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Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction

Jakobsson, Gabriel LU ; Papareddy, Praveen LU orcid ; Andersson, Henrik ; Mulholland, Megan LU ; Bhongir, Ravi LU orcid ; Ljungcrantz, Irena LU ; Engelbertsen, Daniel LU ; Björkbacka, Harry LU orcid ; Nilsson, Jan LU and Manea, Adrian , et al. (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.].

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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
  • pmid:37773186
  • scopus:85172825009
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
2024-04-19 02:26:29
@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}},
}