Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies.

RATIONALE & OBJECTIVE: The role of plasma soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Hospital survivors from the ASSESS-AKI (Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury) and ARID (AKI Risk in Derby) studies with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements. PREDICTORS: We measured sTNFR1 and sTNFR2 from plasma samples obtained 3 months after discharge. OUTCOMES: The associations of biomarkers with longitudinal kidney disease incidence and progression, heart failure, and death were evaluated. ANALYTICAL APPROACH: Cox proportional hazard models. RESULTS: Among 1,474 participants with plasma biomarker measurements, 19% had kidney disease progression, 14% had later heart failure, and 21% died during a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs (AHRs) per doubling in concentration were 2.9 (95% CI, 2.2-3.9) for sTNFR1 and 1.9 (95% CI, 1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the AHRs per doubling in concentration were 1.9 (95% CI, 1.4-2.5) for sTNFR1 and 1.5 (95% CI, 1.2-2.0) for sTNFR2. For mortality, the AHRs were 3.3 (95% CI, 2.5-4.3) for sTNFR1 and 2.5 (95% CI, 2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar in terms of the magnitude of association between biomarkers and outcomes. LIMITATIONS: Different biomarker platforms and AKI definitions; limited generalizability to other ethnic groups. CONCLUSIONS: Plasma sTNFR1 and sTNFR2 measured 3 months after hospital discharge were independently associated with clinical events regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

TNFR1 and the TNFα axis as a targetable mediator of liver injury from stereotactic body radiation therapy.

INTRODUCTION: Radiation therapy for the management of intrahepatic malignancies can adversely affect liver function. Liver damage has been associated with increased levels of inflammatory cytokines, including tumor necrosis factor alpha (TNFα). We hypothesized that an inflammatory state, characterized by increased soluble TNFα receptor (sTNFR1), mediates sensitivity of the liver to radiation. MATERIALS/METHODS: Plasma samples collected during 3 trials of liver radiation for liver malignancies were assayed for sTNFR1 level via enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate logistic regression and longitudinal models were used to characterize associations between liver toxicity (defined as a ≥2-point increase in Child-Pugh [CP] score within 6 months of radiation treatment) and sTNFR1 levels, ALBI score, biocorrected mean liver dose (MLD), age, and baseline laboratory values. RESULTS: Samples from 78 patients given liver stereotactic body radiation therapy [SBRT] (92%) or hypofractionated radiation were examined. There was a significant association between liver toxicity and sTNFR1 levels, and higher values were associated with increased toxicity over a range of mean liver doses. When ALBI score and biocorrected dose were included in the model with sTNFR1, baseline ALBI score and change in ALBI (ΔALBI) were significantly associated with toxicity, but sTNFR1 was not. Baseline aminotransferase levels also predicted toxicity but not independently of ALBI score. CONCLUSIONS: Elevated plasma sTNFR1 levels are associated with liver injury after liver radiation, suggesting that elevated inflammatory cytokine activity is a predictor of radiation-induced liver dysfunction. Future studies should determine whether administration of agents that decrease inflammation prior to treatment is warranted.

The Integration of qSOFA with Clinical Variables and Serum Biomarkers Improves the Prognostic Value of qSOFA Alone in Patients with Suspected or Confirmed Sepsis at ED Admission.

BACKGROUND: The prognostic value of quick sepsis-related organ failure assessment (qSOFA) outside intensive care units has been criticized. Therefore, we aimed to improve its ability in predicting 30-day all-cause mortality, and in ruling out the cases at high risk of death among patients with suspected or confirmed sepsis at emergency department (ED) admission. METHODS: This study is a secondary analysis of a prospective multicenter study. We built three predictive models combining qSOFA with the clinical variables and serum biomarkers that resulted in an independent association with 30-day mortality, in both 848 undifferentiated patients (Group 1) and in 545 patients definitively diagnosed with sepsis (Group 2). The models reaching the highest negative predictive value (NPV) with the minimum expenditure of biomarkers in Group 1 and in Group 2 were validated in two cohorts of patients initially held out due to missing data. RESULTS: In terms of the area under the receiver-operating characteristic curve, all six models significantly exceeded qSOFA in predicting prognosis. An "extended" qSOFA (eqSOFA1) in Group 1 and an eqSOFA2 integrated with C-reactive protein and mid-regional proadrenomedullin (eqSOFA2+CRP+MR-proADM) in Group 2 reached the best NPV (0.94 and 0.93, respectively) and ease of use. eqSOFA1 and eqSOFA2+CRP+MR-proADM performed equally well in both the inception and validation cohorts. CONCLUSIONS: We have derived and validated two prognostic models that outweigh qSOFA in predicting mortality and in identifying the low risk of death among patients with suspected or confirmed sepsis at ED admission.

