Elevated serum levels of S100A8/A9 and HMGB1 at hospital admission are correlated with inferior clinical outcomes in COVID-19 patients.
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ABSTRACT:
SUBMITTER: Chen L
PROVIDER: S-EPMC7332851 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:S100A8 and S100A9 proteins are highly upregulated in patients with psoriasis and have been proposed as potential biomarkers for psoriasis. The present study was designed to analyze the effect of narrowband ultraviolet B therapy on these proteins. S100A8, S100A9 gene expression and S100A8/A9 heterocomplex protein levels were analyzed in lesional and non-lesional skin before and after narrowband-UVB treatment in patients with chronic plaque type psoriasis. In addition, disease severity was measured by psoriasis area and severity index (PASI) and serum protein levels of S100A8/A9 were repeatedly analyzed. Narrowband-UVB treatment significantly reduced S100A8, S100A9 gene expression and S100A8/A9 protein levels in lesional skin while serum levels showed no significant change. No correlation between PASI and serum S100A8/A9 protein levels was found. These results implicate a role of S100A8/A9 in the anti-inflammatory effect of narrowband-UVB. Serum S100A8/A9 levels do not respond to treatment suggesting that serum S100A8/A9 does not originate from psoriasis skin keratinocytes. Serum S100A8/A9 levels do not correlate with PASI questioning serum S100A8/A9 as a biomarker for psoriasis skin activity. Trial Registration: DRKS 00014817.
| S-EPMC6415841 | biostudies-literature
Project description:S100A8 and S100A9 (also known as MRP8 and MRP14, respectively) are Ca2+ binding proteins belonging to the S100 family. They often exist in the form of heterodimer, while homodimer exists very little because of the stability. S100A8/A9 is constitutively expressed in neutrophils and monocytes as a Ca2+ sensor, participating in cytoskeleton rearrangement and arachidonic acid metabolism. During inflammation, S100A8/A9 is released actively and exerts a critical role in modulating the inflammatory response by stimulating leukocyte recruitment and inducing cytokine secretion. S100A8/A9 serves as a candidate biomarker for diagnosis and follow-up as well as a predictive indicator of therapeutic responses to inflammation-associated diseases. As blockade of S100A8/A9 activity using small-molecule inhibitors or antibodies improves pathological conditions in murine models, the heterodimer has potential as a therapeutic target. In this review, we provide a comprehensive and detailed overview of the distribution and biological functions of S100A8/A9 and highlight its application as a diagnostic and therapeutic target in inflammation-associated diseases.
| S-EPMC6004386 | biostudies-literature
Project description:The alarmin calprotectin (S100A8/A9) is thought to drive a cytokine storm, a hallmark of severe COVID-19. Recent studies report circulating S100A8/A9 levels can distinguish COVID-19 severity but have only been conducted in non-U.S. cohorts and mainly focus on serum S100A8/A9 levels. Thus, we quantified S100A8/A9 in serum and urine samples from a hospital cohort in St. Louis, Missouri, to expand the understanding of S100A8/A9 as a prognostic biomarker for COVID-19. Elevated S100A8/A9 serum levels were observed in ICU patients (n = 49, p = 0.0370) and patients with fatal cases of COVID-19 (n = 76, p = 0.0018). We observed no correlation in the S100A8/A9 levels in matched serum and urine samples. Our results support the association of serum S100A8/A9 levels with COVID-19 severity and suggest that further investigation of urine S100A8/A9 as a COVID-19 biomarker is not warranted.
