International Journal of Molecular Sciences

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12 pages, 2798 KiB

Open AccessArticle

Tofacitinib Treatment Suppresses CD4+ T-Cell Activation and Th1 Response, Contributing to Protection against Staphylococcal Toxic Shock

by Anders Jarneborn, Zhicheng Hu, Meghshree Deshmukh, Pradeep Kumar Kopparapu and Tao Jin

Int. J. Mol. Sci. 2024, 25(13), 7456; https://doi.org/10.3390/ijms25137456 - 7 Jul 2024

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Abstract

Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock [...] Read more.

Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against S. aureus sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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15 pages, 1753 KiB

Open AccessArticle

New Insights into Hepatic and Intestinal Microcirculation and Pulmonary Inflammation in a Model of Septic Shock and Veno-Arterial Extracorporeal Membrane Oxygenation in the Rat

by Fabian Edinger, Lena Holtz, Götz Schmidt, Emmanuel Schneck, Thomas Zajonz, Michael Sander and Christian Koch

Int. J. Mol. Sci. 2024, 25(13), 7421; https://doi.org/10.3390/ijms25137421 - 6 Jul 2024

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Abstract

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated [...] Read more.

Despite significant efforts toward improving therapy for septic shock, mortality remains high. Applying veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) in this context remains controversial. Since the cannulation of the femoral artery for V-A ECMO return leads to lower body hyperoxia, this study investigated the impact of V-A ECMO therapy on the intestinal and hepatic microcirculation during septic shock in a rodent model. Thirty male Lewis rats were randomly assigned to receive V-A ECMO therapy with low (60 mL/kg/min) or high (90 mL/kg/min) blood flow or a sham procedure. Hemodynamic data were collected through a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by intravenous administration of lipopolysaccharide (1 mg/kg). The rats received lung-protective ventilation during V-A ECMO therapy. The hepatic and intestinal microcirculation was measured by micro-lightguide spectrophotometry after median laparotomy for two hours. Systemic and pulmonary inflammation was detected via enzyme-linked immunosorbent assays (ELISA) of the plasma and bronchoalveolar lavage (BAL), respectively, measuring tumor necrosis factor-alpha (TNF-α), interleukins 6 (IL-6) and 10 (IL-10), and C-X-C motif ligands 2 (CXCL2) and 5 (CXCL5). Oxygen saturation and relative hemoglobin concentration were reduced in the hepatic and intestinal microcirculation during V-A ECMO therapy, independent of the blood flow rate. Further, rats treated with V-A ECMO therapy also presented elevated systolic, diastolic, and mean arterial blood pressure and increased stroke volume, cardiac output, and left ventricular end-diastolic volume. However, left ventricular end-diastolic pressure was only elevated during high-flow V-A ECMO therapy. Blood gas analysis revealed a dilutional anemia during V-A ECMO therapy. ELISA analysis showed an elevated plasma CXCL2 concentration only during high-flow V-A ECMO therapy and elevated BAL CXCL2 and CXCL5 concentrations only during low-flow V-A ECMO therapy. Rats undergoing V-A ECMO therapy exhibited impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Increased pulmonary inflammation was detected only during low-flow V-A ECMO therapy in septic shock. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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14 pages, 2654 KiB

Open AccessArticle

New Insights into Hepatic and Intestinal Microcirculation and Pulmonary Inflammation in a Model of Septic Shock and Venovenous Extracorporeal Membrane Oxygenation in the Rat

by Fabian Edinger, Thomas Zajonz, Lena Holtz, Götz Schmidt, Emmanuel Schneck, Michael Sander and Christian Koch

Int. J. Mol. Sci. 2024, 25(12), 6621; https://doi.org/10.3390/ijms25126621 - 16 Jun 2024

Viewed by 2123

Abstract

Treatment of critically ill patients with venovenous (V-V) extracorporeal membrane oxygenation (ECMO) has gained wide acceptance in the last few decades. However, the use of V-V ECMO in septic shock remains controversial. The effect of ECMO-induced inflammation on the microcirculation of the intestine, [...] Read more.