Adipose-derived mesenchymal stem cells ameliorate the inflammatory reaction in CLP-induced septic acute lung injury rats via sTNFR1.

We hypothesized that the adipose-derived mesenchymal stem cells (ADMSCs), which secrete high amounts of soluble molecules, such as soluble tumor necrosis factor receptor 1 (sTNFR1), may ameliorate sepsis-induced acute lung injury (ALI). A total of 120 male adult Sprague-Dawley rats were separated into four groups: the sham control (SC), sepsis induced by cecal ligation and puncture (CLP), CLP-ADMSCs, and CLP-sTNFR1 small interfering RNA (siRNA) groups; CLP groups underwent CLP and then received 1 × 106 ADMSCs with or without knockdown of sTNFR1 intravenously at 1 hr after surgery. Rats were killed at 3, 6, 24, and 48 hr after the SC or CLP procedures. 5-Ethynyl-2'-deoxyuridine-labeled ADMSCs extensively colonized the lungs at 6, 24, and 72 hr after injection. The lung wet/dry (W/D) weight ratios in the CLP group were higher than those in SC group; however, ADMSCs ameliorated the W/D weight ratios following CLP, and this effect was abolished by sTNFR1 siRNA treatment. The levels of serum sTNFR1 and interleukin-10 (IL-10) were higher in the CLP-ADMSCs group and lower in the SC group than in other groups; interestingly, these levels were higher in CLP and CLP-sTNFR1 siRNA groups than in SC group. Tumor necrosis factor-α and IL-6 levels increased significantly after CLP, and ADMSCs could alleviate these changes, but the effect was weakened by sTNFR1 siRNA treatment. The lung cell apoptosis and edema levels were consistent with IL-6 levels among all groups. Therapeutically administered ADMSCs secrete sTNFR1, which most likely protects against ALI in septic rats by ameliorating inflammation and lung edema.

Association of Soluble TNFR-1 Concentrations with Long-Term Decline in Kidney Function: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: TNF receptor-1 (TNFR-1), which plays a causative role in endothelial cell dysfunction and inflammation, is expressed on the cell surface in glomerular and peritubular capillary endothelium of the kidneys. Higher soluble TNF receptor-1 (sTNFR-1) concentrations are associated with kidney disease progression among persons with established diabetic kidney disease. However, no studies have assessed sTNFR-1's role in long-term kidney function changes in a multiethnic population without cardiovascular disease at baseline. METHODS: We tested associations between baseline sTNFR-1 concentrations and 10-year decline in eGFR (incident ≥40% decline and annual proportional decline) among 2548 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study. Serum creatinine concentrations were determined at enrollment and study years 3, 5, and 10. RESULTS: Mean age of participants was 61 years old, 53% were women, and mean baseline eGFR was 79 ml/min per 1.73 m2. Serum sTNFR-1 was inversely associated with baseline eGFR. Over median follow-up of 9.3 years, 110 participants developed ≥40% decline in eGFR; each SD higher concentration of sTNFR1 was associated with higher risk of 40% eGFR decline (adjusted hazard ratio, 1.43; 95% confidence interval [95% CI], 1.16 to 1.77; P<0.001). The highest sTNFR-1 tertile was associated with adjusted annualized decline in eGFR of 1.94% (95% CI, 1.79 to 2.09). Associations persisted across subgroups defined by demographics, hypertension, diabetes, and baseline CKD status. CONCLUSIONS: Elevated serum sTNFR-1 concentrations are associated with faster declines in eGFR over the course of a decade in a multiethnic population, independent of previously known risk factors for kidney disease progression.

Carbonyl Stress and Microinflammation-Related Molecules as Potential Biomarkers in Schizophrenia.

