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

Final Report Summary - CELSYS SHOCK (Autodigestion in Hemorrhagic Shock and Acute Heart Failure: a Cell-to-System Approach to Pathophysiology and Therapy)

Hemorrhagic shock resulting from trauma is one of the main causes of mortality worldwide, with a very significant associated financial burden. Despite decades of research there exists no consensus as to the fundamental mechanisms of shock, nor has an optimal treatment strategy been achieved to improve survival and reduce morbidity. Typical therapeutic strategies aim at contrasting symptoms and target the restoration of tissue perfusion, which is compromised by severe blood loss, by maintaining blood pressure stability through intravenous fluid support. However, these approaches are often ineffective to prevent multiple organ failure, which increases mortality rates and morbidity.
The “CelSys Shock: Autodigestion in Hemorrhagic Shock and Acute Heart Failure: a Cell-to-System Approach to Pathophysiology and Therapy” project is based on an innovative approach to the fundamental mechanisms of injury in shock, the “Autodigestion Hypothesis”, which attributes a key pathologic role to digestive enzymes and other proteolytic enzymes. The interest of “CelSys Shock” is in particular focused on the impact of autodigestion on cardiovascular function, in order to assess the features of injury to the heart and vessels, which affects hemodynamic stability. Autodigestion consists in the pathologic proteolysis that digestive enzymes cause in the system after leaking out of the small intestine lumen during intestinal ischemia. Shock is defined as low perfusion, and in the case of hemorrhagic shock reduced tissue perfusion is an obvious consequence of bleeding. In the general context of organ hypoperfusion, the reduced blood flow to the intestine is responsible for the alterations of the gut barrier properties. As a result, bacteria and pancreatic enzymes, which are normally confined to the intestinal lumen leak out of the gut and translocate into the intestinal wall. Then, upon reperfusion following resuscitation (achieved in hemorrhage patients by either fluid support and/or blood transfusions), these pathogens spread to the whole organism. In the case of digestive proteases, such as for instance trypsin, chymotrypsin and elastase, their proteolytic activity in organs other than the small intestine entails the pathologic degradation of circulating proteins and transmembrane receptors, with a severe impact on several physiological functions.
The “CelSys Shock” project has produced important new evidence on the features of heart dysfunction, vasopressor resistance, autonomic impairment and pathologic proteolysis in hemorrhagic shock by working on a well-established animal model of trauma and hemorrhagic shock in the rat. Further, “CelSys Shock” has also contributed to propose a novel therapeutic protocol for next generation resuscitation protocols of shock patients, consisting in the combination of intravenous fluid support and enteral protease inhibition, now made possible by a new technology developed in the framework of this project, and aimed at ensuring an effective, efficient and safe enteral delivery of protease inhibitor.
The work plan of “CelSys Shock” stems from four main parallel lines of research:
1. new data analysis methods for the determination of the impairment of autonomic control of circulation in circulatory shock;
2. assessment of heart injury and cardiovascular dysfunction in shock;
3. integration of low- and high-throughput techniques for the investigation of systemwide effects of proteolysis in shock;
4. development of a new technology for enteral delivery of protease inhibitor and design of an innovative next generation resuscitation protocol, comprising standard intravenous fluid resuscitation and enteral protease inhibition.
“CelSys Shock” has utilized data from rat models of shock, specifically an intestinal occlusion-induced shock model (research line 1. above), and trauma/hemorrhagic shock (research lines 2-4). The main results of “CelSys Shock”, have been:
1. the demonstration of the presence of intrinsic dynamics in the blood pressure signal of rats during shock, related to the likelihood of irreversible hemodynamic instability and cardiovascular collapse, with a possible involvement of the parasympathetic nervous system;
2. the systematic description of the expression and density of several key transmembrane receptors in the left ventricle of hemorrhagic shock rats, and the observation of the effects of the enteral administration of protease inhibitor, i.e. tranexamic acid (TXA). In particular, the analysis of the main receptors, which mediate adrenergic control of heart rate and contractility (the α1, β1, and β2 adrenergic receptors) and the metabolic supply to cardiomyocytes (FATP6 and CD36 receptors), via electrophoresis of ventricle homogenates and immunohistochemistry of left ventricle cross-sections showed a compensatory response to shock consisting in the increased expression of these receptor. When the shocked rats are treated with enteral TXA, though, the baseline (i.e. healthy, physiologic) levels of these receptors are restored, and the activity of serine proteases and metalloproteinases in the heart is also reduced to baseline levels. In addition to the analysis of heart receptors, it was also shown that the α1 adrenergic receptor density in large arteries is decreased in shock, while vasopressor resistance is increased. This result, combined with the observation that enteral TXA mitigates such changes, suggests a possible novel mechanism to explain vasopressor resistance;
3. the mass-spectroscopy analysis of circulating plasma proteins and peptides, which showed a systematic degradation of circulating and cytoplasmic proteins and the formation of circulating peptides, which might act as signaling molecules or directly interfere with important vital functions, such as vasopressor responsiveness;
4. the development of a (provisionally patented) novel system for the safe continuous delivery of protease inhibitor into the intestinal lumen via enteral placement of an orogastric or nasogastric tube. The novelty of this system, in comparison to the current state-of-the-art in the field of enteral feeding, consists in the ability of efficiently delivering solution to the intestine at high flow rates while incorporating solutions to prevent the risk of aspiration in the upper airways.
The outcomes of “CelSys Shock” provide important new evidence and solutions in response to the need for new paradigms of hemorrhagic shock treatment. This carries the important societal implication of contributing to reduce the mortality and morbidity of the disease, to improve survival and life quality of survivors, and to limit the massive financial burden for the community while providing quality care to shock patients and families. The conclusions reached by “CelSys Shock” could prove of great importance to advance the current thinking on hemorrhagic shock treatment, thanks both to the novel mechanisms highlighted at the cellular and molecular level in the general context of shock-induced organ dysfunction and to the newly developed technology, which is expected to be further validated in order to pursue a possible industrial translation.