Thesis

Inflammatory and proliferative characteristics of late arteriovenous fistula stenosis : therapeutic potential of diclofenac

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Awarding institution
  • University of Strathclyde
Date of award
  • 2014
Thesis identifier
  • T13729
Qualification Level
Qualification Name
Department, School or Faculty
Abstract
  • An arteriovenous fistula (AVF) is a vein graft which is created to permit vascular access allowing haemodialysis to be performed. AVFs are associated with failure rates as high as 50% at 6 months. Failure is principally due to vascular smooth muscle cell proliferation, leading to the development of neointima causing stenosis and impaired blood flow. The aims of this study were to; 1) explore the inflammatory and proliferative characteristics of AVF stenosis and the role of TLR-4, 2) assess the ability of anti-inflammatory diclofenac to inhibit VSM cell proliferation, 3) develop a novel model of AVF in the rabbit to assess the impact of cannulation injury and the effect of topical diclofenac and 4) investigate the mechanisms responsible for diclofenac mediated activity. Human stenotic AVF segments and cell explants taken from haemodialysis patients vs. healthy long saphenous vein controls were shown to have significantly higher TLR-4 expression and activation of the downstream kinase IRAK-4. Also associated with AVF stenosis was an increased expression of pro-inflammatory cytokines including MCP-1. VSM cell explants derived from stenosed AVF had a significantly increased capacity to proliferative vs. healthy controls, which was inhibited by diclofenac treatment. Using a novel rabbit AVF model, cannulation injury was shown for the first time to drive stenosis. Topical diclofenac significantly inhibited this injury response, reducing mean vein wall width from 46.8±5.7μM to 15.8±1.8μM, comparable to 16.7±1.6μM in the non-injured AVF. In addition to previously well defined COX inhibition, evidence was generated in this study to implicate AMPK in the anti-proliferative activity of diclofenac. Therefore, activation of TLR-4 in AVF stenosis appears to play a significant role in the generation of an inflammatory and proliferative VSM cell response. Cannulation injury, which undoubtedly causes a pro-inflammatory response, significantly contributes to AVF stenosis which is inhibited by prophylactic topical diclofenac via the activation of AMPK.
Resource Type
DOI
Date Created
  • 2014
Former identifier
  • 1032493

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