Our group is interested in molecular mechanisms regulating endothelial barrier function in response to inflammation. We have been focusing on the Angiopoietin (Angpt) / Tie2 ligand receptor system over the last decade. Tie2 is a transmembrane receptor tyrosine kinase that is essential for embryonic vessel development. In mature organisms, its function shifts toward maintenance of endothelial homeostasis and reaction to insults. Angpt-1 is the major circulating Tie2 agonist that promotes protective anti-permeability signals, whereas Angpt-2 has antagonistic properties. Our group was the first to prove in a murine knockout model that Angpt-2 directly contributes to sepsis morbidity and mortality.

Our group is interested in molecular mechanisms regulating endothelial barrier function in response to inflammation. We have been focusing on the Angiopoietin (Angpt) / Tie2 ligand receptor system over the last decade. 

Tie2 is a transmembrane receptor tyrosine kinase that is essential for embryonic vessel development. In mature organisms, its function shifts toward maintenance of endothelial homeostasis and reaction to insults. Angpt-1 is the major circulating Tie2 agonist that promotes protective anti-permeability signals, whereas Angpt-2 has antagonistic properties. Our group was the first to prove in a murine knockout model that Angpt-2 directly contributes to sepsis morbidity and mortality.

Based on this finding we have conducted a series of experiments exploring potential therapeutic strategies (antibody, siRNA etc.) to eliminate or block the injurious Angpt-2 protein in sepsis models. We are also conducting drug-repurposing screens to identify potential off-target Angpt-2 regulators. Recently, we have gained much attention in the regulation of the Tie2 receptor expression per se and are currently working on the underlying mechanisms of posttranslational Tie2 modifications.

We are also interested in the interaction between endothelial cells and pericytes– both with regard to Angiopoietin signaling and the regulation of bioactive adrenomedullin (bioADM).

Another focus lies in the investigation of the endothelial glycocalyx both in vivo (SDF imaging) and in vitro (endothelial microperfusion chip model). As injury of the endothelial glycocalyx can be found early in critical illness and substantially contributes to endothelial dysfunction we investigate regulation of glycocalyx degradation both in septic shock as well as severe COVID-19.

The hallmark of sepsis is a pathological host response to an infection that may lead to organ dysfunction, shock and ultimately to a high mortality. Besides numerous circulating mediators triggering an inflammatory cascade, vascular barrier breakdown and microvascular hypoperfusion, the consumption and subsequent lack of protective plasmatic factors additionally contributes to sepsis pathophysiology. A causative sepsis therapy that targets the pathological host response is still missing as selective inhibition of singular mediators such as TLR4 or TNF was so far not effective in humans.

We believe that therapeutic plasma exchange (TPE) might eliminate numerous circulating injurious mediators in a short intervention and simultaneously replace essential but already consumed protective factors. We have therefore initiated a study program investigating the effect of early TPE in patients with early refractory septic shock (EXCHANGE study program). In a prospective non-randomized pilot study, we could demonstrate that early TPE improves hemodynamics and endothelial permeability as well as reduces inflammatory cytokines in patients with septic shock (EXCHANGE Pilot). In a subsequent bicentric (Hannover and Bonn) randomized controlled trial, we could confirm this finding concerning the effect of TPE on rapid restoration of hemodynamic stability in a controlled setting (EXCHANGE I). Funding for a multicenter randomized controlled trial investigating use of TPE in septic shock (EXCHANGE II) was granted to our group by the DFG and the study is about to start recruiting in more than 20 centers in Germany, Austria and Switzerland.

Currently, we perform several translational investigations that further elucidate the molecular mechanisms of sepsis (e.g. endothelial dysfunction, glycocalyx injury, dysregulation of immune responses and coagulation) that are potentially all influenced by additive TPE as well as predictors of response to TPE.

Neutrophil extracellular traps (NETs) play a major role in pathophysiology of sepsis and ARDS as they are actively involved in hyperinflammation and microvascular coagulation. Together with our colleagues from Guy´s and St. Thomas NHS Foundation Trust, London, we have planned a multicenter randomized controlled trial to investigate the additive use of a NET specific adsorbing column in patients with sepsis and ARDS (NucCap study).

