George, Marc Jonathan; (2019) Interleukin-6 Antagonism in a Rat Model of Acute Myocardial Infarction. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

BACKGROUND: Interleukin-6 (IL-6) is elevated during Myocardial Infarction (MI) and higher levels are associated with adverse outcomes. IL-6 signalling may be mediated by binding to its membrane-bound receptor, termed classic signalling. This pathway is associated with anti-inflammatory effects. Alternatively, IL-6 may bind to a circulating, soluble form of its receptor (sIL-6R) which may then bind to membrane-bound gp130 to effect signalling. This is termed trans-signalling and has pro-inflammatory effects. Current strategies to antagonise IL-6 block both of these pathways (pan blockade). HYPOTHESIS: Exclusive blockade of IL-6 trans-signalling with the novel recombinant protein ‘sgp130Fc’ during MI would result in a greater reduction in infarct size (IS) and improved Left Ventricular Ejection Fraction (LVEF) relative to pan blockade. METHODS: MI was induced in male Sprague-Dawley rats by occluding the leftanterior descending artery for 50-minutes prior to reperfusion. The model was characterised by measuring the temporal profile of cytokines and inflammatory cells within cardiac tissue and plasma up to 28-days post MI. Anti-IL-6 proteins were validated in vitro. Subsequently rats received sgp130Fc, anti-IL-6-Ab or vehicle intravenously 1-minute prior to reperfusion. IS as a percentage of Area-At-Risk (AAR) was measured histologically at 24 hours, LVEF by cardiac magnetic resonance imaging at 28 days and inflammatory/other parameters at 4 hours, 1, 3 and 28-days post MI. KEY RESULTS: Compared with vehicle, IS/AAR was significantly reduced by the administration of sgp130Fc but not by the anti-IL-6-Ab (vehicle: 42.74%, anti-IL-6- Ab: 45.43, sgp130Fc: 28.39%, p=0.008 n=7-9/group). Relative to age-matched naïve rats LVEF at 28-days was significantly reduced in the vehicle and anti-IL-6-Ab group but not in the sgp130Fc group (Naïve: 72.94%, vehicle: 62.58% (p=0.004), anti-IL-6-Ab 63.34% (p=0.01), sgp130Fc 67.91% (p=ns) n=7-9/group). CONCLUSIONS: Specific IL-6 trans-signalling blockade with sgp130Fc reduces IS/AAR and preserves LVEF in an animal model of MI with reperfusion whereas pan-blockade with an anti-IL-6-Ab does not.

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