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Sökning: id:"swepub:oai:lup.lub.lu.se:b60eddef-3e2a-4b56-858b-972924f5fb32" > Therapeutic S100A8/...

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

Jakobsson, Gabriel (författare)
Lund University,Lunds universitet,Hjärtinflammationsforskningsgrupp,Forskargrupper vid Lunds universitet,Cardiac Inflammation Research Group,Lund University Research Groups,Lund Univ, Sweden; Clin Res Ctr, Sweden
Papareddy, Praveen (författare)
Lund University,Lunds universitet,Host parasite interactions,Forskargrupper vid Lunds universitet,Lund University Research Groups,Lund Univ, Sweden
Andersson, Henrik (författare)
Linköpings universitet,Linköping University,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten,Region Östergötland, ANOPIVA US
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Mulholland, Megan (författare)
Lund University,Lunds universitet,Kardiovaskulär forskning - cellulär metabolism och inflammation,Forskargrupper vid Lunds universitet,Cardiovascular Research - Cellular Metabolism and Inflammation,Lund University Research Groups,Lund Univ, Sweden
Bhongir, Ravi (författare)
Lund University,Lunds universitet,Infektionsmedicin,Sektion III,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Infection Medicine (BMC),Section III,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund Univ, Sweden
Ljungcrantz, Irena (författare)
Lund University,Lunds universitet,Kardiovaskulär forskning - immunitet och ateroskleros,Forskargrupper vid Lunds universitet,Cardiovascular Research - Immunity and Atherosclerosis,Lund University Research Groups,Lund Univ, Sweden
Engelbertsen, Daniel (författare)
Lund University,Lunds universitet,Kardiovaskulär forskning - cellulär metabolism och inflammation,Forskargrupper vid Lunds universitet,Kardiovaskulär forskning - immunreglering,Cardiovascular Research - Cellular Metabolism and Inflammation,Lund University Research Groups,Cardiovascular research - Immune regulation,Lund Univ, Sweden
Björkbacka, Harry (författare)
Lund University,Lunds universitet,Kardiovaskulär forskning - immunitet och ateroskleros,Forskargrupper vid Lunds universitet,Kardiovaskulär forskning - cellulär metabolism och inflammation,Kardiovaskulär forskning - matrix och inflammation i ateroskleros,Kardiovaskulär forskning - immunreglering,Cardiovascular Research - Immunity and Atherosclerosis,Lund University Research Groups,Cardiovascular Research - Cellular Metabolism and Inflammation,Cardiovascular Research - Matrix and Inflammation in Atherosclerosis,Cardiovascular research - Immune regulation,Lund Univ, Sweden
Nilsson, Jan (författare)
Lund University,Lunds universitet,Kardiovaskulär forskning - immunitet och ateroskleros,Forskargrupper vid Lunds universitet,Cardiovascular Research - Immunity and Atherosclerosis,Lund University Research Groups,Lund Univ, Sweden
Manea, Adrian (författare)
Institute of Cellular Biology and Pathology “Nicolae Simionescu”,Nicolae Simionescu Inst Cellular Biol & Pathol, Romania
Herwald, Heiko (författare)
Lund University,Lunds universitet,Host parasite interactions,Forskargrupper vid Lunds universitet,Lund University Research Groups,Lund Univ, Sweden
Ruiz-Meana, Marisol (författare)
Vall d'Hebron University Hospital,Vall dHebron Hosp Univ, Spain; Inst Salud Carlos III, Spain
Rodríguez-Sinovas, Antonio (författare)
Vall d'Hebron University Hospital,Vall dHebron Hosp Univ, Spain; Inst Salud Carlos III, Spain
Chew, Michelle (författare)
Linköpings universitet,Linköping University,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten,Region Östergötland, ANOPIVA US
Schiopu, Alexandru (författare)
Lund University,Lunds universitet,Hjärtinflammationsforskningsgrupp,Forskargrupper vid Lunds universitet,Cardiac Inflammation Research Group,Lund University Research Groups,Skåne University Hospital,Institute of Cellular Biology and Pathology “Nicolae Simionescu”,Lund Univ, Sweden; Nicolae Simionescu Inst Cellular Biol & Pathol, Romania; Skane Univ Hosp, Sweden; Clin Res Ctr, Sweden
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 (creator_code:org_t)
BMC, 2023
2023
Engelska.
Ingår i: Critical Care. - : BMC. - 1364-8535 .- 1466-609X. ; 27, s. 1-16
Relaterad länk:
http://dx.doi.org/10... (free)
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https://liu.diva-por... (primary) (Raw object)
https://lup.lub.lu.s...
https://doi.org/10.1...
https://urn.kb.se/re...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.].

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

Nyckelord

Endotoxemia
Inflammation
Mitochondrial function
Neutrophils
S100A8/A9
Sepsis-induced myocardial dysfunction
S100A8/A9; Sepsis-induced myocardial dysfunction; Endotoxemia; Mitochondrial function; Inflammation; Neutrophils

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