| S-EPMC10580308 | biostudies-literature
Project description:ObjectiveElevated inflammation and psychological distress in patients with breast cancer (BCa) have been related to poorer health outcomes. Regulation of the hypothalamic-pituitary-adrenal axis and signaling of the receptor for advanced glycation end products (RAGE) are important in the inflammatory response and have been associated with increased stress and poorer health outcomes in patients with cancer. This study examined relationships among circulating cortisol, a measure of hypothalamic-pituitary-adrenal axis activity and physiological stress; s100A8/A9, a RAGE ligand and emerging cancer-related biological measure; and self-reported cancer-related distress.MethodsPatients with BCa ( N = 183, stages 0-IIIb) were recruited 2 to 10 weeks after surgery but before receiving adjuvant therapies. Participants provided blood samples, from which serum cortisol and s100A8/A9 levels were determined, and completed a psychosocial questionnaire. Regression analyses, adjusting for age, cancer stage, time since surgery, race, and menopausal status, were conducted examining the relationships between cortisol, s100A8/A9, and cancer-related distress (Impact of Event Scale [IES]-Revised).ResultsCortisol and s100A8/A9 levels were positively related ( β = 0.218, t (112) = 2.332, p = .021), although the overall model was not significant. Cortisol levels were also positively associated with IES-Intrusions ( β = 0.192, t (163) = 2.659, p = .009) and IES-Hyperarousal subscale scores ( β = 0.171, t (163) = 2.304, p = .022).ConclusionsPatients with higher cortisol levels also reported higher s100A8/A9 levels and more cancer-related distress. The relationship between cortisol and s100A8/A9 supports a link between the stress response and proinflammatory physiological processes known to predict a greater metastatic risk in BCa. Stress processes implicated in cancer biology are complex, and replication and extension of these initial findings are important.
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Project description:COVID-19 is a disease with a variable clinical course ranging from mild symptoms to critical illness, organ failure, and death. Prospective biomarkers may help to predict the severity of an individual's clinical course and mortality risk. We analyzed asymmetric (ADMA) and symmetric dimethylarginine (SDMA) in blood samples from 31 patients hospitalized for COVID-19. We calculated associations of ADMA and SDMA with mortality and organ failure, and we developed a predictive algorithm based upon these biomarkers to predict mortality risk. Nine patients (29%) experienced in-hospital death. SDMA and ADMA serum concentrations were significantly higher at admission in COVID-19 patients who died than in survivors. Cut-offs of 0.90 µmol/L for SDMA (AUC, 0.904, p = 0.0005) and 0.66 µmol/L for ADMA (AUC, 0.874, p = 0.0013) were found in ROC analyses to best discriminate both subgroups of patients. Hazard ratio for in-hospital mortality was 12.2 (95% CI: 2.2-31.2) for SDMA and 6.3 (1.1-14.7) for ADMA above cut-off. Sequential analysis of both biomarkers allowed discriminating a high-risk group (87.5% mortality) from an intermediate-risk group (25% mortality) and a low-risk group (0% mortality). Elevated circulating concentrations of SDMA and ADMA may help to better identify COVID-19 patients with a high risk of in-hospital mortality.
| S-EPMC8110746 | biostudies-literature
Project description:BackgroundBacterial products add to mechanical ventilation in enhancing lung injury. The role of endogenous triggers of innate immunity herein is less well understood. S100A8/A9 proteins are released by phagocytes during inflammation. The present study investigates the role of S100A8/A9 proteins in ventilator-induced lung injury.MethodsPulmonary S100A8/A9 levels were measured in samples obtained from patients with and without lung injury. Furthermore, wild-type and S100A9 knock-out mice, naive and with lipopolysaccharide-induced injured lungs, were randomized to 5 hours of spontaneously breathing or mechanical ventilation with low or high tidal volume (VT). In addition, healthy spontaneously breathing and high VT ventilated mice received S100A8/A9, S100A8 or vehicle intratracheal. Furthermore, the role of Toll-like receptor 4 herein was investigated.ResultsS100A8/A9 protein levels were elevated in patients and mice with lung injury. S100A8/A9 levels synergistically increased upon the lipopolysaccharide/high VT MV double hit. Markers of alveolar barrier dysfunction, cytokine and chemokine levels, and histology scores were attenuated in S100A9 knockout mice undergoing the double-hit. Exogenous S100A8/A9 and S100A8 induced neutrophil influx in spontaneously breathing mice. In ventilated mice, these proteins clearly amplified inflammation: neutrophil influx, cytokine, and chemokine levels were increased compared to ventilated vehicle-treated mice. In contrast, administration of S100A8/A9 to ventilated Toll-like receptor 4 mutant mice did not augment inflammation.ConclusionS100A8/A9 proteins increase during lung injury and contribute to inflammation induced by HVT MV combined with lipopolysaccharide. In the absence of lipopolysaccharide, high levels of extracellular S100A8/A9 still amplify ventilator-induced lung injury via Toll-like receptor 4.
