FGF15 Protects Septic Mice by Inhibiting Inflammation and Modulating Treg Responses.

Background: Fibroblast growth factor 15 (FGF15) through its FGF-receptor (FGFR)-4 inhibits hepatic inflammation. The current study aimed at investigating whether FGF15 could inhibit septic inflammation and its compensative regulatory T cell (Treg) responses in a mouse sepsis model of cecal ligation and puncture (CLP) and in vitro transwell co-culture. Methods: Following the sham or CLP procedure, male CLP C57BL/6 mice were intravenously injected with vehicle saline or FGF15 beginning at 2 h post the procedure every 12 h for three days. Some mice were euthanized and their serum and liver samples were collected for examination of cytokines and Tregs by enzyme-linked immunosorbent assay (ELISA), Western blot and flow cytometry. The remaining mice were monitored for their survival up to 14 days post procedure. Moreover, the purified hepatic CD4+ T cells were co-cultured in transwell plates with unmanipulated NCTC 1469 cells or the cells that had been transfected with the control or FGFR4-specific siRNA and treated with, or without, Lipopolysaccharides (LPS) for 24 h, followed by treatment with vehicle PBS or FGF15 for 48 h. Results: Compared with the CLP group of mice, treatment with FGF15 significantly prolonged the mean survival days of mice (12 vs 1.17 in the CLP group, P = 0.022), mitigated hepatic inflammation and reduced the frequency of apoptotic cells in the liver of mice. FGF15 treatment decreased the percentages of hepatic Tregs, hepatic IL-2, TGF-ß and FOXP3 expression in septic mice, accompanied by decreasing serum IL-1ß, TNF-α, IL-6 and IL-10 levels. Similarly, FGF15 treatment also attenuated the LPS-increased frequency of Tregs, FOXP3 and IL-2 expression and IL-1ß, TNF-α, IL-6 and IL-10 secretion in vitro after co-culture with NCTC 1469 cells, but not co-cultured FGFR4-silenced NCTC 1649 cells. Conclusion: FGF15 treatment through FGFR4 ameliorated hepatic inflammation and its compensative Treg responses, which were associated with protecting from septic death in mice.

High concentration of serum FGF19 at ICU admission is associated with 28-day mortality in sepsis patients.

BACKGROUND: Sepsis remains associated with a high mortality rate despite recent advances in treatment. Traditional biomarkers are inadequate for stratification of patients by sepsis severity. We examined use of the baseline concentration of fibroblast growth factor 19 (FGF19) in predicting 28-day mortality from sepsis. METHODS: A total of 220 consecutive adult patients with sepsis who were admitted to our intensive care unit (ICU) during 2020 were prospectively recruited. Patients were categorized as survivors or non-survivors according to status at 28 days. Baseline concentrations of FGF19 and other parameters were measured. Receiver operating characteristic (ROC) analysis was used to determine the sensitivity, specificity, predictive value, and optimal cutoff of FGF19 in prediction of survival. Prognostic factors were identified using Cox regression analysis. RESULTS: The serum FGF19 concentration was much higher in non-survivors than in survivors (355.0 pg/ml [range: 37.2, 2315.6] vs. 127.3 pg/ml [5.7, 944.1]; P < 0.05]. ROC analysis indicated an FGF19 concentration of 180 pg/ml was the optimal cutoff value. Multivariable Cox regression analysis showed that FGF19 concentration and the change in sequential organ failure assessment (ΔSOFA) score at baseline were independently and significantly associated with 28-day mortality. ROC analysis indicated that FGF19 had a better predictive value than PCT or CRP. Although ΔSOFA had a better predictive value than FGF19, ΔSOFA and FGF19 together had a significantly better predictive value than ΔSOFA alone. CONCLUSION: Sepsis patients with high serum concentrations of FGF19 at ICU admission were associated with an increased risk of 28-day mortality in our ICU.

Does an increase in serum FGF21 level predict 28-day mortality of critical patients with sepsis and ARDS?

