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Autodigestion in Hemorrhagic Shock and Acute Heart Failure: a Cell-to-System Approach to Pathophysiology and Therapy

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Molecular triggers of haemorrhagic shock

Haemorrhagic shock (HS) and systemic inflammation followed by multiple organ failure are the main causes of mortality worldwide. European scientists studied the molecular triggers of shock using an innovative framework of the autodigestion hypothesis.

Fundamental Research
Health

Current therapeutic management of HS includes restoring tissue perfusion and maintaining blood pressure stability through intravenous fluid support. However, this approach is often ineffective in preventing organ failure, resulting in high mortality rates. The goal of the EU-funded CELSYS SHOCK (Autodigestion in haemorrhagic shock and acute heart failure: a cell-to-system approach to pathophysiology and therapy) study was to identify the cause of haemodynamic instability, specifically shock-induced heart failure, and to propose a novel therapeutic strategy. The project is based on the autodigestion hypothesis, an attempt to explore the fundamental mechanisms of injury in shock. The team focussed on the impact of autodigestion on cardiovascular function and the injury to the heart and blood vessels. Autodigestion constitutes pathologic proteolysis caused by digestive enzymes leaking out of the small intestine lumen during intestinal ischaemia. As a result of restorative perfusion, bacteria and pancreatic enzymes leak out of the gut and translocate into the intestinal wall. Upon resuscitation (achieved in haemorrhage patients by fluid support and blood transfusions), these pathogens and proteases might spread to the whole organism. Such proteolytic activity in organs other than the small intestine leads to the degradation of circulating proteins and transmembrane receptors, impairing physiological functions. The CELSYS SHOCK project produced new evidence on the mechanisms of heart dysfunction and pathologic proteolysis in case of haemorrhagic shock, using the well-established rat model of trauma and shock. The most important observation of the project was associated with the enteral administration of protease inhibitor tranexamic acid (TXA). The shocked rats treated with enteral TXA demonstrated restored physiological levels of cardiovascular adrenergic receptors. At the same time, the activity of serine proteases and metalloproteinases in the heart was reduced to normal levels. CELSYS SHOCK results propose a novel therapeutic approach for incorporation into a next-generation resuscitation protocol for HS patients. It involves a combination of intravenous fluid support and efficient and safe supply of enteral protease inhibitors.

Keywords

Haemorrhagic shock, multiple organ failure, CELSYS SHOCK, digestive enzyme, protease inhibitor

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