Forschungsgruppe Prof. Dr. Sascha David

The experimental focus of this group lies on endothelial permeability, injury to the glycocalyx and microcirculatory dysfunction in any critical illness. Over the last years our group has been focusing on blood purification techniques in particular on therapeutic plasma exchange in septic shock and we are currently planning a large international multicenter RCT (EXCHANGE-2).

Focus topics

Experimental

• Molecular mechanism and therapeutic implications of capillary leakage
• Angiopoietin / Tie System in heath and disease
• Interaction between endothelium, the glycocalyx and pericytes

Clinical

• Blood purification in sepsis
• therapeutic plasma exchange
• Acute Respiratory Distress Syndrome (ARDS)
• Extracorporeal membrane oxygenation (ECMO)
• Vascular function in sepsis – capillary leakage

Ongoing Experimental Research

We are 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 (Elife. 2020 Aug 24;9:e59520.). Dorothea and Mattia are working under

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 (Am J Respir Crit Care Med. 2020 Oct 15;202(8):1178-1181).

Clinical Research

A major clinical research interest focuses on blood purification in sepsis and septic shock. In a prospective non-randomized pilot study, we could demonstrate that early therapeutic plasma exchange (TPE) improves hemodynamics and endothelial permeability as well as reduced inflammatory cytokines in patients with severe septic shock (EXCHANGE Pilot, Crit Care. 2018 Oct 30;22(1):285.). Recently, we finished a bicentric RCT with the University Hospital Bonn (Bode / Putensen) analyzing the role of PEX in septic shock on hemodynamic stability (EXCHANGE I, NCT04231994, Intensive Care Med. 2021 Jan 20. doi: 10.1007/s00134-020-06339-1). Funding for a multicenter RCT with a clinically meaningful endpoint is currently under review (EXCHANGE II).

We have built-up a biobank combining local and systemic biomaterials (bronchoalveolar lavage fluids (BALf) and blood) together with a thorough clinical characterization from ARDS patients in Hannover. This Sepsis and ARDS Register (termed SPARE-14) will help to translate experimental findings of our basic research group from bench to bedside. We are currently extending towards a second collection side at the USZ in Zurich.

Support of non-intubated patients with both chronic and acute lung failure with extra-corporeal membrane oxygenation, termed awake ECMO, is an innovative strategy that has been first implicated as ultra-protective approach to bridge end-stage lung disease patients to transplant without the injurious side effects of invasive ventilation. We continue to explore this strategy in selected patient cohorts such as patients with PcP associated ARDS (Crit Care. 2019 Dec 23;23(1):418.). ECMO support in special patient cohorts, e.g. patients with diffuse alveolar hemorrhage, and conditions, e.g. heparin free ECMO, are further clinical interests of our group.

We are also conducting research on extracorporeal cytokine removal in patients treated with CAR-T cells suffering from severe cytokine release syndrome (CytoreleaseEx, NCT04048434). This RCT has been initiated at Hannover and is currently extended to USZ, Zurich (financially supported by Cytosorbents).

Given our interest on plasma exchange and the observation that severe Covid-19 leads to a relative deficiency in the vWF cleaving protease (ADAMTS13) and coagulopathy we have applied for a biological proof of principle RCT in Zurich (PEXCoV, NCT04613986) (supported by Terumo and Octapharma).

