Background Sepsis mortality has remained unchanged for greater than a decade, and early recognition continues to be the most important factor in mortality outcome. Plasma resistin concentration is increased in sepsis, but its mechanism and clinical relevance is unclear. As one function, resistin interacts with toll-like receptor 4 in competition with lipopolysaccharide, a main component of the gram-negative bacterial cell wall. It is not known if the type of infection leading to sepsis influences resistin production. The objective of this study was to investigate whether 1) early plasma resistin concentration can predict mortality, 2) elevated plasma resistin concentration is associated with clinical disease severity scores, such as SOFA, mSOFA and APACHE II, and 3) plasma resistin concentrations differ between gram negative versus other etiologies of sepsis. Methods This was an exploratory study in the framework of a prospective observational design. Peripheral venous blood samples were obtained from subjects admitted to the intensive care unit at clinical recognition of sepsis (0 hour) and at 6 and 24 hours. Vasopressor utilization was not a requirement for inclusion. Plasma was analyzed for resistin concentration by ELISA. Cytokine concentrations including IL-6, IL-8, and IL-10 were determined by cytokine bead array. Cytokine data were evaluated against publicly available sepsis RNA expression datasets to compare protein versus RNA expression levels in predicting clinical disease state. Clinical data were collected from electronic health records for clinical severity index calculations and context for interpretation of resistin and cytokine concentrations. Subjects were followed up to 60 days, or until death, whichever came first. Statistical analysis was completed with R package and SPSS software. Results Resistin levels were elevated in subjects admitted to the intensive care unit with sepsis. Four-hundred subjects were screened with 45 subjects included in the final analysis. Thirteen of 45 patients were non-survivors. Mortality within 60 days correlated with significantly higher resistin concentrations than in survivors. A resistin concentration of >126 ng/mL at clinical recognition of sepsis and >197 ng/mL within the first 24 hours were associated with mortality within 60 days with an area under the curve of 0.82 and 0.88, respectively. Most subjects with resistin concentration greater than these threshold values were deceased prior to 30 days. Resistin concentrations correlated with SOFA, mSOFA, and APACHE II scores in addition to having association with increases in inflammatory and sepsis biomarkers. These associations were validated with analysis of RNA expression datasets. Conclusion Plasma resistin concentrations of >126 ng/mL at clinical recognition of sepsis and >197 ng/mL within the first 24 hours of clinical sepsis recognition are associated with all-cause mortality. Resistin concentration wi...
Human resistin protein has been shown to competitively inhibit the interaction of Toll-like receptor 4 (TLR4) and lipopolysaccharide (LPS) in a murine model, resulting in survival from lethal injection of LPS by a proposed anti-inflammatory mechanism. The purpose of this study is to affirm that serum resistin concentrations can predict mortality in the early hours of sepsis and to determine if sepsis associated with gram-negative (GN) bacteria significantly alters serum resistin concentration.
Sepsis is a major healthcare challenge worldwide with no effective therapies. Sepsis pathogenesis involves immune dysregulation, however, the underlying mechanisms of inflammation that are protective or pathogenic in sepsis remain unclear. Human resistin is an immune cell-derived protein that is elevated in sepsis. Employing human resistin-expressing transgenic mouse we identified a protective role for resistin in preventing fatal LPS endotoxic shock. Resistin binds to the LPS receptor, Toll-like receptor 4, through its N-terminal helix and triggers a switch from pro-inflammatory to anti-inflammatory responses. We hypothesize that resistin is a novel therapeutic for sepsis. We generated recombinant resistin and resistin N-terminal helices and tested their anti-inflammatory function in peripheral blood mononuclear cells (PBMC). Resistin, or its N-terminal helix alone, inhibited LPS-induced TNFa secretion by PBMC from healthy donors, but this inhibitory activity was abrogated without the helical structure. Next, we recruited 46 septic patients; 52% infection with LPS-rich gram-negative bacteria, and 30% mortality. Preliminary analysis revealed that circulating resistin was significantly higher in all septic patients compared to healthy donors, but that there were three distinct groups in the septic samples: high, medium and low resistin expression. Flow cytometry analysis revealed striking changes in immune cell subsets including monocytes, neutrophils, T cells and natural killer cells. Ongoing studies are investigating the immunomodulatory potential of resistin and its N-terminal helix in septic samples and associations with the infectious pathogen, circulating cytokines and immune cell subsets.
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