The biological heterogeneity that is encountered in sepsis and ARDS might contribute to the disappointing results of randomized controlled trials that studied the effects of pharmacological interventions in an unselected population. Precision medicine focuses on the identification of therapeutic strategies that are effective for a group of patients based on similar unifying characteristics. Since precision medicine approaches in non-critical care settings such as cancer treatment have been recently performed with success, we aim to understand the biological underpinings of sepsis and ARDS subphenotypes so that personalized therapeutic approaches can be applied.

To furhter stratify patients with sepsis and ARDS by both clinical and biological phenotyping, we have initiated a prospective register of patients with ARDS and sepsis (SPARE-14 register) in combination with a longitudinal human biobank (blood and bronchoalveolar lavage fluids). So far more than 250 highly characterized sepsis/ARDS patients have been included in this databank. We aspire to explore individualized patient characteristics, both concerning routine clinical parameters as well as non-routinely measured disease mediators, that might shape disease progression and response to treatment.

Although there is still a lack of clear data that support the use of Extracorporeal Membrane Oxygenation (ECMO) in severe ARDS regarding survival benefits, ECMO has emerged as a therapeutic cornerstone for many patients and its use is of major interest in modern critical care medicine.

Our group tries to better understand who might ultimately benefit from ECMO and is trying to improve the way ECMO support is performed (e.g. individualized choice of anticoagulation intensity). We also explore ECMO support in non-traditional patient cohorts such as patients with diffuse alveolar hemorrhage. Support of non-intubated patients with both chronic and acute lung failure with ECMO, termed Awake ECMO, is an innovative strategy as it potentially completely avoids the multiple potential side effects of invasive ventilation. We explore this strategy in highly selected patient cohorts with singular lung failure such as patients with Pneumocystis-associated ARDS.

Fever after ECMO decannulation is a very common phenomenon which clinical significance however has been unclear to date. In a recent study we elucidated the role of hyper- and hypothermia following ECMO decannulation.

A work that analyzed the long-term outcome of triple cannulation ARDS patients who developed additional heart failure (VVA-ECMO) with Rolf Erlebach and Klaus Stahl in the lead was recently awarded with grants from the ESICM and the DGIIN.

Non-occlusive mesenteric ischemia (NOMI) is a life-threatening condition occurring in patients with shock and is characterized by vasoconstriction of the mesenteric arteries leading to intestinal ischemia and multiorgan failure. Although minimal invasive local intra-arterial infusion of vasodilators into the mesenteric circulation has been suggested as a therapeutic option in NOMI, current knowledge is based on retrospective case series and it remains unclear which patients might benefit. Our group has identified, togther with Jan Hinrich´s group, both early clinical indicators of NOMI and has prospectively analyzed predictors of response to intra-arterial therapy in patients with NOMI. We participate in a multi-center study to explore novel biomarkers for better diagnosing acute mesenteric ischemia (BIPAMI study).

Amatoxin related acute liver failure (AT-ALF) is associated with high mortality if no urgent liver transplantation (LTX) is performed. Therapeutic plasma exchange (PEX) has been demonstrated to improve LTX-free survival in patients with ALF of other etiologies. It is however unclear, if PEX may also improve LTX-free survival in AT-ALF and clinical practice in utilizing PEX in AT-ALF varies substantially between different centers. Of note, due to the scarcity of this ALF entity, realization of a randomized controlled trial investigating use of PEX in AT-ALF does not appear to be feasible in the future.

We (Richard Taubert, Bahar Nalbant and Klaus Stahl) initiated an ongoing multicenter, international, retrospective cohort study (Amanita-PEX study, NCT06187220) to investigate the effect of additive PEX compared to standard medical therapy (SMT) alone in AT-ALF. So far already 20 centers contributed more than 120 patients and a clear trend towards benefit of PEX in AT-ALF is observed. We are open for further centers to contribute.