Treatment of critically ill patients with venovenous (V-V) extracorporeal membrane oxygenation (ECMO) has gained wide acceptance in the last few decades. However, the use of V-V ECMO in septic shock remains controversial. The effect of ECMO-induced inflammation on the microcirculation of the intestine, liver, and critically damaged lungs is unknown. Therefore, the aim of this study was to measure the hepatic and intestinal microcirculation and pulmonary inflammatory response in a model of V-V ECMO and septic shock in the rat. Twenty male Lewis rats were randomly assigned to receive V-V ECMO therapy or a sham procedure. Hemodynamic data were measured by a pressure-volume catheter in the left ventricle and a catheter in the lateral tail artery. Septic shock was induced by the intravenous infusion of lipopolysaccharide (1 mg/kg). During V-V ECMO therapy, rats received lung-protective ventilation. The hepatic and intestinal microcirculation was assessed by micro-lightguide spectrophotometry after median laparotomy for 2 h. Systemic and pulmonary inflammation was measured by enzyme-linked immunosorbent assays of plasma and bronchoalveolar lavage (BAL), respectively, which included tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), IL-10, C-X-C motif ligand 2 (CXCL2), and CXCL5. Reduced oxygen saturation and relative hemoglobin concentration were measured in the hepatic and intestinal microcirculation during treatment with V-V ECMO. These animals also showed increased systolic, mean, and diastolic blood pressures. While no differences in left ventricular ejection fraction were observed, animals in the V-V ECMO group presented an increased heart rate, stroke volume, and cardiac output. Blood gas analysis showed dilutional anemia during V-V ECMO, whereas plasma analysis revealed a decreased concentration of IL-10 during V-V ECMO therapy, and BAL measurements showed increased concentrations of TNF-α, CXCL2, and CXCL5. Rats treated with V-V ECMO showed impaired microcirculation of the intestine and liver during septic shock despite increased blood pressure and cardiac output. Despite lung-protective ventilation, increased pulmonary inflammation was recognized during V-V ECMO therapy in septic shock. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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19 pages, 1440 KiB

Open AccessArticle

Elevated Serum KIM-1 in Sepsis Correlates with Kidney Dysfunction and the Severity of Multi-Organ Critical Illness

by Jonathan Frederik Brozat, Neval Harbalioğlu, Philipp Hohlstein, Samira Abu Jhaisha, Maike Rebecca Pollmanns, Jule Katharina Adams, Theresa Hildegard Wirtz, Karim Hamesch, Eray Yagmur, Ralf Weiskirchen, Frank Tacke, Christian Trautwein and Alexander Koch

Int. J. Mol. Sci. 2024, 25(11), 5819; https://doi.org/10.3390/ijms25115819 - 27 May 2024

Cited by 1 | Viewed by 1334

Abstract

The kidney injury molecule (KIM)-1 is shed from proximal tubular cells in acute kidney injury (AKI), relaying tubular epithelial proliferation. Additionally, KIM-1 portends complex immunoregulation and is elevated after exposure to lipopolysaccharides. It thus may represent a biomarker in critical illness, sepsis, and [...] Read more.

The kidney injury molecule (KIM)-1 is shed from proximal tubular cells in acute kidney injury (AKI), relaying tubular epithelial proliferation. Additionally, KIM-1 portends complex immunoregulation and is elevated after exposure to lipopolysaccharides. It thus may represent a biomarker in critical illness, sepsis, and sepsis-associated AKI (SA-AKI). To characterise and compare KIM-1 in these settings, we analysed KIM-1 serum concentrations in 192 critically ill patients admitted to the intensive care unit. Irrespective of kidney dysfunction, KIM-1 serum levels were significantly higher in patients with sepsis compared with other critical illnesses (191.6 vs. 132.2 pg/mL, p = 0.019) and were highest in patients with urogenital sepsis, followed by liver failure. Furthermore, KIM-1 levels were significantly elevated in critically ill patients who developed AKI within 48 h (273.3 vs. 125.8 pg/mL, p = 0.026) or later received renal replacement therapy (RRT) (299.7 vs. 146.3 pg/mL, p < 0.001). KIM-1 correlated with markers of renal function, inflammatory parameters, hematopoietic function, and cholangiocellular injury. Among subcomponents of the SOFA score, KIM-1 was elevated in patients with hyperbilirubinaemia (>2 mg/dL, p < 0.001) and thrombocytopenia (<150/nL, p = 0.018). In univariate and multivariate regression analyses, KIM-1 predicted sepsis, the need for RRT, and multi-organ dysfunction (MOD, SOFA > 12 and APACHE II ≥ 20) on the day of admission, adjusting for relevant comorbidities, bilirubin, and platelet count. Additionally, KIM-1 in multivariate regression was able to predict sepsis in patients without prior (CKD) or present (AKI) kidney injury. Our study suggests that next to its established role as a biomarker in kidney dysfunction, KIM-1 is associated with sepsis, biliary injury, and critical illness severity. It thus may offer aid for risk stratification in these patients. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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16 pages, 2735 KiB