This literature review primarily aims to summarize our research, comprising both cross-sectional and longitudinal studies, and discuss the possibility of using microinflammation-related biomarkers as peripheral biomarkers in the diagnosis and monitoring of patients with schizophrenia. To date, several studies have been conducted on peripheral biomarkers to recognize the potential markers for the diagnosis of schizophrenia and to determine the state and effects of therapy in patients with schizophrenia. Research has established a correlation between carbonyl stress, an environmental factor, and the pathophysiology of neuropsychiatric diseases, including schizophrenia. In addition, studies on biomarkers related to these stresses have achieved results that are either replicable or exhibit consistent increases or decreases in patients with schizophrenia. For instance, pentosidine, an advanced glycation end product (AGE), is considerably elevated in patients with schizophrenia; however, low levels of vitamin B6 [a detoxifier of reactive carbonyl compounds (RCOs)] have also been reported in some patients with schizophrenia. Another study on peripheral markers of carbonyl stress in patients with schizophrenia revealed a correlation of higher levels of glyceraldehyde-derived AGEs with higher neurotoxicity and lower levels of soluble receptors capable of diminishing the effects of AGEs. Furthermore, studies on evoked microinflammation-related biomarkers (e.g., soluble tumor necrosis factor receptor 1) have reported relatively consistent results, suggesting the involvement of microinflammation in the pathophysiology of schizophrenia. We believe that our cross-sectional and longitudinal studies as well as various previous inflammation marker studies that could be interpreted from several perspectives, such as mild localized encephalitis and microvascular disturbance, highlighted the importance of early intervention as prevention and distinguished the possible exclusion of inflammations in schizophrenia.

Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression.

Several pro-inflammatory cytokines have been implicated in depression and in antidepressant response. This exploratory analysis assessed: 1) the extent to which baseline cytokine levels predicted positive antidepressant response to ketamine; 2) whether ketamine responders experienced acute changes in cytokine levels not observed in non-responders; and 3) whether ketamine lowered levels of pro-inflammatory cytokines, analogous to the impact of other antidepressants. Data from double-blind, placebo-controlled studies of patients with major depressive disorder (MDD) or bipolar disorder (BD) who received a single infusion of sub-anesthetic dose ketamine were used (N = 80). Plasma levels of the eight cytokines were measured at baseline and at 230 min, 1 day, and 3 days post-ketamine. A significant positive correlation was observed between sTNFR1 and severity of depression at baseline. Cytokine changes did not correlate with changes in mood nor predict mood changes associated with ketamine administration. Ketamine significantly increased IL-6 levels and significantly decreased sTNFR1 levels. IL-6 and TNF-α levels were also significantly higher-and sTNFR1 levels were significantly lower-in BD compared to MDD subjects. The functional significance of this difference is unknown. Changes in cytokine levels post-ketamine were not related to antidepressant response, suggesting they are not a primary mechanism involved in ketamine's acute antidepressant effects. Taken together, the results suggest that further study of cytokine levels is warranted to assess their potential role as a surrogate outcome in the rapid antidepressant response paradigm.

Inflammatory biomarkers and spontaneous preterm birth among obese women.

OBJECTIVE: To identify associations between second-trimester serum inflammatory biomarkers and preterm birth among obese women. METHODS: In this nested case-control study, we compared 65 serum inflammatory biomarkers in obese women whose pregnancies resulted in early spontaneous preterm birth (<32 weeks gestation, n = 34) to obese women whose pregnancies resulted in term birth (n = 34). These women were selected from a larger population-based California cohort. Random forest and classification and regression tree techniques were employed to identify biomarkers of importance, and adjusted odds ratios (aORs) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Random forest and classification and regression tree techniques found that soluble vascular endothelial growth factor receptor-3 (sVEGFR3), soluble interleukin-2 receptor alpha-chain (sIL-2RA) and soluble tumor necrosis factor receptor-1 (sTNFR1) were related to preterm birth. Using multivariable logistic regression to compare preterm cases and term controls, decreased serum levels of sVEGFR3 and increased serum levels of sIL-2RA and sTNFR1 were associated with increased risk of preterm birth among obese women, aOR = 3.2 (95% CI: 1.0-9.9), aOR = 2.8 (95% CI: 0.9-9.0), and aOR = 4.1 (95% CI: 1.2-14.1), respectively. CONCLUSIONS: In this pilot study, we identified three serum biomarkers indicative of inflammation to be associated with spontaneous preterm birth among obese women: sVEGFR3, sIL-2RA and sTNFR1.

Combination of PAPPA, fhCGß, AFP, PlGF, sTNFR1, and Maternal Characteristics in Prediction of Early-onset Preeclampsia.

OBJECTIVE: To evaluate the efficacy of first-trimester markers-pregnancy-associated plasma protein A (PAPPA), free human chorionic gonadotropin ß (fhCGß), alpha-fetoprotein (AFP), placental growth factor (PlGF), and soluble tumor necrosis factor receptor-1 (sTNFR1) together with maternal characteristics (MC) for prediction of early-onset preeclampsia (EOPE). METHODS: During 2005-2010, the abovementioned biomarkers were analyzed with logistic regression analysis in 64 EOPE and 752 control subjects to determine whether these biomarkers separately and in combination with MC would predict development of EOPE. RESULTS: PAPPA, fhCGß, and PlGF levels were lower, whereas AFP and sTNFR1 levels were higher in mothers with EOPE compared to controls. The combination of all markers with MC (age, weight, and smoking status) detected 48% of the mothers with EOPE, with a 10% false-positive rate (FPR). CONCLUSIONS: First-trimester maternal serum levels of PAPPA, fhCGß, AFP, PlGF, and sTNFR1, together with MC, are predictive of development of subsequent EOPE. These markers, along with MC, form a suitable panel for predicting EOPE.

