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Immunomodulatory Effects of Trifluorinated Small Molecules: New Therapeutic Opportunities for Ischemia-Reperfusion Injury

English title Immunomodulatory Effects of Trifluorinated Small Molecules: New Therapeutic Opportunities for Ischemia-Reperfusion Injury
Applicant Beck Schimmer Beatrice
Number 141216
Funding scheme Project funding (Div. I-III)
Research institution Institut für Anästhesiologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.04.2012 - 31.03.2015
Approved amount 537'000.00
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All Disciplines (2)

Discipline
Immunology, Immunopathology
Surgery

Keywords (6)

Thoracic Surgery; Ischemia-Reperfusion Injury; Immunomodulation; Volatile Anesthetics; Metastatic Cancer; Organprotection

Lay Summary (English)

Lead
Lay summary

Numerous studies have shown that volatile anesthetics such as sevoflurane, isoflurane or desflurane can efficiently protect liver, lung, heart and brain from tissue damage caused by procedures correlated with oxygen depletion and re-application of oxygen (ischemia-reperfusion or hypoxia-reoxygenation). Most of these studies performed so far have focused on the characterization of inflammatory mediators and tissue damage markers. Scarce information is available about the clinical relevance of these surrogate markers of protective effects and the translation into clinical outcomes. This research program has been designed to address this question at a preclinical and clinical level. In parallel, this program explores the potential benefits of intravenously administering a soluble experimental compound delivering on one side the active component of volatile anesthetics that is hypothesized to be responsible for the protective effects and on the other side lacks the sedating effects of anesthetics.

Clinical relevance of tissue protection through volatile anesthetics. To study definite clinical outcomes of tissue protection through volatile anesthetics we designed a large multicentre randomized controlled clinical trial (early outcome). Four hundred eighty-six patients undergoing thoracic surgery with intraoperative one-lung ventilation are be randomly assigned to an anesthesia, either performed with the volatile anesthetic desflurane, or intravenously applied propofol as active control. One-lung ventilation is a method, which allows isolation of the individual lungs under anesthesia to the benefit of the surgical procedure, however, this method is associated with the induction of hypoxia and ischemia in the non-ventilated lung. Upon re-ventilation, the deflated lung is reoxygenated, which leads to a well-characterized hypoxia-reoxygenation injury. In this clinical trial, major postoperative complications as primary endpoint (re-interventions without and with anesthesia, single-organ and mulitorgan failure and all-cause mortality) are compared for the desflurane and the propofol group. At an in vivo preclinical level we define tumor spread and recurrence rate as a late outcome of clinical relevance to be assessed in a mouse model after resection of liver metastasis of colorectal cancer, performed with liver inflow occlusion to minimize blood loss. Desflurane and sevoflurane are applied intraoperatively to the animals and tumor spread and hepatic tumor recurrence rate are determined and compared to animals without desflurane/sevoflurane anesthesia as a control.

