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Prospective evaluation of S100A12 and S100A8/A9 (calprotectin) in dogs with sepsis or the systemic inflammatory response syndrome.

ABSTRACT: Pattern recognition receptors (e.g., S100A12 or S100A8/A9) hold promise as inflammatory biomarkers. We prospectively determined and compared serum S100A12 and S100A8/A9 concentrations in dogs with sepsis (n = 11) or systemic inflammatory response syndrome (SIRS; n = 8) over a 3-d period with each other, healthy controls (n = 50), and other clinical and clinicopathologic variables. Serum S100A12 and S100A8/A9 concentrations were significantly higher in dogs with sepsis or SIRS (all p < 0.05) at the time of hospital admission (day 1) compared to healthy controls, with no differences between patient groups. However, septic dogs had significantly lower serum S100A12 concentrations on day 2 and day 3 (both p < 0.05) compared to dogs with SIRS. Likewise, dogs with sepsis had significantly lower S100A8/A9 concentrations on day 2 (p < 0.05). Neither serum S100A12 nor S100A8/A9 concentrations were associated with survival to discharge. Our results suggest a differential expression of the S100/calgranulins between dogs with sepsis and those with SIRS. Serum S100A12 or S100A8/A9 concentration at the time of hospital admission did not differentiate dogs with sepsis from those with SIRS, but the trend of S100/calgranulin concentrations during the following 24-48 h may be a useful surrogate marker for differentiating sepsis from SIRS.

SUBMITTER: Thames BE

PROVIDER: S-EPMC6857009 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and aimsThe 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.MethodsThe 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.ResultsIn 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.ConclusionElevated 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.

Project description:BackgroundTyphoid fever, caused by the Gram-negative bacterium Salmonella enterica serovar Typhi, is a major cause of community-acquired bacteremia and death worldwide. S100A8 (MRP8) and S100A9 (MRP14) form bioactive antimicrobial heterodimers (calprotectin) that can activate Toll-like receptor 4, promoting lethal, endotoxin-induced shock and multi-organ failure. We aimed to characterize the expression and function of S100A8/A9 in patients with typhoid fever and in a murine invasive Salmonella model.Methods and principal findingsS100A8/A9 protein levels were determined in acute phase plasma or feces from 28 Bangladeshi patients, and convalescent phase plasma from 60 Indonesian patients with blood culture or PCR-confirmed typhoid fever, and compared to 98 healthy control subjects. To functionally characterize the role of S100A8/A9, we challenged wildtype (WT) and S100A9-/- mice with S. Typhimurium and determined bacterial loads and inflammation 2- and 5- days post infection. We further assessed the antimicrobial function of recombinant S100A8/A9 on S. Typhimurium and S. Typhi replication in vitro. Typhoid fever patients demonstrated a marked increase of S100A8/A9 in acute phase plasma and feces and this increases correlated with duration of fever prior to admission. S100A8/A9 directly inhibited the growth of S. Typhimurium and S. Typhi in vitro in a dose and time dependent fashion. WT mice inoculated with S. Typhimurium showed increased levels of S100A8/A9 in both the liver and the systemic compartment but S100A9-/- mice were indistinguishable from WT mice with respect to bacterial growth, survival, and inflammatory responses, as determined by cytokine release, histopathology and organ injury.ConclusionS100A8/A9 is markedly elevated in human typhoid, correlates with duration of fever prior to admission and directly inhibits the growth of S. Typhimurium and S. Typhi in vitro. Despite elevated levels in the murine invasive Salmonella model, S100A8/A9 does not contribute to an effective host response against S. Typhimurium in mice.

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Prospective evaluation of S100A12 and S100A8/A9 (calprotectin) in dogs with sepsis or the systemic inflammatory response syndrome.

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