Open AccessArticle

Suppression PCR-Based Selective Enrichment Sequencing for Pathogen and Antimicrobial Resistance Detection on Cell-Free DNA in Sepsis—A Targeted, Blood Culture-Independent Approach for Rapid Pathogen and Resistance Diagnostics in Septic Patients

by Mirko Sonntag, Vanessa K. Elgeti, Yevhen Vainshtein, Lucca Jenner, Jan Mueller, Thorsten Brenner, Sebastian O. Decker and Kai Sohn

Int. J. Mol. Sci. 2024, 25(10), 5463; https://doi.org/10.3390/ijms25105463 - 17 May 2024

Cited by 1 | Viewed by 2001

Abstract

Sepsis is a life-threatening syndrome triggered by infection and accompanied by high mortality, with antimicrobial resistances (AMRs) further escalating clinical challenges. The rapid and reliable detection of causative pathogens and AMRs are key factors for fast and appropriate treatment, in order to improve [...] Read more.

Sepsis is a life-threatening syndrome triggered by infection and accompanied by high mortality, with antimicrobial resistances (AMRs) further escalating clinical challenges. The rapid and reliable detection of causative pathogens and AMRs are key factors for fast and appropriate treatment, in order to improve outcomes in septic patients. However, current sepsis diagnostics based on blood culture is limited by low sensitivity and specificity while current molecular approaches fail to enter clinical routine. Therefore, we developed a suppression PCR-based selective enrichment sequencing approach (SUPSETS), providing a molecular method combining multiplex suppression PCR with Nanopore sequencing to identify most common sepsis-causative pathogens and AMRs using plasma cell-free DNA. Applying only 1 mL of plasma, we targeted eight pathogens across three kingdoms and ten AMRs in a proof-of-concept study. SUPSETS was successfully tested in an experimental research study on the first ten clinical samples and revealed comparable results to clinical metagenomics while clearly outperforming blood culture. Several clinically relevant AMRs could be additionally detected. Furthermore, SUPSETS provided first pathogen and AMR-specific sequencing reads within minutes of starting sequencing, thereby potentially decreasing time-to-results to 11–13 h and suggesting diagnostic potential in sepsis. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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16 pages, 2106 KiB

Open AccessArticle

Antiseptic Functions of CGK012 against HMGB1-Mediated Septic Responses

by Yun Jin Park, Jong Beom Heo, Yoon-Jung Choi, Sanghee Cho, Taeho Lee, Gyu Yong Song and Jong-Sup Bae

Int. J. Mol. Sci. 2024, 25(5), 2976; https://doi.org/10.3390/ijms25052976 - 4 Mar 2024

Cited by 2 | Viewed by 1235

Abstract

High mobility group box 1 (HMGB1), a protein with important functions, has been recognized as a potential therapeutic target for the treatment of sepsis. One possible mechanism for this is that inhibiting HMGB1 secretion can exert antiseptic effects, which can restore the integrity [...] Read more.

