Impact of aging on combined traumatic brain injury and hemorrhage: role of the H2S system

• Applicant: Dr. Tamara Merz
• Subject Area: Anaesthesiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465409392

Hemorrhagic shock (HS) and/or traumatic brain injury (TBI) determine post-traumatic outcome. Rapid “repayment of the O2 debt” and prevention of brain tissue hypoxia are cornerstones of the management of both HS and TBI. Restoring tissue perfusion, however, represents an ischemia/reperfusion (I/R) injury due to formation of reactive oxygen (ROS) and nitrogen (RNS) species. Ageing and/or cardiovascular disease are characterized by progressively increasing ROS formation and mitochondrial dysfunction, and, hence, the elderly and/or vascular comorbid patient presents with a several fold higher risk of mortality and sustained brain damage after TBI + HS. Aging and/or cardiovascular comorbidity also coincide with disturbed endogenous availability of the so-called "3rd Gaseous Mediator" H2S; genetic deletion of cystathionine-γ-lyase (CSE-/-), the major vascular endothelial H2S producing enzyme, leads to development of arterial hypertension, the most frequent chronic co-morbidity in the elderly. Moreover, endogenous, CSE-related H2S formation is crucial for the adaptive response during acute stress states, and, finally, exogenous administration of H2S donors was beneficial in various models of TBI and/or HS. Using a new, resuscitated murine model of combined acute subdural hematoma (ASDH)-induced TBI + HS in wild type and CSE-/- mice, the project will therefore investigate the impact of age and the role of the CSE/H2S-system on brain injury after ASDH + HS. ASDH-induced TBI will be studied, because ASDH is a well-reproducible model of TBI and particularly important in the elderly, vascular co-morbid TBI patient. Readouts comprise multi-model brain monitoring, markers of brain damage and ROS/RNS release, and post mortem brain region-specific analyses of cell death, neuro-inflammation, and mitochondrial respiration. In addition to the mechanistic approach addressed by the use of CSE-/- animals, the translational aspect will be addressed by exogenous H2S administration: as a therapeutic adjunct to the standard ICU measures according to TBI management guidelines to mitigate post ASDH + HS-induced brain injury, we will use sodium thiosulfate (Na2S2O3), a recognized drug devoid of major undesired side effects, which we previously demonstrated to attenuate visceral organ injury and dysfunction after combined blunt chest trauma + HS in CSE-/- mice and swine with coronary artery disease and, hence, consecutively reduced CSE expression.

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