Team Members

• Pedro David Wendel-Garcia pursued a Bachelor and Master of Science in Mechanical Engineering at the ETH Zurich. Thereafter he studied Medicine as well as Biostatistics at the University of Zurich. He currently is a research associate at the Institute of Intensive Care Medicine at the University Hospital Zurich. Following his mechanical engineering studies, he focused his research primarily on novel materials and micro- and nanorobots for biomedical applications. Now, his main research interests lie in mechanical ventilation and extracorporeal membrane oxygenation in ARDS, as well as blood purification therapies and novel biomarkers in sepsis and septic shock.
• Daniel Hofmänner is physician scientist with a board certification in internal medicine and intensive care. Scientifically, he is interested in the regulation of lipids in critical illnesses such as sepsis in a translational context and he has recently published on bacterial coinfections in Covid-19 patients. Daniel has just finished a postdoctoral research fellowship in the laboratory of Mervyn Singer in the U.K. He will be working as an ICU consultant beginning Oct 2022 in the Institute of Intensive Care at the USZ.
• Rolf Erlebach is an intensivist in training who has performed his MD thesis (Dr. med) at our institute a few years ago investigating non-invasive methods for extended hemodynamic monitoring. In our group, he is currently the lead investigators in an evaluation of hemodynamic monitoring via intra-aortal measurements (AoPP CO). He has led a project on triple cannulated ECMO patients (VVA) that has been granted with research awards from the ESICM and DGIIN.
• Mattia Müller is a certified anesthesiologist and in training for a specialization degree in intensive care medicine. His academic interest is in the investigation of inflammatory response and therapeutic strategies in sepsis and ARDS. Currently, he works on COVID-19-associated inflammation and impact on malfunction of renal replacement devices. He will be joining a clinical fellowship program in critical care at the University of Toronto until October 2023 and will reinforce our team at the bench for the investigation of new therapeutic approaches for the reversal of endothelial leakage after his return to Zurich.
• Rea Andermatt, senior ICU consultant with board certifications in Internal Medicine and Intensive Care Medicine. She recently has been promoted as vice head of our transplant ICU and has a clinical and scientific interest in liver disease and inflammatory reaction in critical ill and transplant patients.
• Eva Maria Kleinert is an experienced clinical trial coordinator at our Institute. As the good soul of the institute she supports all clinical projects in our group from the planning process to the final analysis. She has been working in the field over many years and has supported several large multicenter trials.
• Dorothea Heuberger is a Postdoc in the lab who is interested in coagulation and endothelial dysfunction. After finishing her Master in Human Biology she did her PhD in Prof. Schüpbach`s laboratory on the topic of protease-activated receptor 2 and its novel role in thrombin-induced inflammation. She is the head of our experimental laboratory and is supported by Gabor Kadler (MSc Plant Molecular Biology). Doro has supervised various medical and biological master students as well as a PhD student.
• Sascha David, group leader, has conducted basic translational research as a physician-scientist over more than 15 years. He interrupted his residency in internal medicine in 2009 for 2 years to work in the lab of Prof. Parikh at Harvard Medical School. He has afterwards build up a mixed research group of clinicians and molecular biologists at Hannover Medical School in Germany where he worked till Summer 2020 when he was recruited as Head of the Medical ICU at the USZ in Zurich. There is an ongoing active collaboration with a translational research group between these two places with multiple shared projects.

Society Memberships

• SGI (Schweizer Gesellschaft für Intensivmedizin)
• European Society of Intensive Care Medicine (ESICM)
• Deutsche Gesellschaft für Internistische Intensiv- und Notfallmedizin (DGIIN)
• Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin (DIVI)
• International Symposium on Intensive Care and Emergency Medicine (ISICEM)

Recent important publications 

Experimental

• Karagiannis F, Peukert K, Surace L, Michla M, Nikolka F, Fox M, Weiss P, Feuerborn C, Maier P, Schulz S, Al B, Seeliger B, Welte T, David S, Grondman I, de Nooijer AH, Pickkers P, Kleiner JL, Berger MM, Brenner T, Putensen C; Bonn COVIMMUNE Consortium, Kato H, Garbi N, Netea MG, Hiller K, Placek K, Bode C, Wilhelm C. Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19. Nature. 2022 Jul 28. doi: 10.1038/s41586-022-05128-8.
• Peukert K, Fox M, Schulz S, Feuerborn C, Frede S, Putensen C, Wrigge H, Kümmerer BM, David S, Seeliger B, Welte T, Latz E, Klinman D, Wilhelm C, Steinhagen F, Bode C. Inhibition of Caspase-1 with Tetracycline Ameliorates Acute Lung Injury. Am J Respir Crit Care Med. 2021 Mar 24.
• Etzrodt V, Idowu TO, Schenk H, Seeliger B, Prasse A, Thamm K, Pape T, Müller-Deile J, van Meurs M, Thum T, Garg A, Geffers R, Stahl K, Parikh SM, Haller H, David S Role of endothelial microRNA 155 on capillary leakage in systemic inflammation. Crit Care. 2021 Feb 22;25(1):76
• Stahl K, Gronski PA, Kiyan Y, Seeliger B, Bertram A, Pape T, Welte T, Hoeper MM, Haller H, David S. Injury to the Endothelial Glycocalyx in Critically Ill Patients with COVID-19. Am J Respir Crit Care Med. 2020 Oct 15;202(8):1178-1181
• Idowu TO, Etzrodt V, Seeliger B, Bolanos-Palmieri P, Thamm K, Haller H, David S. Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis. Elife. 2020 Aug 24;9:e59520.
• Thamm K, Schrimpf C, Retzlaff J, Idowu TO, van Meurs M, Zijlstra JG, et al. Molecular Regulation of Acute Tie2 Suppression in Sepsis. Critical care medicine. 2018;46(9):e928-e36.
• Retzlaff J, Thamm K, Ghosh CC, Ziegler W, Haller H, Parikh SM, et al. Flunarizine suppresses endothelial Angiopoietin-2 in a calcium – dependent fashion in sepsis. Scientific reports. 2017;7:44113.