High mobility group box 1 (HMGB1), a protein with important functions, has been recognized as a potential therapeutic target for the treatment of sepsis. One possible mechanism for this is that inhibiting HMGB1 secretion can exert antiseptic effects, which can restore the integrity of the vascular barrier. (7S)-(+)-cyclopentyl carbamic acid 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester (CGK012) is a newly synthesized pyranocoumarin compound that could function as a novel small-molecule inhibitor of the Wnt/β-catenin signaling pathway. However, no studies have yet determined the effects of CGK012 on sepsis. We investigated the potential of CGK012 to attenuate the excessive permeability induced by HMGB1 and enhance survival rates in a mouse model of sepsis with reduced HMGB1 levels following lipopolysaccharide (LPS) treatment. In both LPS-stimulated human endothelial cells and a mouse model exhibiting septic symptoms due to cecal ligation and puncture (CLP), we assessed proinflammatory protein levels and tissue damage biomarkers as indicators of reduced vascular permeability. CGK012 was applied after induction in human endothelial cells exposed to LPS and the CLP-induced mouse model of sepsis. CGK012 effectively mitigated excessive permeability and suppressed HMGB1 release, resulting in improved vascular stability, decreased mortality, and enhanced histological conditions in the mouse model of CLP-induced sepsis. In conclusion, our findings indicate that CGK012 treatment in mice with CLP-induced sepsis diminished HMGB1 release and increased the survival rate, suggesting its potential as a pharmaceutical intervention for sepsis. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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19 pages, 10449 KiB

Open AccessArticle

Immune-Related Molecules CD3G and FERMT3: Novel Biomarkers Associated with Sepsis

by Nanxi Li, Peng Ren, Jingya Wang, Xiaohui Zhu, Xuan Qiao, Zhirui Zeng, Tong Ye, Shanshan Wang, Zhiyun Meng, Hui Gan, Shuchen Liu, Yunbo Sun, Xiaoxia Zhu, Guifang Dou and Ruolan Gu

Int. J. Mol. Sci. 2024, 25(2), 749; https://doi.org/10.3390/ijms25020749 - 6 Jan 2024

Viewed by 1819

Abstract

Sepsis ranks among the most common health problems worldwide, characterized by organ dysfunction resulting from infection. Excessive inflammatory responses, cytokine storms, and immune-induced microthrombosis are pivotal factors influencing the progression of sepsis. Our objective was to identify novel immune-related hub genes for sepsis [...] Read more.

Sepsis ranks among the most common health problems worldwide, characterized by organ dysfunction resulting from infection. Excessive inflammatory responses, cytokine storms, and immune-induced microthrombosis are pivotal factors influencing the progression of sepsis. Our objective was to identify novel immune-related hub genes for sepsis through bioinformatic analysis, subsequently validating their specificity and potential as diagnostic and prognostic biomarkers in an animal experiment involving a sepsis mice model. Gene expression profiles of healthy controls and patients with sepsis were obtained from the Gene Expression Omnibus (GEO) and analysis of differentially expressed genes (DEGs) was conducted. Subsequently, weighted gene co-expression network analysis (WGCNA) was used to analyze genes within crucial modules. The functional annotated DEGs which related to the immune signal pathways were used for constructing protein–protein interaction (PPI) analysis. Following this, two hub genes, FERMT3 and CD3G, were identified through correlation analyses associated with sequential organ failure assessment (SOFA) scores. These two hub genes were associated with cell adhesion, migration, thrombosis, and T-cell activation. Furthermore, immune infiltration analysis was conducted to investigate the inflammation microenvironment influenced by the hub genes. The efficacy and specificity of the two hub genes were validated through a mice sepsis model study. Concurrently, we observed a significant negative correlation between the expression of CD3G and IL-1β and GRO/KC. These findings suggest that these two genes probably play important roles in the pathogenesis and progression of sepsis, presenting the potential to serve as more stable biomarkers for sepsis diagnosis and prognosis, deserving further study. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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13 pages, 1483 KiB

Open AccessArticle

Elevated Midkine Serum Levels Are Associated with Long-Term Survival in Critically Ill Patients

by Philipp Hohlstein, Samira Abu Jhaisha, Eray Yagmur, Dennis Wawer, Maike R. Pollmanns, Jule K. Adams, Theresa H. Wirtz, Jonathan F. Brozat, Lukas Bündgens, Karim Hamesch, Ralf Weiskirchen, Frank Tacke, Christian Trautwein and Alexander Koch

Int. J. Mol. Sci. 2024, 25(1), 454; https://doi.org/10.3390/ijms25010454 - 29 Dec 2023

Cited by 3 | Viewed by 1188

Abstract

Midkine (Mdk) is a multifunctional protein involved in inflammatory processes. Hence, circulating Mdk is increased in sepsis and has been previously suggested as a potential biomarker in these patients. The aim of this study was to elucidate the role of Mdk serum concentrations [...] Read more.

