Attenuation of damage to endothelium in transplanted heart by targeting the IL-6/S1P signalling axis

There is both a scarcity of suitable hearts for transplantation and a need to prolong their functionality after transplantation. Ischaemia reperfusion injury (IRI) and concomitant inflammation is associated with primary graft dysfunction (PGD). One way to address this problem is to reduce the level of IRI to donor organs. There are currently no condition-specific therapeutics available. Our group has in vivo data showing that agonism of sphingosine-1-phosphate receptor-1 (S1PR1) can augment endothelial barrier function. We also observe that the proinflammatory cytokine IL-6 upregulated in IRI disrupts normal S1PR1 signalling. We hypothesise that agonism of S1PR1 and blocking IL-6 in the heart would protect and/or improve vascular endothelial integrity, therefore limiting IRI. Using an in vitro model of IRI, we will interrogate the potential crosstalk between S1P and IL-6 signalling pathways. We will further evaluate targeting of the IL-6 and S1PR1 pathways (using compounds approved for clinical use) as a potential therapeutic strategy for protecting the vascular endothelial barrier. Finally, we will challenge the model with human heart perfusates from ex vivo perfusion experiments and characterise the effect of combination therapy. This research could lead to improved post-transplant outcomes by reducing IRI and increasing the number of organs suitable for transplantation.