PIs: P. Radermacher, M. Huber-Lang

Hemorrhagic shock (HS) accounts for 30-40% of trauma mortality. During the first funding period, we showed that pre-traumatic cigarette smoke (CS) exposure to induce COPD aggravated both acute lung injury (ALI) after blunt chest trauma (TxT) as well as circulatory failure and acute kidney injury (AKI) after TxT and hemorrhagic shock (HS). COPD frequently co-occurs with diabetes mellitus, both leading to chronic hyper- inflammation including increased formation of reactive oxygen (ROS) and nitrogen (RNS) species. Similar to CS-induced COPD, diabetes aggravates AKI after HS. Mechanistically, both, COPD and diabetes impair endogenous H2S release due to reduced cystathionine--lyase (CSE) expression, which is crucial for the adaptive response during ALI and maintaining renal function. We showed that genetic CSE deletion (CSE-/-) worsened post-traumatic ALI after pre-traumatic CS exposure, and that CSE-expression is inversely related to barrier dysfunction and AKI severity. Acute stress-induced hyperglycemia also down-regulates CSE, thereby reducing mitochondrial respiration. Exogenous H2S restores hyperglycemia-induced impairment of mitochondrial function in vitro, attenuates CS-induced COPD, reduces diabetes-induced ROS release and endothelial dysfunction, and protects against both diabetic nephropathy and AKI. Using our well-established model of murine trauma-and-hemorrhage with subsequent intensive care, the project aims to define the role of diabetes for the development of ALI and AKI after TxT and HS in CS-induced COPD. The impact ofendogenous and exogenous H2S availability is studied using CSE-/- mice and administration of Na2S2O3. Any differences in the posttraumatic response between type 1 and 2 diabetes are addressed using streptozotocin injection or db/db mice. Organ injury and (dys)function are monitored together with glucose metabolism (stable isotope approaches and online calorimetry, quantified with newly developed sensor techniques), ROS/RNS release, and post mortem mitochondrial respiration and the innate cellular/fluid phase immune response.