Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction
© 2023. BioMed Central Ltd., part of Springer Nature..
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.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Critical care (London, England) - 27(2023), 1 vom: 29. Sept., Seite 374 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jakobsson, Gabriel [VerfasserIn] |
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| Links: |
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| Themen: |
ABR-238901 |
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| Anmerkungen: |
Date Completed 02.10.2023 Date Revised 24.04.2024 published: Electronic CommentIn: Crit Care. 2023 Dec 6;27(1):480. - PMID 38057840 Citation Status MEDLINE |
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| doi: |
10.1186/s13054-023-04652-x |
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| 245 | 1 | 0 | |a Therapeutic S100A8/A9 blockade inhibits myocardial and systemic inflammation and mitigates sepsis-induced myocardial dysfunction |
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| 500 | |a Date Revised 24.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a CommentIn: Crit Care. 2023 Dec 6;27(1):480. - PMID 38057840 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023. BioMed Central Ltd., part of Springer Nature. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Endotoxemia | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Mitochondrial function | |
| 650 | 4 | |a Neutrophils | |
| 650 | 4 | |a S100A8/A9 | |
| 650 | 4 | |a Sepsis-induced myocardial dysfunction | |
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| 650 | 7 | |a Calgranulin A |2 NLM | |
| 650 | 7 | |a Calgranulin B |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 700 | 1 | |a Papareddy, Praveen |e verfasserin |4 aut | |
| 700 | 1 | |a Andersson, Henrik |e verfasserin |4 aut | |
| 700 | 1 | |a Mulholland, Megan |e verfasserin |4 aut | |
| 700 | 1 | |a Bhongir, Ravi |e verfasserin |4 aut | |
| 700 | 1 | |a Ljungcrantz, Irena |e verfasserin |4 aut | |
| 700 | 1 | |a Engelbertsen, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Björkbacka, Harry |e verfasserin |4 aut | |
| 700 | 1 | |a Nilsson, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Manea, Adrian |e verfasserin |4 aut | |
| 700 | 1 | |a Herwald, Heiko |e verfasserin |4 aut | |
| 700 | 1 | |a Ruiz-Meana, Marisol |e verfasserin |4 aut | |
| 700 | 1 | |a Rodríguez-Sinovas, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Chew, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Schiopu, Alexandru |e verfasserin |4 aut | |
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