Increased plasma soluble tumor necrosis factor receptor-1 and myeloperoxidase activity in patients with obstructive sleep apnea syndrome.

PURPOSE/AIM: Obstructive sleep apnea (OSA) is characterized by recurrent respiratory disorders associated with increased cardiovascular morbidity and mortality. The increment of systemic inflammation in OSA has been considered as the major pathogenic mechanism leading to cardiovascular diseases. There is limited and conflicting information in the literature investigating myeloperoxidase (MPO) activity and soluble tumor necrosis factor receptor-1 (sTNF-R1) levels in OSA patients. The aim of our study is to assess the clinical utility of plasma MPO activity and sTNF-R1 levels as risk markers for systemic inflammation and development of cardiovascular diseases in OSA patients. MATERIALS AND METHODS: 59 OSA patients diagnosed with polysomnograhpy for Apnea-Hypopnea index (AHI), and 26 healthy volunteers enrolled into the study. Plasma MPO activity was measured using a spectrophotometric method. An enzyme-linked immunosorbent assay (ELISA) method was used to detect plasma sTNF-R1 levels. RESULTS: Plasma MPO activity and sTNF-R1 levels were significantly higher (43.2 ± 21.65 vs. 30.44 ± 8.05 p = .0046; 2.379 ± 1.2 vs. 1.086 ± 0.86 p < .0001, respectively) in the total OSA patients compared to the control group. There was a significant weak correlation between MPO activity and disease severity indicator AHI (p = .03 r = .27). CONCLUSIONS: Elevated plasma MPO activity and sTNF-R1 levels in the OSA patients indicate increased systemic inflammation and oxidative stress which might contribute to the higher incidence of cardiovascular diseases. Therefore, we recommend measurement of plasma MPO activity and sTNF-R1 levels in the OSA patients as potential risk predictors for cardiovascular diseases.

Cerebrospinal fluid oxidative stress marker levels and cytokine concentrations in a neonate with incontinentia pigmenti.

BACKGROUND: Some children with incontinentia pigmenti exhibit encephalopathic features with severe seizures and disturbed consciousness, from the neonatal through the early infantile period. However, the pathological mechanism of brain lesion development is not fully understood. METHODS: We measured the cerebrospinal fluid levels of cytokines and oxidative stress markers (8-hydroxy-2-deoxyguanosine and the hexanoyl-lysine adduct) in a young girl with incontinentia pigmenti complicated by an encephalopathic event that occurred on her first day of life. Magnetic resonance imaging revealed widespread reduction of water diffusion in the basal ganglia, the periventricular and subcortical white matter, and the corpus callosum. RESULTS: Oxidative stress markers were elevated at 4 days of age but decreased mildly by 25 days of age. Elevated levels of soluble tumor necrosis factor receptor 1 were observed at both 4 and 25 days of age, although tumor necrosis factor-α levels were below the limit of detection. No other cytokine levels were elevated, except for those of interleukin-10 at 25 days of age. CONCLUSIONS: Tumor necrosis factor-α expression and oxidative stress are involved in the pathogenesis of brain lesions in children with incontinentia pigmenti, and elevated cerebrospinal fluid cytokine levels may not be apparent during encephalopathic events.

Persistent inflammation and its relationship to leptin and insulin in phases of bipolar disorder from acute depression to full remission.

