UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Hyperglycaemia and Ischaemia Impair Wound Healing via Toll-like Receptor 4 Pathway Activation in vitro and in an Experimental Murine Model

Portou, MJ; Yu, R; Baker, D; Xu, S; Abraham, D; Tsui, J; (2020) Hyperglycaemia and Ischaemia Impair Wound Healing via Toll-like Receptor 4 Pathway Activation in vitro and in an Experimental Murine Model. European Journal of Vascular and Endovascular Surgery , 59 (1) pp. 117-127. 10.1016/j.ejvs.2019.06.018. Green open access

[thumbnail of Tsui_Portou et al EJVES 2018 final draft.pdf]
Preview
Text
Tsui_Portou et al EJVES 2018 final draft.pdf - Accepted version

Download (1MB) | Preview

Abstract

OBJECTIVE: Diabetes mellitus has reached epidemic proportions. Foot ulceration is a multifactorial complication of diabetes associated with marked morbidity and mortality. Innate immune Toll-like receptor 4 (TLR4) mediated inflammation has been implicated in the systemic pathogenesis of diabetes and may contribute to impairment of wound healing. This study investigates the effect of high glucose and hypoxic conditions on TLR4 activation and signalling in vitro and in vivo. METHODS: Fibroblasts cultured at physiological glucose concentration (5.5 mM) were exposed to glucose concentrations from 0 mM to 25 mM, with duplicates placed in a hypoxic chamber. TLR4 inhibition was assessed in the 25 mM glucose groups. Diabetes was induced in wild type (WT) and TLR4 knockout (KO) C57BL/6 mice by intraperitoneal injection of low dose streptozocin (STZ). Hindlimb ischaemia was induced by femoral artery ligation four weeks post streptozocin, and a full thickness 4 mm skin wound inflicted below the knee. Wound healing was assessed via digital planimetry on days 3, 7, and 14 post surgery. RESULTS: Hypoxic and high glucose (25 mM) conditions led to an increase in TLR4 protein expression, apoptosis, and interleukin (IL)-6 release. Inhibition with a TLR4 neutralising antibody and specific TLR4 antagonist ameliorated the effects of high glucose and ischaemia (p < .05). In vivo, wound healing was significantly impaired in the diabetic ischaemic group at day 14 (p < .05). Diabetic ischaemic wounds in TLR4 KO mice exhibited significantly improved healing rates compared with those in WT mice at all time points. CONCLUSION: Hypoxia stimulates upregulation of TLR4 protein expression and this effect is exaggerated by hyperglycaemia. In TLR4 KO mice, there is a significant improvement in the healing of diabetic ischaemic wounds compared with WT. It is suggested that a synergistic effect between hypoxia and hyperglycaemia impairing wound healing exists, through TLR4 mediated inflammation.

Type: Article
Title: Hyperglycaemia and Ischaemia Impair Wound Healing via Toll-like Receptor 4 Pathway Activation in vitro and in an Experimental Murine Model
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ejvs.2019.06.018
Publisher version: https://doi.org/10.1016/j.ejvs.2019.06.018
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Diabetes, Hyperglycaemia, Inflammation, Ischaemia, Toll-like receptor 4, Wound healing
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/10086177
Downloads since deposit
18Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item