BACKGROUND: Sepsis may be accompanied by acute respiratory distress syndrome (ARDS) in patients admitted to intensive care units (ICUs). It is essential to identify prognostic biomarkers in patients with sepsis and ARDS. OBJECTIVE: Determine whether changes in the level of serum fibroblast growth factor 21 (FGF21) can predict the 28-day mortality of ICU patients with sepsis and ARDS. METHODS: Consecutive sepsis patients were divided into two groups (Sepsis + ARDS and Sepsis-only), and the Sepsis + ARDS group was further classified as survivors or non-survivors. Demographic data and comorbidities were recorded. The Sequential Organ Failure Assessment (SOFA) score and serum levels of cytokines and other biomarkers were recorded 3 times after admission. Multiple Cox proportional hazards regression was used to identify risk factors associated with 28-day mortality in the Sepsis + ARDS group. Multivariate receiver operating characteristic curve analysis was used to assess the different predictive value of FGF21 and SOFA. RESULTS: The Sepsis + ARDS group had a greater baseline SOFA score and serum levels of cytokines and other biomarkers than the Sepsis-only group; the serum level of FGF21 was almost twofold greater in the Sepsis + ARDS group (P < 0.05). Non-survivors in the Sepsis + ARDS group had an almost fourfold greater level of FGF21 than survivors in this group (P < 0.05). The serum level of FGF21 persistently increased from the baseline to the peak of shock and death in the non-survivors, but persistently decreased in survivors (P < 0.05). Changes in the serum FGF21 level between different time points were independent risk factors for mortality. No statistical difference was observed between the AUC of FGF21 and SOFA at baseline.  CONCLUSION: A large increase of serum FGF21 level from baseline is associated with 28-day mortality in ICU patients with sepsis and ARDS.

Predictive value of combined serum FGF21 and free T3 for survival in septic patients.

BACKGROUND: We examined the correlation between thyroid hormone (TH) concentrations and the serum fibroblast growth factor 21 (FGF21) concentration in septic patients and to assess the collaborative value of these factors in predicting 28-day mortality in septic patients. METHODS: A total of 120 consecutive patients with sepsis were divided into two groups according to their survival or death within 28 days after initial diagnosis of sepsis. RESULTS: Patients in the non-survivor group had significantly higher serum FGF21 concentrations but lower total and free triiodothyronine (T3) and tetraiodothyronine (T4) concentrations than those in the survivor group. Thyroid hormone concentrations, including T3, free T3, T4 and free T4, were significantly negatively correlated with the ∆SOFA and APACHE II scores as well as the serum FGF21, IL-6, tumor necrosis factor-α, IL-10, procalcitonin, and C-reactive protein concentrations. Logistic regression analysis showed that the ∆SOFA score, serum FGF21 concentration, and free T3 concentration were significant predictors of 28-day mortality. The model with variables of ∆SOFA score and serum FGF21 and free T3 concentrations had the greatest area under the curve of 0.969. CONCLUSION: The addition of free T3 and serum FGF21 to ∆SOFA score provided a significantly improved ability to predict 28-day mortality in septic patients.

Early increases in serum FGF21 levels predict mortality of septic patients.

BACKGROUND: Potential prognostic biomarkers for patients with sepsis have yet to be identified. The present study evaluated the prognostic value of fibroblast growth factor 21 (FGF21) levels in patients with sepsis. METHODS: A total of 120 consecutive Chinese patients with sepsis were prospectively included, and serum levels of FGF21 and biomarkers such as interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL-10, procalcitonin (PCT), C-reactive protein (CRP), and lactate (LAC) were measured within 24 h after intensive care unit admission. The demographic and clinical characteristics including underlying diseases, Sequential Organ Failure Assessment (△SOFA), and acute physiology and chronic health evaluation II (APACHE II) scores were recorded. Patients were categorized into survival and non-survival groups according to the 28-day mortality. Correlations between FGF21, serum indicators, severity score and 28-day mortality were analyzed, and Cox regression analysis was performed to identify prognostic factors. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off of FGF21 for survival prediction. RESULTS: Non-survivors had significantly higher levels of FGF21, IL-6, TNF-α, IL-10, PCT, CRP, and LAC as well as higher SOFA and APACHE II scores compared with the survivors. FGF21 levels were positively correlated with age, waist circumference, levels of IL-6, IL-10, TNF- α, PCT, CRP, and LAC, △SOFA and APACHE II scores. ROC curves showed that FGF21 had a high sensitivity of 81.3% and specificity of 89.8% for predicting 28-day mortality. Patients with a FGF21 levels <3200 pg/ml had a significantly better survival rate than those with levels >3200 pg/ml, and thus, FGF21 was an independent prognostic factor for survival. CONCLUSION: FGF21 could serve as a new prognostic biomarker for sepsis survival.