Membrane-controlled release of carbon monoxide in extracorporeal life support protects from neurological injury after hypoxic cardiac arrest
Pharmacy
Final Report Abstract
Cardiac arrest (CA) still represents a major challenge to modern medicine. If survived, subsequent problems often arise in the context of temporary and/or persistent organ damage. Pathophysiologically, CA is based on a systemic ischemia / reperfusion (I/R) reaction. This is associated with cell death, the formation of oxygen free radicals and a profound pro-inflammatory reaction. In addition to ischemic injury, reperfusion syndrome plays a critical role in organ damage. Carbon monoxide (CO), known as a toxic gas, is a physiologically active, endogenously produced gasotransmitter invovled in many processes in the human body. The therapeutic use of CO may be of great interest in the context of the I/R, while first clinical studies on its effectiveness (e.g. ARDS) have already been carried out. However, the route of application of CO is controversial. Additional to inhalation, CO can also be applied locally or systemically via CO-releasing molecules (CORMs). All of these methods show considerable disadvantages., so that we propagated an "extracorporeal CO-releasing system" (ECCORS) system which can be integrated into an extracorporeal circuit thereby enabling precise CO application, controllability and limiting its toxicity. In the course of this work, the improvement of macro- and microhemodynamics after extracorporeal resuscitation using ECCORS were demonstrated. Histological and molecular cardiac damage was significantly reduced. In addition, there also was a reduction in acute kidney damage and relevant neuroprotective properties. The mechanistic basis for these phenomena seems to be a reduced inflammatory reaction (due to an altered expression of DAMPs). Nephroprotection by CO may also be particularly promising in transplant medicine. On the basis of our experimental data, CO may present an effective therapeutic agent for various clinical scenarios, especially in post-resuscitation treatment and in complex intensive care medical conditions (sepsis, ARDS, AKI, etc.). However, its reliable controllability while avoiding toxic limit dosages is an inevitable prerequisite before use. Application with systems such as ECCORS could therefore present a starting point.
Publications
- Overcoming safety challenges in CO therapy - Extracorporeal CO delivery under precise feedback control of systemic carboxyhemoglobin levels. J Control Release. 2018 Jun 10;279: 336-344
Wollborn J, Hermann C, Goebel U, Merget B, Wunder C, Maier S, Schäfer T, Heuler D, Müller-Buschbaum K, Buerkle H, Meinel L, Schick MA, Steiger C
(See online at https://doi.org/10.1016/j.jconrel.2018.04.017) - Extracorporeal resuscitation with carbon monoxide improves renal function by targeting inflammatory pathways in cardiac arrest in pigs. Am J Physiol Renal Physiol. 2019 Dec 1;317(6):F1572-F1581
Wollborn J, Schlueter B, Steiger C, Hermann C, Wunder C, Schmidt J, Diel P, Meinel L, Buerkle H, Goebel U, Schick MA
(See online at https://doi.org/10.1152/ajprenal.00241.2019) - Carbon Monoxide Exerts Functional Neuroprotection After Cardiac Arrest Using Extracorporeal Resuscitation in Pigs. Crit Care Med. 2020 Apr;48(4):e299-e307
Wollborn J, Steiger C, Doostkam S, Schallner N, Schroeter N, Kari FA, Meinel L, Buerkle H, Schick MA, Goebel U
(See online at https://doi.org/10.1097/ccm.0000000000004242) - Carbon monoxide improves haemodynamics during extracorporeal resuscitation in pigs. Cardiovasc Res. 2020 Jan 1;116(1):158-170
Wollborn J, Steiger C, Ruetten E, Benk C, Kari FA, Wunder C, Meinel L, Buerkle H, Schick MA, Goebel U
(See online at https://doi.org/10.1093/cvr/cvz075) - Carbon monoxide in intensive care medicine-time to start the therapeutic application?! Intensive Care Med Exp. 2020 Jan 9;8(1):2
Goebel U, Wollborn J
(See online at https://doi.org/10.1186/s40635-020-0292-8) - Role of Carbon Monoxide in Host-Gut Microbiome Communication. Chem Rev. 2020 Dec 23;120(24):13273-13311
Hopper CP, De La Cruz LK, Lyles KV, Wareham LK, Gilbert JA, Eichenbaum Z, Magierowski M, Poole RK, Wollborn J, Wang B
(See online at https://doi.org/10.1021/acs.chemrev.0c00586)