Midkine (Mdk) is a multifunctional protein involved in inflammatory processes. Hence, circulating Mdk is increased in sepsis and has been previously suggested as a potential biomarker in these patients. The aim of this study was to elucidate the role of Mdk serum concentrations in critical illness and sepsis and to verify its value as a prognostic biomarker. Thus, we analyzed the Mdk serum concentrations of 192 critically ill patients on admission to the medical intensive care unit (ICU). While the serum levels of Mdk at admission were similar in septic and nonseptic critical illness (362 vs. 337 ng/L, p = 0.727), we found several interesting correlations of Mdk to laboratory and clinical markers associated with ischemia or hypoxia, e.g., to renal failure and hepatic injury. Mdk serum concentrations at admission did not differ between various causes of sepsis or other critical illness. Most noticeable, we observed upregulated Mdk serum concentrations at admission in patients surviving in the long-term, which was only seen in nonseptic critical illness but not in sepsis. Our study suggests a relevant role of Mdk in critically ill patients in general and highlights the possible protective features of Mdk in critical illness. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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18 pages, 2898 KiB

Open AccessArticle

Extracellular Vesicles as Possible Plasma Markers and Mediators in Patients with Sepsis-Associated Delirium—A Pilot Study

by Konstanze Plaschke, Thorsten Brenner, Mascha O. Fiedler, Tobias Hölle, Maik von der Forst, Robert Christian Wolf, Jürgen Kopitz, Johannes Gebert and Markus A. Weigand

Int. J. Mol. Sci. 2023, 24(21), 15781; https://doi.org/10.3390/ijms242115781 - 30 Oct 2023

Cited by 1 | Viewed by 1673

Abstract

Patients with sepsis-associated delirium (SAD) show severe neurological impairment, often require an intensive care unit (ICU) stay and have a high risk of mortality. Hence, useful biomarkers for early detection of SAD are urgently needed. Extracellular vesicles (EVs) and their cargo are known [...] Read more.

Patients with sepsis-associated delirium (SAD) show severe neurological impairment, often require an intensive care unit (ICU) stay and have a high risk of mortality. Hence, useful biomarkers for early detection of SAD are urgently needed. Extracellular vesicles (EVs) and their cargo are known to maintain normal physiology but also have been linked to numerous disease states. Here, we sought to identify differentially expressed proteins in plasma EVs from SAD patients as potential biomarkers for SAD. Plasma EVs from 11 SAD patients and 11 age-matched septic patients without delirium (non-SAD) were isolated by differential centrifugation, characterized by nanoparticle tracking analysis, transmission electron microscopy and Western blot analysis. Differential EV protein expression was determined by mass spectrometry and the resulting proteomes were characterized by Gene Ontology term and between-group statistics. As preliminary results because of the small group size, five distinct proteins showed significantly different expression pattern between SAD and non-SAD patients (p ≤ 0.05). In SAD patients, upregulated proteins included paraoxonase-1 (PON1), thrombospondin 1 (THBS1), and full fibrinogen gamma chain (FGG), whereas downregulated proteins comprised immunoglobulin (IgHV3) and complement subcomponent (C1QC). Thus, plasma EVs of SAD patients show significant changes in the expression of distinct proteins involved in immune system regulation and blood coagulation as well as in lipid metabolism in this pilot study. They might be a potential indicator for to the pathogenesis of SAD and thus warrant further examination as potential biomarkers, but further research is needed to expand on these findings in longitudinal study designs with larger samples and comprehensive polymodal data collection. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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18 pages, 5211 KiB

