Heparanase and macrophage migration inhibitory factor as diagnostic/therapeutic targets in trauma and haemorrhagic shock-associated multiple organ failure

• Applicant: Privatdozent Dr. Lukas Martin
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465409392

Injuries with multiple traumata are one of the leading causes of death worldwide, resulting in 4.8-5 million deaths per year. One of the most common consequences in multiple traumata is the multi organ failure (MOF), which is responsible for 51-61% of all deaths in trauma and is associated with longer stays in the intensive care units (ICU) and raised costs for healthcare systems, as there is no specific, preventive treatment. MOF can be a result of a trauma-induced inflammation and/or organ ischemia. The systemic inflammation after trauma is triggered by a multitude of factors including poor oxygen supply due to haemorrhagic shock and the release of damage-associated molecular patterns (DAMPs) caused by tissue injury. Heparanase specifically releases heparan sulfate (HS) fragments after sterile or infectious insults which leads to endothelial glycocalyx degradation and elevated vascular permeability. The proinflammatory cytokine MIF (macrophage migration inhibitory factor) is associated with local or systemic inflammation and increased plasma MIF levels correlate with poor outcome in patients with sepsis, systemic inflammatory response syndrome and other critical illnesses.In our own preliminary work, we identified 2 key families that are involved in the pathogenesis of critical illness: MIF and heparanase. We could show that polytrauma patients exhibited significantly enhanced MIF levels on arrival to the emergency room (ER). Similar findings could be detected in a murine model of severe haemorrhage followed by resuscitation. Treatment with the MIF-inhibitor ISO-1 significantly reduced MIF levels and attenuated organ damage and the fall in blood pressure. In additions, we could show, that heparanase activity and HS serum levels were significantly elevated in patients with septic shock compared to healthy volunteers. The question that arises now is how the MIF- and heparanase system interact in trauma patients. Our goal is to improve our understanding of the kinetics and clinical relevance of these families in polytrauma and elucidate potential signalling pathways responsible for the protective effects of MIF inhibition. Our preliminary data suggest a therapeutic potential of inhibiting MIF, which shall be confirmed by this project to provide an adequate therapeutic strategy to prevent and/or reverse organ damage/failure and improve outcome after polytrauma. Therefore, we propose the following hypothesis:H1: Elevated serum levels of members of the Heparanase-System and MIF-System are associated with a complicated clinical course and increased mortality in patients with polytrauma. H2: Heparanase, MIF, MIF-2 and sCD74 contribute to organ injury and dysfunction caused by polytrauma by mediating CD74/AMPK pathway, the JNK- and PI3K-Akt pathways and ERK-1/2 pathway. H3: Pharmacological inhibition of MIF by ISO-1 attenuates the post-traumatic immunosuppression, organ damage/failure and improves outcome after experimental polytrauma.

• DFG Programme: Research Units
• Subproject of: FOR 5417: Translational Polytrauma Research to Provide Diagnostic and Therapeutic Tools for Improving Outcomes
• Co-Investigator: Professor Dr. Gernot Marx