Clinical

• Wendel-Garcia PD, Erlebach R, Hofmaenner DA, Camen G, Schuepbach RA, Jüngst C, Müllhaupt B, Bartussek J, Buehler PK, Andermatt R, David S. Long-term ketamine infusion-induced cholestatic liver injury in COVID-19-associated acute respiratory distress syndrome. Crit Care. 2022 May 23;26(1):148.
• Stahl K, Wand P, Seeliger B, Wendel-Garcia PD, Schmidt JJ, Schmidt BMW, Sauer A, Lehmann F, Budde U, Busch M, Wiesner O, Welte T, Haller H, Wedemeyer H, Putensen C, Hoeper MM, Bode C, David S. Clinical and biochemical endpoints and predictors of response to plasma exchange in septic shock: results from a randomized controlled trial. Crit Care. 2022 May 12;26(1):134.
• David S, Bode C, Putensen C, Welte T, Stahl K; EXCHANGE study group. Adjuvant therapeutic plasma exchange in septic shock. Intensive Care Med. 2021 Jan 20. doi: 10.1007/s00134-020-06339-1.
• Seeliger B, Döbler M, Friedrich R, Stahl K, Kühn C, Bauersachs J, Steinhagen F, Ehrentraut SF, Schewe JC, Putensen C, Welte T, Hoeper MM, Tiede A, David S, Bode C. Comparison of anticoagulation strategies for veno-venous ECMO support in acute respiratory failure. Crit Care. 2021 Jan 4;24(1):701
• Stahl K, Schmidt BMW, Hoeper MM, Skripuletz T, Mohn N, Beutel G, et al. Extracorporeal cytokine removal in severe CAR-T cell associated cytokine release syndrome. Journal of critical care. 2020;57:124-9.
• Stahl K, Schmidt JJ, Seeliger B, Schmidt BMW, Welte T, Haller H, et al. Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock. Crit Care. 2020;24(1):71.
• Seeliger B, Stahl K, Schenk H, Schmidt JJ, Wiesner O, Welte T, et al. Extracorporeal Membrane Oxygenation for Severe ARDS Due to Immune Diffuse Alveolar Hemorrhage: A Retrospective Observational Study. Chest. 2020;157(3):744-7.
• Stahl K, Schenk H, Seeliger B, Wiesner O, Schmidt JJ, Bauersachs J, et al. Extracorporeal membrane oxygenation for acute respiratory distress syndrome due to Pneumocystis pneumonia. Eur Respir J. 2019 Sep 19;54(3):1900410.
• Knaup H, Stahl K, Schmidt BMW, Idowu TO, Busch M, Wiesner O, et al. Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers. Crit. Care. 2018;22(1):285.

Funding

Our experiments are currently supported by the „Schweizerischer Nationalfonds“ (SNF), „Deutsche Forschungsgemeinschaft“ (DFG), „Deutsches Zentrum Lungenforschung (DZL)”, and by unrestricted industrial grants from Cytosorbents, Terumo and Octapharma.