Open AccessArticle

Aloe-Emodin Ameliorates Cecal Ligation and Puncture-Induced Sepsis

by Jingqian Su, Siyuan Chen, Jianbin Xiao, Zhihua Feng, Shan Hu, Qiaofen Su, Qi Chen and Duo Chen

Int. J. Mol. Sci. 2023, 24(15), 11972; https://doi.org/10.3390/ijms241511972 - 26 Jul 2023

Cited by 10 | Viewed by 1892

Abstract

Sepsis remains a major challenge owing to its severe adverse effects and high mortality, against which specific pharmacological interventions with high efficacy are limited. Mitigation of hyperactive inflammatory responses is a key factor in enhancing the likelihood of survival in patients with sepsis. [...] Read more.

Sepsis remains a major challenge owing to its severe adverse effects and high mortality, against which specific pharmacological interventions with high efficacy are limited. Mitigation of hyperactive inflammatory responses is a key factor in enhancing the likelihood of survival in patients with sepsis. The Aloe genus has several health benefits, including anti-inflammatory properties. The toxicological implications of aloe-emodin (AE), extracted from various Aloe species, remain uncertain in clinical contexts. However, AE has been shown to inhibit inflammatory responses in lipopolysaccharide-induced mice, indicating its potential as a therapeutic approach for sepsis treatment. Nonetheless, there is a paucity of data regarding the therapeutic benefits of AE in the widely recognized cecal ligation and puncture (CLP)-induced sepsis model, which is commonly used as the gold standard model for sepsis research. This study demonstrates the potential benefits of AE in the treatment of CLP-induced sepsis and investigates its underlying mechanism, along with the efficacy of postoperative AE treatment in mice with CLP-induced sepsis. The results of this study suggest that AE can mitigate sepsis in mice by diminishing systemic inflammation and regulating the gut microbiota. The study provides novel insights into the molecular mechanisms underlying the anti-inflammatory effects of AE. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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11 pages, 1884 KiB

Open AccessArticle

Evaluation of the Novel Sepsis Biomarker Host-Derived Delta-like Canonical Notch Ligand 1—A Secondary Analysis of 405 Patients Suffering from Inflammatory or Infectious Diseases

by Tobias Hölle, Patrick Rehn, Konstantinos Leventogiannis, Antigone Kotsaki, Theodora Kanni, Nikolaos Antonakos, Christos Psarrakis, Georgia Damoraki, Judith Schenz, Felix C. F. Schmitt, Florian Uhle, Markus A. Weigand, Evangelos J. Giamarellos-Bourboulis and Maximilian Dietrich

Int. J. Mol. Sci. 2023, 24(11), 9164; https://doi.org/10.3390/ijms24119164 - 23 May 2023

Cited by 1 | Viewed by 1868

Abstract

Sepsis is defined as organ failure caused by dysregulated host response to infection. While early antibiotic treatment in patients with acute infection is essential, treating non-infectious patients must be avoided. Current guidelines recommend procalcitonin (PCT) to guide discontinuation of antibiotic treatment. For initiation [...] Read more.

Sepsis is defined as organ failure caused by dysregulated host response to infection. While early antibiotic treatment in patients with acute infection is essential, treating non-infectious patients must be avoided. Current guidelines recommend procalcitonin (PCT) to guide discontinuation of antibiotic treatment. For initiation of therapy, there is currently no recommended biomarker. In this study, we evaluated Host-Derived Delta-like Canonical Notch Ligand 1 (DLL1), a monocyte membrane ligand that has shown promising results in differentiating infectious from non-infectious critically ill patients. Soluble DLL1 levels were measured in plasma samples of six different cohorts. The six cohorts comprise two cohorts with non-infectious inflammatory auto-immune diseases (Hidradenitis Suppurativa, Inflammatory Bowel Disease), one cohort of bacterial skin infection, and three cohorts of suspected systemic infection or sepsis. In total, soluble DLL1 plasma levels of 405 patients were analyzed. Patients were divided into three groups: inflammatory disease, infection, and sepsis (defined according to the Sepsis-3 definition), followed by the evaluation of its diagnostic performance via Area Under the Receiver Operating Characteristics (AUROC) analyses. Patients of the sepsis group showed significantly elevated plasma DLL1 levels compared to patients with uncomplicated infections and sterile inflammation. However, patients with infections had significantly higher DLL1 levels than patients with inflammatory diseases. Diagnostic performance was evaluated and showed better performance for DLL1 for the recognition of sepsis (AUC: 0.823; CI 0.731–0.914) than C-reactive protein (AUC 0.758; CI 0.658–0.857), PCT (AUC 0.593; CI 0.474–0.711) and White Blood Cell count (AUC 0.577; CI 0.46–0.694). DLL1 demonstrated promising results for diagnosing sepsis and was able to differentiate sepsis from other infectious and inflammatory diseases. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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Review

