechanism of MMP3 regulation by TGF-β1 and IFN-γ revealed that SMAD and MAPK pathways are involved in the induction of MMP3 by TGF-β1 and are not inhibited by IFN-γ. Analysis of the AP-1 promoter site in the MMP3 revealed that this site may be involved in basal MMP3 expression but is not modulated by TGF-β1 and IFN-γ. Further examination of MMP3 regulation may provide a potential target in helping protect against peritoneal fibrosis, thus helping reduce technique failure in peritoneal dialysis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:669161 |
| Date | January 2015 |
| Creators | Bodenham, Tanya Jayne |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/79074/ |
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