In vitro and in vivo studies of tissue protection through trifluorinated carbon group-containing small molecules. In clinical practice, the beneficial immunomodulatory properties of volatile anesthetics are limited to patients in well-controlled environments such as operating theatres or intensive care units due to their anesthetic effect. In cases of acute myocardial or cerebral vascular occlusion, administration of tissue-protective compounds without an anesthetic effect would be of high value. In recent experiments in a model of endotoxin-induced cell injury we could demonstrate that the immunomodulating effects of volatile anesthetics are essentially mediated by trifluorinated carbon groups. This finding now allows the design of injectable, cytoprotective molecules carrying trifluorinated carbon groups, which could overcome the limitations of volatile anesthetics regarding intravenous injection and anesthetic side effects. The potential of such trifluorinated small molecules in attenuating the inflammatory response and tissue necrosis are evaluated in well-established models of ischemia-reperfusion in the heart. First, inflammatory mediators and necrosis are determined in rat cardiac myocytes exposed to anoxia, followed by reoxygenation. In a consecutive animal study, the in vitro data are then confirmed in a model of acute myocardial infarction in rats. Future intravenous administration of trifluorinated molecules without anesthetic effect may open new therapeutic strategies for the treatment of patients with acute vascular occlusion upon initiation of reoxygenation, e.g. thrombolysis or percutaneous transluminal angioplasty. In conclusion, this research program is a fully integrated approach to systematically investigate the immunomodulatory effects of trifluorinated small molecules (e.g. volatile anesthetics) and their beneficial effects on outcome in ischemia-reperfusion-injury and cancer recurrence rate on a preclinical as well as clinical level.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Insight into the beneficial immunomodulatory mechanism of the sevoflurane metabolite hexafluoro-2-propanol in a rat model of endotoxemia.
Urner Martin, Schläpfer Martin, Herrmann Inge K, Hasler Melanie, Schimmer Roman R, Booy Christa, Roth Z'graggen Birgit, Rehrauer Hubert, Aigner Fabian, Minshall Richard D, Stark Wendelin J, Beck-Schimmer Beatrice (2015), Insight into the beneficial immunomodulatory mechanism of the sevoflurane metabolite hexafluoro-2-propanol in a rat model of endotoxemia., in Clinical and experimental immunology, Epub ahead of print(XX), XX-XX.
Propofol increases morbidity and mortality in a rat model of sepsis.
Schläpfer Martin, Piegeler Tobias, Dull Randal O, Schwartz David E, Mao Mao, Bonini Marcelo G, Z'Graggen Birgit Roth, Beck-Schimmer Beatrice, Minshall Richard D (2015), Propofol increases morbidity and mortality in a rat model of sepsis., in Critical care (London, England), 19, 45-45.
Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling.
Müller-Edenborn B, Frick R, Piegeler T, Schläpfer M, Roth-Z'graggen B, Schlicker A, Beck-Schimmer B (2015), Volatile anaesthetics reduce neutrophil inflammatory response by interfering with CXC receptor-2 signalling., in British journal of anaesthesia, 114(1), 143-9.
Intravenous application of a primary sevoflurane metabolite improves outcome in murine septic peritonitis: first results.
Herrmann Inge K, Castellon Maricela, Schwartz David E, Hasler Melanie, Urner Martin, Hu Guochang, Minshall Richard D, Beck-Schimmer Beatrice (2013), Intravenous application of a primary sevoflurane metabolite improves outcome in murine septic peritonitis: first results., in PloS one, 8(8), 72057-72057.
Volatile anesthetics improve survival after cecal ligation and puncture.
Herrmann Inge K, Castellon Maricela, Schwartz David E, Hasler Melanie, Urner Martin, Hu Guochang, Minshall Richard D, Beck-Schimmer Beatrice (2013), Volatile anesthetics improve survival after cecal ligation and puncture., in Anesthesiology, 119(4), 901-6.

Collaboration

Group / person Country
Types of collaboration
Wendelin Stark, ETH Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Industry/business/other use-inspired collaboration
Richard Minshall, Chicago United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Annual Meeting Euroanaesthesia, Satellite Symposium 'General anaesthesia and its effects on organ function - What do we know?' Talk given at a conference Conditioning of liver, lung and kidneys during anaesthesia 03.06.2013 Barcelona, Spain Beck Schimmer Beatrice;


Awards

Title Year
Dr. Inge Herrmann: Best Oral Presentation Award Annual Meeting of Swiss Anesthesiologists Effects of the sevoflurane primary metabolite on inflammatory and hemodynamic responses in a rat model of endotoxic shock 2012

Associated projects

Number Title Start Funding scheme
179247 From damage control to pre-emptive repair. Understanding the role of hypoxia in perioperative liver protection 01.04.2018 Project funding (Div. I-III)
150803 Perioperative immunomodulation with volatile anesthetics in cancer surgery 01.01.2014 R'EQUIP
109558 Acute lung injury: key role of the respiratory epithelial compartment 01.10.2005 Project funding (Div. I-III)
109558 Acute lung injury: key role of the respiratory epithelial compartment 01.10.2005 Project funding (Div. I-III)
160283 Does anesthetic management have an impact on circulating tumor cells? 01.04.2015 Project funding (Div. I-III)