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10 pages, 225 KiB

Open AccessReview

MicroRNA as Sepsis Biomarkers: A Comprehensive Review

by Khalid Bindayna

Int. J. Mol. Sci. 2024, 25(12), 6476; https://doi.org/10.3390/ijms25126476 - 12 Jun 2024

Viewed by 1470

Abstract

Sepsis, a life-threatening condition caused by the body’s dysregulated response to infection, presents a significant challenge in clinical management. Timely and accurate diagnosis is paramount for initiating appropriate interventions and improving patient outcomes. In recent years, there has been growing interest in identifying [...] Read more.

Sepsis, a life-threatening condition caused by the body’s dysregulated response to infection, presents a significant challenge in clinical management. Timely and accurate diagnosis is paramount for initiating appropriate interventions and improving patient outcomes. In recent years, there has been growing interest in identifying biomarkers that can aid in the early detection and prognostication of sepsis. MicroRNAs (miRNAs) have emerged as potential biomarkers for sepsis due to their involvement in the regulation of gene expression and their stability in various biological fluids, including blood. MiRNAs are small non-coding RNA molecules that play crucial roles in post-transcriptional gene regulation by binding to target messenger RNAs (mRNAs), leading to mRNA degradation or translational repression. The diagnostic and prognostic potential of miRNAs in sepsis stems from their ability to serve as sensitive and specific biomarkers reflective of the underlying pathophysiological processes. Compared to traditional biomarkers such as C-reactive protein (CRP) and procalcitonin (PCT), miRNAs offer several advantages, including their early and sustained elevation during sepsis, as well as their stability in stored samples, making them attractive candidates for clinical use. However, despite their promise, the clinical translation of miRNAs as sepsis biomarkers faces several challenges. These include the need for standardized sample collection and processing methods, the identification of optimal miRNA panels or signatures for differentiating sepsis from other inflammatory conditions, and the validation of findings across diverse patient populations and clinical settings. In conclusion, miRNAs hold great promise as diagnostic and prognostic biomarkers for sepsis, offering insights into the underlying molecular mechanisms and potential therapeutic targets. However, further research is needed to overcome existing challenges and realize the full clinical utility of miRNAs in improving sepsis outcomes. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

18 pages, 1248 KiB

Open AccessReview

Septic Hyperinflammation—Is There a Role for Extracorporeal Blood Purification Techniques?

by Dominik Jarczak, Stefan Kluge and Axel Nierhaus

Int. J. Mol. Sci. 2024, 25(6), 3120; https://doi.org/10.3390/ijms25063120 - 8 Mar 2024

Cited by 2 | Viewed by 3392

Abstract

This manuscript investigates the role of extracorporeal blood purification techniques in managing septic hyperinflammation, a critical aspect of sepsis characterized by an uncontrolled immune response leading to multiorgan dysfunction. We provide an overview of sepsis, focusing on the dynamics of immune response, the [...] Read more.

