Liver Inflammation

Hepatic ischaemia-reperfusion (I/R) injury is a major adverse consequence of liver transplantation, haemorrhagic shock, or extensive hepatic surgery and associated with a high mortality rate. The underlying pathomechanisms are incompletely understood and treatment options are limited. The recruitment of activated leukocytes and a subsequent parenchymal injury are hallmarks of liver I/R. I/R tissue damage can be limited by prompt elimination of the disposed leukocytes. This resolution of inflammation is an active process coordinated by a complex regulatory network of cells and mediators that ideally results in reconstituted organ function. Progressing inflammation can result in severe ongoing critical illness. Recent work has linked platelets with liver I/R injury, but their role is incompletely understood. Our preliminary data indicate a dual role of platelets in liver injury with a proinflammatory role in the early phase, but support of resolution at later time points. Using in vitro assays with human platelets and immune cells we will analyse how platelets modulate neutrophils and macrophages. We have established a platelet transfer protocol which allows us – in combination with transgenic mouse models – to specifically study the molecular pathways via which platelets modulate the resolution of liver I/R. This approach will be complemented by measurements of specialised lipid mediators (SPM). In addition we will perform confocal intravital imaging (IVM), supported by histological analyses, to map the cellular interactions following liver I/R. These studies will provide new insights into the pathomechanisms underlying sterile inflammation and resolution programmes in general.

We also take advantage of our liver IVM to study platelet clearance in normal physiology and under conditions of immune thrombocytopenia.