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Role of Toll-like receptor 4 in critical limb ischaemia

Navi, Ali H.; (2018) Role of Toll-like receptor 4 in critical limb ischaemia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Toll-like receptors (TLR) are key pattern recognition receptors in the innate immune system. In particular, TLR4-mediated immune response has been implicated in ischaemia-induced tissue injury. Mounting evidence supports a detrimental role of the innate immune system in the pathophysiology of skeletal muscle damage in patients with critical limb ischaemia (CLI), in whom patient oriented functional outcomes are poor. The overall aim of this study was to investigate the potential role of TLR4 in skeletal muscle dysfunction and damage in CLI. The role of TLR4 in ischaemic muscle was studied with three aims: 1) To develop a biobank of human gastrocnemius muscle from stratified patients and to explore TLR4 expression and distribution in these biopsies 2) To investigate the TLR4 pathway and functional consequences of TLR4 inhibition in myotubes derived from human muscle biopsies 3) To evaluate the therapeutic potential of modulating TLR4 signalling in ischaemic muscle using a relevant mouse hind-limb ischaemia model. TLR4 was found to be expressed in muscle biopsies, with significant upregulation in samples from patients with CLI. In vitro studies using cultured human myotubes demonstrated upregulation of TLR4 in ischaemia, with activation of the downstream signalling pathway. Inhibition of TLR4 prior to ischaemia was associated with reduced ischaemia-induced apoptosis. The mouse hind-limb ischaemia model also showed upregulation of TLR4 in ischaemic muscle. Inhibition of TLR4 was associated with reduced inflammatory cell infiltration and diminished apoptosis in the ischaemic limb. In conclusion, work presented in this thesis demonstrated that TLR4 is upregulated and activated in ischaemic skeletal muscle in patients with CLI. Modulating TLR4 signalling in vitro and in vivo was associated with attenuation of ischaemia-induced skeletal muscle damage. This strategy could be explored further for potential clinical application.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Role of Toll-like receptor 4 in critical limb ischaemia
Event: UCL (University College London)
Language: English
URI: http://discovery.ucl.ac.uk/id/eprint/10053896
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