| S-EPMC3715539 | biostudies-literature
Project description:S100A8 and S100A9 are myeloid cell-derived proteins that are elevated in several types of inflammatory lung disorders. Pro- and anti-inflammatory properties are reported and these proteins are proposed to activate TLR4. S100A8 and S100A9 can function separately, likely through distinct receptors but a systematic comparison of their effects in vivo are limited. Here we assess inflammation in murine lung following S100A9 and S100A8/A9 inhalation. Unlike S100A8, S100A9 promoted mild neutrophil and lymphocyte influx, possibly mediated in part, by increased mast cell degranulation and selective upregulation of some chemokine genes, particularly CXCL-10. S100 proteins did not significantly induce proinflammatory mediators including TNF-α, interleukin-1β (IL-1β), IL-6 or serum amyloid A3 (SAA3). In contrast to S100A8, neither preparation induced S100A8 or IL-10 mRNA/protein in airway epithelial cells, or in tracheal epithelial cells in vitro. Like S100A8, S100A9 and S100A8/A9 reduced neutrophil influx in acute lung injury provoked by lipopolysaccharide (LPS) challenge but were somewhat less inhibitory, possibly because of differential effects on expression of some chemokines, IL-1β, SAA3 and IL-10. Novel common pathways including increased induction of an NAD+-dependent protein deacetylase sirtuin-1 that may reduce NF-κB signalling, and increased STAT3 activation may reduce LPS activation. Results suggest a role for these proteins in normal homeostasis and protective mechanisms in the lung.
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Project description:BackgroundHyponatremia is the most common electrolyte disorder among hospitalized patients. Controversies still exist over the relationship between hyponatremia and outcomes of hospitalized patients.MethodsTo analyze the association of low serum sodium levels at hospital admission with in-hospital mortality and patient disposition and to compare the distribution of the risk of death associated with hyponatremia across the lifespan of hospitalized patients, we conducted an observational study of 2.3 million patients using data extracted from the Cerner Health Facts database between 2000 and 2014. Logistic regression models were used in the analyses.ResultsAt hospital admission 14.4% of hospitalized patients had serum sodium levels [Na] <135 mEq/L. In adjusted multinomial logistic regression analysis, we found that the risk of in-hospital mortality significantly increases for [Na] levels < 135 or ?143 to ?145 mEq/L compared to the reference interval of 140 to <143 mEq/L (p<0.001). We observed similar trends for the relationship between [Na] levels and discharge to hospice or to a nursing facility. We demonstrated that younger age groups (18 to <45, 45 to <65) had a higher risk of in-hospital mortality compared to older age groups (65 to <75, ?75) for [Na] levels <130 mEq/L or 143 to ?145 mEq/L (p<0.001).ConclusionsHyponatremia is common among hospitalized patients and is significantly associated with in-hospital mortality, discharge to hospice or to a nursing facility. The risk of death and other outcomes was more evident for [Na] <135 mEq/L. The mortality associated with low [Na] was significantly higher in younger versus older patients.
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Project description:Study Design:This study was performed to investigate the diagnostic values of some inflammatory biomarkers in abdominal pain. Methods:Patients over 18 years of age with acute recent abdominal pain who presented to the Emergency Department were evaluated. Serum and urinary samples were taken and evaluated for serum and urine S100A8/A9 and serum amyloid A. All patients were referred to a surgeon and were followed up until the final diagnosis. In the end, the final diagnosis was compared with the levels of biomarkers. Results:Of a total of 181 patients, 71 underwent surgery and 110 patients did not need surgery after they were clinically diagnosed. Mean levels of serum and urine S100A8/A9 had a significant difference between two groups, but serum amyloid A did not show. The diagnostic accuracy of serum S100A8/A9, urine S100A8/A9, and serum amyloid A was 86%, 79%, and 50%, respectively, in anticipation of the need or no need for surgery in acute abdominal pain. Conclusions:Our study showed that in acute abdominal pain, serum and urine S100A8/A9 can be useful indicators of the need for surgery, but serum amyloid A had a low and nonsignificant diagnostic accuracy.
| S-EPMC6051260 | biostudies-literature
Project description:BackgroundMyocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear.MethodsUsing a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI.ResultsInduction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1β secretion. The released interleukin-1β interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes.ConclusionsOur study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1β) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.
| S-EPMC7122461 | biostudies-literature