Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction
(2023) In Critical Care 27. p.1-16- Abstract
Background and Aims: The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods: The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced... (More)
Background and Aims: The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods: The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9−/− mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results: In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9−/− mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9−/− mice, confirming target specificity. Conclusion: Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis. Graphical Abstract: [Figure not available: see fulltext.].
(Less)
- author
- organization
-
- Cardiac Inflammation Research Group (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- Host parasite interactions (research group)
- Cardiovascular Research - Cellular Metabolism and Inflammation (research group)
- Infection Medicine (BMC)
- Cardiovascular Research - Immunity and Atherosclerosis (research group)
- Cardiovascular research - Immune regulation (research group)
- Cardiovascular Research - Matrix and Inflammation in Atherosclerosis (research group)
- EpiHealth: Epidemiology for Health
- publishing date
- 2023
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Endotoxemia, Inflammation, Mitochondrial function, Neutrophils, S100A8/A9, Sepsis-induced myocardial dysfunction
- in
- Critical Care
- volume
- 27
- article number
- 374
- pages
- 1 - 16
- publisher
- BioMed Central (BMC)
- external identifiers
-
- scopus:85172825009
- pmid:37773186
- ISSN
- 1364-8535
- DOI
- 10.1186/s13054-023-04652-x
- language
- English
- LU publication?
- yes
- additional info
- Funding Information: Open access funding provided by Lund University. This study was supported by grants from the Marianne and Marcus Wallenberg Foundation the Swedish Heart and Lung Foundation, the Swedish Research Council, the Bundy Academy foundation at Lund University, Skåne Region Research Funds, Malmö University Hospital Funds, the Crafoord Foundation, the Royal Physiographic Society in Lund, Swedish Research Council, Östergotland Region Research Funds, and the Ministry of Research and Education of Romania (PNRR-C9/I8-CF148). Publisher Copyright: © 2023, BioMed Central Ltd., part of Springer Nature.
- id
- b60eddef-3e2a-4b56-858b-972924f5fb32
- date added to LUP
- 2023-10-17 11:30:16
- date last changed
- 2024-08-10 12:50:58
@article{b60eddef-3e2a-4b56-858b-972924f5fb32, abstract = {{<p>Background and Aims: The triggering factors of sepsis-induced myocardial dysfunction (SIMD) are poorly understood and are not addressed by current treatments. S100A8/A9 is a pro-inflammatory alarmin abundantly secreted by activated neutrophils during infection and inflammation. We investigated the efficacy of S100A8/A9 blockade as a potential new treatment in SIMD. Methods: The relationship between plasma S100A8/A9 and cardiac dysfunction was assessed in a cohort of 62 patients with severe sepsis admitted to the intensive care unit of Linköping University Hospital, Sweden. We used S100A8/A9 blockade with the small-molecule inhibitor ABR-238901 and S100A9<sup>−/−</sup> mice for therapeutic and mechanistic studies on endotoxemia-induced cardiac dysfunction in mice. Results: In sepsis patients, elevated plasma S100A8/A9 was associated with left-ventricular (LV) systolic dysfunction and increased SOFA score. In wild-type mice, 5 mg/kg of bacterial lipopolysaccharide (LPS) induced rapid plasma S100A8/A9 increase and acute LV dysfunction. Two ABR-238901 doses (30 mg/kg) administered intraperitoneally with a 6 h interval, starting directly after LPS or at a later time-point when LV dysfunction is fully established, efficiently prevented and reversed the phenotype, respectively. In contrast, dexamethasone did not improve cardiac function compared to PBS-treated endotoxemic controls. S100A8/A9 inhibition potently reduced systemic levels of inflammatory mediators, prevented upregulation of inflammatory genes and restored mitochondrial function in the myocardium. The S100A9<sup>−/−</sup> mice were protected against LPS-induced LV dysfunction to an extent comparable with pharmacologic S100A8/A9 blockade. The ABR-238901 treatment did not induce an additional improvement of LV function in the S100A9<sup>−/−</sup> mice, confirming target specificity. Conclusion: Elevated S100A8/A9 is associated with the development of LV dysfunction in severe sepsis patients and in a mouse model of endotoxemia. Pharmacological blockade of S100A8/A9 with ABR-238901 has potent anti-inflammatory effects, mitigates myocardial dysfunction and might represent a novel therapeutic strategy for patients with severe sepsis. Graphical Abstract: [Figure not available: see fulltext.].</p>}}, author = {{Jakobsson, Gabriel and Papareddy, Praveen and Andersson, Henrik and Mulholland, Megan and Bhongir, Ravi and Ljungcrantz, Irena and Engelbertsen, Daniel and Björkbacka, Harry and Nilsson, Jan and Manea, Adrian and Herwald, Heiko and Ruiz-Meana, Marisol and Rodríguez-Sinovas, Antonio and Chew, Michelle and Schiopu, Alexandru}}, issn = {{1364-8535}}, keywords = {{Endotoxemia; Inflammation; Mitochondrial function; Neutrophils; S100A8/A9; Sepsis-induced myocardial dysfunction}}, language = {{eng}}, pages = {{1--16}}, publisher = {{BioMed Central (BMC)}}, series = {{Critical Care}}, title = {{Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction}}, url = {{http://dx.doi.org/10.1186/s13054-023-04652-x}}, doi = {{10.1186/s13054-023-04652-x}}, volume = {{27}}, year = {{2023}}, }