Klinik für Anästhesiologie und Intensivmedizin

Research Focus

Projects:

1. The importance of heme oxygenase 1 (HO-1) and carbon monoxide for erythrophagocytosis in the microglial context in subarachnoid hemorrhage (SAH)

1. The central importance of heme oxygenase 1 (HO-1) dependent carbon monoxide production in the regulation of the circadian rhythm in the microglial context in subarachnoid hemorrhages (SAH)

1. Local and systemic markers of inflammation and circadian rhythm in COVID-19 disease - importance for the clinical-neurological outcome

1. (Current) Characterizing the role of myeloid-specific heme oxygenase-1 (HO-1) in the regulation of circadian rhythms, neuroinflammation, and  neuronal damage after traumatic brain injury (TBI)

Description/Details:

1. Excess heme is normally broken down by the enzymatic activity of heme oxygenases (HO). Heme is first converted to biliverdin, then to iron and finally to gaseous carbon monoxide (CO). Induction of HO-1 mediates organ protection in various damage models including visceral organs, the heart and the central nervous system. We were able to identify a novel function of HO-1 in neuronal microglial cells. In an SAB damage model, the induction of HO-1 not only led to accelerated hematoma breakdown, but also to increased production of the gaseous molecule CO, which in turn regulated phagocytosis of deposited erythrocytes. The exact molecular mechanisms, i.e. how the microglial HO-1/CO signaling pathway modulates the phagocytosis of red blood cells, was to explore. We investigated various possible signaling pathways that provided us with information on how the enzymatic system around HO-1 and CO regulates erythrophagocytosis in the SAB, e.g. via the modulation of radical oxygen species.

1. The heme oxygenase-1 (HO-1) enzyme pathway is of crucial importance in the removal of toxic blood components and regulation of neuroinflammation following hemorrhagic stroke. As circadian dependency in the incidence and severity of hemorrhagic stroke exists, a functional circadian dependency of the HO-1 system involving carbon monoxide (CO) and CD36 surface-expression in the context of hemorrhagic injury was the object of this study in cell lines, primary cells, mice and patients.

1. What is the molecular basis of the interaction between HO-1 derived CO and effector genes of the circadian cycle?
2. Is microglial neuroinflammation and CD36-dependent erythrophagocytosis after hemorrhagic stroke dependent on the expression of circadian rhythm genes?
3. What is the anatomical and physiological correlate of the mutual interaction between the central nervous system and peripheral organs that ensures circadian synchronization and injury response?
4. Is there a functional correlate for the observed disturbance in molecular circadian rhythmicity after brain injury and does brain injury affect kidney function in the critical ill patient?

1. The lung disease COVID-19, which is triggered by the novel coronavirus SARS-CoV-2, poses challenges for physicians all over the world. Especially in intensive care, objective parameters for prognosis and course assessment would be helpful for direct clinical assessment. Goal of the investigation was the establishment of new laboratory values ​​for patients suffering from COVID-19, which could contribute to a better assessment of these patients with regard to the clinical course and long-term results in the future. In patients with symptomatic COVID-19 disease requiring intensive care treatment, molecular biological and laboratory chemical ex vivo analysis of the expression of inflammatory mediators and genes regulating the circadian rhythm were done. Results were correlated to further recorded parameters like rate of renal failure (KDIGO criteria) and thromboembolic events, CAM-ICU score, need for sedation, duration of mechanical ventilation, duration of ICU stay and survival at 6 months were recorded. We identified local and systemic inflammation biomarkers which help to predict certain outcomes of COVID-19 patients within the intensive care.

1. Some transcription factors that control circadian rhythms contain heme and therefore the degradation of this heme requires HO-1, which is CO-dependent. In earlier experiments, we have detected the circadian dependency and influence of HO-1/CO-system and its role in regulation of neuroinflammation. In this study we further analyze these findings in the context of traumatic brain injury (TBI). HO-1 induction in TBI was detected to be time-dependent. Further, HO-1 deficiency correlated altered circadian gene expression and a severer neuronal damage post TBI. The role of glia-specific heme oxygenase-1 (HO-1) in the regulation of circadian rhythmicity, neuroinflammation and neuronal injury following brain trauma is to further investigate in this study in cell lines, primary cells, mice and patients.

1. What is the molecular mechanism underlying the neuroprotective properties of HO-1 and CO after TBI?
2. HO-1 expression in what glial cell type is responsible for the protective effects following TBI?
3. How does the HO enzyme system interact with molecular circadian regulation in TBI and does this interplay determine the extent of neuronal injury?
4. Can HO-1/Per-2 induction in the CSF of patients suffering from TBI predict functional neurological outcome?

Hämoxygenase-1 und Kohlenmonoxid im Kontext von SAB und SHT

Die Subarachnoidalblutung (SAB) stellt eine Form des Schlaganfalls dar, der bei etwa 10 von 10.000 Patient*innen im Jahr auftritt und zu erheblichen neuronalen Schäden führen kann. Mit unserer Forschung beschäftigen wir uns mit der Neuronalen-Schädigung, die durch Entzündung und Toxizität verschiedener Blutbestandteile im Gehirn nach Einblutungen hervorgerufen wird. Darüber hinaus betrachten wir Zusammenhänge der Entzündungsreaktionen im Gehirn nach einer Schädelhirnverletzung bzw. Schädelhirntraumata (SHT).
Man geht von etwa 200-300 stationär zu behandelnden Schädelhirntraumata pro 100.000 Einwohner*innen pro Jahr in Deutschland aus. Ursachen für SHT können Verkehrsunfälle, Stürze sowie Sportverletzungen sein. Es konnte in Patient*innen beobachtet werden, dass der Schweregrad der Symptome und Schädigung nach einer SAB und SHT in einem Zusammenhang mit der Tageszeit des Entstehens der Verletzung steht.
Es ist bekannt, dass unser Körper einen Tageskreislauf, auch circadianer Rhythmus genannt, innerhalb 24h durchlebt. Dabei werden täglich in den Zellen Eiweiße und Gene hoch- und herunterreguliert. Dies ist wichtig für ein gesundes Zusammenspiel im ganzen Körper. Da im Gehirn unter anderem das Zentrum für die Regulation der circadianen Rhythmik liegt, im sogenannten Nucleus suprachiasmaticus (SCN), kann sich ein Schaden im Gehirn auch negativ auf den notwendigen circadianen Rhythmus in weiteren Organen wie z.B. der Niere auswirken. Daher ist das Erforschen des Einflusses und Zusammenhangs zwischen Entzündungsabläufen im Gehirn nach Schädigung und dem circadianen Rhythmus von wissenschaftlichem und klinischem Interesse.
Unsere Arbeitsgruppe betrachtet in diesem Kontext besonders, welche Rolle die Mikroglia (Immunzellen des Zentralen-Nervensystems), sowie ganz speziell das Enzym Hämoxygenase-1 (HO-1) und das damit verbundene Kohlenmonoxid in nicht-toxischen, natürlich vorkommenden Mengen spielen. Ein klinisches Ziel ist in Zukunft, die Patient*innen-Versorgung durch bessere Einschätzungen des zu erwartenden Krankheits-Verlaufes durch Messung sogenannter Biomarker zu verbessern und durch Gabe von therapeutischen geringen Dosen von Kohlenmonoxid den Schaden im Gehirn nach Verletzungen zu verringern sowie die Heilungsprozesse zu aktivieren.