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Project summary

Ischaemic injury to vital organs is common in critically ill patients, producing deleterious effects on other organ systems. This is particularly common in the gut, with intestinal hypoperfusion inducing systemic inflammation and multiorgan organ dysfunction syndrome.

Although inflammation is a well-defined key factor associated with remote organ injury following intestinal ischemia reperfusion (IR), anti-inflammatory agents have not been particularly effective in reducing lung injury, suggesting that targeting alternative mechanisms are needed. In addition to promoting inflammation, prolonged ischemic injury to the intestines can also lead to the development of a systemic thrombotic response (pathological formation of blood clots), which is particularly common in the lung, and leads to a very poor prognosis (>90% mortality).

We have identified a new mechanism of pathological blood clotting (thrombosis) and vascular occlusion that is triggered by dying platelets, leading to platelet-neutrophil macroaggregates, and vascular occlusion microvasculature.

In these ongoing studies, our ultimate aim is to investigate novel therapeutic treatment(s) to reduce formation of platelet-neutrophil aggregates post-IR and remote organ injury. In addition, we propose to design a new diagnostic marker of platelet-neutrophil aggregates post-IR, through measurement of circulating dying platelet-neutrophil complexes in remote organs following IR.

In an extension of these studies, we are characterising novel anti-clotting agents to treat vascular obstruction post-IR, a process also known as the ‘no-reflow’ phenomenon, which ultimately leads to irreversible tissue damage. Thrombin, by far the most potent and robust activator of platelets and the coagulation cascade during both physiological and pathological blood clotting, is believed to play a key role in accumulating platelets and fibrin and occluding the vessels during IR injury. Although current therapeutic inhibition of thrombin has been shown to be an effective anti-thrombotic agent, all currently approved therapies cause severe bleeding complications.

In collaboration with Professor Richard Payne and his research group in the Department of Chemistry (The University of Sydney), we hope to identify and characterise novel therapeutic treatments that interfere with the formation of blood clots (antithrombotics), albeit with safer profiles (ie, less bleeding) in the context of vascular diseases, including IR injury.

Collaborators

Professor Richard Payne (USyd)