OBJECTIVE: A proinflammatory phase with various immunomodulatory mechanisms has been noted in bipolar mania and major depression. Weight gain and increased production of leptin may be associated with immunomodulation and insulin resistance in bipolar disorder. However, immunomodulation and its linkage with leptin and insulin in the depressive episode of bipolar disorder remain unclear. We investigated alterations in inflammatory markers and their relationship with leptin and insulin levels in patients with phases of bipolar disorder from acute depression to full remission. METHODS: Thirty-two physically healthy bipolar I depressed patients aged <45 years and age- and sex-matched healthy controls participated in this study. We measured their circulating levels of leptin, insulin, high-sensitivity C-reactive protein (hs-CRP), soluble interleukin-2 receptor (sIL-2R), soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor receptor 1 (sTNF-R1), and interleukin-1 receptor antagonist (IL-1Ra) in three phases, i.e., acute depression, subsequent partial remission, and full remission. RESULTS: In acute depression, subsequent partial remission, and full remission, patients with bipolar disorder had significantly higher mean levels of hs-CRP, IL-1Ra, sTNF-R1, and sIL-2R compared with control subjects. The IL-1Ra and sTNF-R1 levels in various affective phases were significantly correlated to body mass index, leptin level, circulating lipids, and medication status. The sIL-2R levels in the three affective phases were all independent of other inflammatory markers and clinical and laboratory variables. Patients showed no alteration of sIL-6R levels through the depressive episode. CONCLUSIONS: Patients with bipolar disorder in depressive episodes may exhibit persistent inflammation with elevated levels of hs-CRP, IL-1Ra, sTNF-R1, and sIL-2R but not sIL-6R from the acute phases to full remission. Only sIL-2R production seems to be tightly linked with the pathophysiology of bipolar depression and is independent of insulin and leptin levels.

The effect of capsaicin on circulating biomarkers, soluble tumor necrosis factor and soluble tumor necrosis factor-receptor-1 and -2 levels in vivo using lipopolysaccharide-treated mice.

The circulating soluble tumor necrosis factor (sTNF) and sTNF-receptor (R) 1 and -R2 have known as septic biomarker. The pungent component of capsicum, capsaicin (Cap), has several associated physiological activities, including anti-oxidant, anti-bacterial and anti-inflammatory effects. The aim of this study was to elucidate the effect of Cap on circulating sTNF and sTNF-R1 and -R2 in vivo using lipopolysaccharide (LPS)-treated mice. LPS (20 mg/kg, ip)-treated group was significantly increased circulating sTNF, sTNF-R1, and -R2 and TNF-α mRNA expression levels compared to the vehicle group. Treatment with LPS (20 mg/kg, ip) + Cap (4 mg/kg, sc)-treated group was significantly decreased both circulating sTNF levels (after 1 h only) and TNF-α mRNA expression (after 6 h) compared to the LPS-treated group. There is an early increase in circulating sTNF, sTNR-R1, and -R2 observed in the LPS-treated mice. Since Cap inhibits this initial increase as biomarkers, circulating sTNF, it is considered a potent treatment option for TNF-α-related diseases, such as septicemia. In conclusion, Cap interferes with TNF-α mRNA transcription and exerts an inhibiting effect on TNF-α release from macrophages in the early phase after LPS stimulation. Thus, Cap is considered a potent agent for the treatment of TNF-α-related diseases, such as septicemia.

Soluble tumor necrosis factor receptor mediates cell proliferation on lipopolysaccharide-stimulated cultured human decidual stromal cells.

The tumor necrosis factor-alpha (TNF-alpha) cytokine receptor system modulates apoptosis in many cell types, so we have investigated the role of sTNFR1 in bacterial lipopolysaccharide (LPS)-induced cell death in cultured human decidual stromal cells, hypothesizing that sTNFR1 might play a central role in this action. In this work we characterized in vitro decidual stromal cell viability with LPS treatment and LPS and sTNFR1 co-treatment. We found that LPS treatment induced decidual stromal cell death in a dose-dependent manner and that sTNFR1 blocked the effect of the LPS treatment. There was a significant proliferation among cells co-incubated with LPS at 10 microg/mL and sTNFR1 at 0.1 microg/mL compared with LPS and sTNFR1 at 0.01, 0.05, 0.2 and 0.5 microg/mL (p < 0.01). This study demonstrated that LPS led to decidual stromal cell death in vitro but sTNFR1 down-regulates the cell death due to LPS under the same conditions. Taken together, these results suggested that sTNFR1 could participate in a protective mechanism against endotoxin.

Characteristic expression of tumor necrosis factor receptor 1 in decidua tissue and serum of normal pregnancy and in spontaneous abortion mice / 中国免疫学杂志

Objective:Comparing the expression of tumor necrosis factor receptor 1 (TNFR1) in decidua tissue and soluble tumor necrosis factor receptor 1(sTNFR1) in serum of normal pregnancy and spontaneous abortion mice to probe the relationship between TNFR1 and unexplained spontaneous abortion.Methods:The abortion-prone CBA?DBA/2 mating was established as the model of spontaneous abortion and nonabortion-prone CBA?BALB/c matings were used as the model of normal pregnancy.Immunohistochemistry method(SABC) was employed to detect the expression of TNFR1 in decidua tissue at the day 9 of gestation.The level of sTNFR1 in serum at the same time was determined by ABC-ELISA.Results:Compared with normal pregnancy model,the expression of TNFR1 in decidua tissue of spontaneous abortion was significantly increased (P