Translational Critical Care

What we do

We investigate the basic mechanisms of organ injury during diseases of acute systemic inflammation (e.g. sepsis, burns and major trauma) focussing on the roles of circulating extracellular vesicles (EVs) as both biomarkers and mediators.

Circulating EVs provide unique insights into processes of vascular inflammation and injury. Information on the parent cell source and status can be derived from EV expression of lineage specific and functional markers.  Adhesive interactions between circulating EVs and their target cell populations enable them to perform roles as long-range vehicles of intercellular communication.

We recently observed a significant redistribution of circulating EV uptake between organs takes place in the early stages of acute systemic inflammation. Specifically, the lungs become a major de novo target for EVs via their capture and internalisation by pulmonary intravascular monocytes. We are currently investigating the consequences of this phenomenon for the development of acute lung injury. 

Why it is important

Sepsis and non-infectious systemic inflammatory response syndrome (SIRS) are life-threatening conditions resulting from body’s acute immune responses to infection and tissue injury. Despite decades of research, therapeutic strategies for sepsis/SIRS treatment based on systemic targeting single inflammatory mediators have failed.

The  inflammatory molecular cargoes of EVs are shielded  from endogenous neutralising agents by association with, or encapsulation within, their lipid membrane. This property enables EV mediators to escape and propagate systemic inflammation between tissues unimpaired. Therefore, EVs could be central to the development of sepsis/SIRS associated acute lung injury and represent a completely novel therapeutic target.

How it can benefit patients

Development of specific treatments to reduce circulating EV uptake by the lungs could provide an alternative, vascular-bed specific strategy for attenuating acute lung injury.  This ‘organ-specific’ strategy would avoid off-target effects that currently encumber systemic targeting of soluble mediators in sepsis/SIRS.

Summary of current research

• EV cellular interactions and functions within the pulmonary microvasculature. (MT, DT, ES, AG)
• EV pro-inflammatory signalling mechanisms (MT, DT, ES, AG)
• Circulating EV phenotyping in sepsis and burns patients (+ AG, DA, ES, MVP)
• Extracorporeal circulation: RD EBP/ BP ECMO
• EVs in cell death (BP)
• EVs in septic shock and pregnancy Mark Johnson