Abstract

Numerous studies have shown that volatile anesthetics such as sevoflurane, isoflurane or desflurane can efficiently protect liver, lung, heart and brain from tissue damage caused by ischemia-reperfusion injury. Most of these studies performed so far have focused on the characterization of inflammatory mediators and tissue damage markers. Scarce information is available about the clinical relevance of these surrogate markers of protective effects and the translation into clinical outcomes. This research program has been designed to address this question at a preclinical and clinical level. In a parallel work stream, this program will explore the potential benefits of intravenously administering a soluble experimental compound delivering on one side the active component of volatile anesthetics that is hypothesized to be responsible for the protective effects and on the other side lacks the sedating effects of anesthetics.Part 1. Clinical relevance of tissue protection through volatile anesthetics (work stream I). To study definite clinical outcomes (early outcome) of tissue protection through volatile anesthetics we designed a large multicentre randomized controlled clinical trial. Four hundred eighty-six patients undergoing thoracic surgery with intraoperative one-lung ventilation will be randomly assigned to an anesthesia, either performed with the volatile anesthetic desflurane, or intravenously applied propofol as active control. One-lung ventilation is a method, which allows isolation of the individual lungs under anesthesia to the benefit of the surgical procedure, however, this method is associated with the induction of hypoxia and ischemia in the non-ventilated lung. Upon re-ventilation, the deflated lung is reoxygenated, which leads to a well characterized hypoxia-reoxygenation injury. In this clinical trial, major postoperative complications as primary endpoint (re-interventions without and with anesthesia, single-organ and mulitorgan failure and all-cause mortality) will be compared for the desflurane and the propofol group, At an in vivo preclinical level we define tumor spread and recurrence rate as a late outcome of clinical relevance to be assessed in a mouse model after hepatic metastasis resection of colorectal cancer, performed with liver inflow occlusion to minimize blood loss. In this situation, matrix metalloproteinases (MMP) have been shown to play a crucial role for tumor spread, being significantly upregulated in the inflammatory orchestration of ischemia-reperfusion injury. Based on previous studies, we hypothesize that the volatile anesthetic desflurane downregulates neutrophilic expression of MMP-9. Desflurane will be applied intraoperatively to the animals and tumor spread and hepatic tumor recurrence rate will be determined and compared to animals without desflurane anesthesia as a control.Part 2. In vitro and in vivo studies of tissue protection through trifluorinated carbon group-containing small molecules (work stream II) In clinical practice, the beneficial immunomodulatory properties of volatile anesthetics are limited to patients in well-controlled environments such as operating theatres or intensive care units due to their anesthetic effect. In cases of acute myocardial or cerebral vascular occlusion, administration of tissue-protective compounds without an anesthetic effect would be of high value. In recent experiments in a model of endotoxin-induced cell injury we could demonstrate that the immunomodulating effects of volatile anesthetics are essentially mediated by trifluorinated carbon groups. This finding now allows the design of injectable, cytoprotective molecules carrying trifluorinated carbon groups, which could overcome the limitations of volatile anesthetics regarding intravenous injection and anesthetic side effects. The potential of such trifluorinated small molecules in attenuating the inflammatory response and tissue necrosis will be evaluated in well-established models of myocardial ischemia-reperfusion. First, inflammatory mediators and necrosis will be determined in primary rat cardiac myocytes exposed to anoxia, followed by reoxygenation. In a consecutive animal study, the in vitro data will then be confirmed in a model of acute myocardial infarction in rats. Future intravenous administration of trifluorinated molecules without anesthetic effect may open new therapeutic strategies for the treatment of patients with acute vascular occlusion upon initiation of reoxygenation, e.g. thrombolysis or percutaneous transluminal angioplasty. In conclusion, this research program is a fully integrated approach to systematically investigate the immunomodulatory effects of trifluorinated small molecules (e.g. volatile anesthetics) and their beneficial effects on outcome in ischemia-reperfusion-injury and cancer recurrence rate on a preclinical as well as clinical level.
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