This manuscript investigates the role of extracorporeal blood purification techniques in managing septic hyperinflammation, a critical aspect of sepsis characterized by an uncontrolled immune response leading to multiorgan dysfunction. We provide an overview of sepsis, focusing on the dynamics of immune response, the involvement of neutrophils, and the role of the endothelium in the disease’s progression. It evaluates the effectiveness of various blood purification methods, including high-cut-off membranes, high-volume hemofiltration, adsorption techniques, and albumin dialysis, in removing cytokines and endotoxin and improving hemodynamic stability. Despite some very promising results, we conclude that the current evidence does not strongly support these techniques in significantly improving survival rates in septic patients, clearly underlining the need for further research. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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17 pages, 1002 KiB

Open AccessReview

Controversies Surrounding Albumin Use in Sepsis: Lessons from Cirrhosis

by Christian J. Wiedermann

Int. J. Mol. Sci. 2023, 24(24), 17606; https://doi.org/10.3390/ijms242417606 - 18 Dec 2023

Cited by 4 | Viewed by 7220

Abstract

This narrative review critically examines the role of albumin in sepsis management and compares it to its well-established application in liver cirrhosis. Albumin, a key plasma protein, is effective in the management of fluid imbalance, circulatory dysfunction, and inflammation-related complications. However, its role [...] Read more.

This narrative review critically examines the role of albumin in sepsis management and compares it to its well-established application in liver cirrhosis. Albumin, a key plasma protein, is effective in the management of fluid imbalance, circulatory dysfunction, and inflammation-related complications. However, its role in sepsis is more intricate and characterized by ongoing debate and varied results from clinical studies. In sepsis, the potential benefits of albumin include maintaining vascular integrity and modulating inflammation, yet its consistent clinical efficacy is not as definitive as that in cirrhosis. This review evaluated various clinical trials and evidence, highlighting their limitations and providing practical insights for clinicians. It emphasizes identifying sepsis patient subgroups that are most likely to benefit from albumin therapy, particularly exploring the correction of hypoalbuminemia. This condition, which is significantly corrected in patients with cirrhosis, may have similar therapeutic advantages in sepsis. The potential effectiveness of albumin in the low-volume resuscitation and deresuscitation phases of sepsis management was noted. Given the safety concerns observed in cirrhosis, such as pulmonary edema and hypervolemia associated with albumin therapy, cautious integration of albumin into sepsis treatment is mandatory. Personalized albumin therapy is advocated for tailoring strategies to the specific needs of each patient, based on their clinical presentation and underlying conditions. The need for further research to delineate the role of albumin in sepsis pathophysiology is underscored. The review emphasizes the importance of conducting trials to assess the effectiveness of albumin in correcting hypoalbuminemia in sepsis, its impact on patient outcomes, and the establishment of appropriate dosing and administration methods. This approach to albumin use in sepsis management is posited as a way to potentially improve patient outcomes in this complex clinical scenario while being mindful of the lessons learned from its use in cirrhosis. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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Open AccessReview

Endotoxic Septic Shock: Diagnosis and Treatment

by Debra M. Foster and John A. Kellum

Int. J. Mol. Sci. 2023, 24(22), 16185; https://doi.org/10.3390/ijms242216185 - 10 Nov 2023

Cited by 11 | Viewed by 4241

Abstract

Endotoxin, also referred to as lipopolysaccharide (LPS), is a potent stimulator of the inflammatory cascade which may progress to sepsis and septic shock. The term endotoxic septic shock has been used for patients who have a clinical phenotype that is characterized by high [...] Read more.

Endotoxin, also referred to as lipopolysaccharide (LPS), is a potent stimulator of the inflammatory cascade which may progress to sepsis and septic shock. The term endotoxic septic shock has been used for patients who have a clinical phenotype that is characterized by high endotoxin activity in addition to a high burden of organ failure; especially a pattern of organ failure including hepatic dysfunction, acute kidney injury, and various forms of endothelial dysfunction. Endotoxic septic shock has been a target for drug therapy for decades with no success. A likely barrier to their success was the inability to quantify endotoxin in the bloodstream. The Endotoxin Activity Assay (EAA) is positioned to change this landscape. In addition, medical devices using adsorptive technology in an extra-corporeal circulation has been shown to remove large quantities of endotoxin from the bloodstream. Focusing on the use of EAA to determine high concentrations of endotoxin will allow patients with endotoxic septic shock to be identified quickly and these patients may benefit most from removal of endotoxin using extracorporeal methods. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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15 pages, 480 KiB

Open AccessReview

Exploring Neuroprotective Agents for Sepsis-Associated Encephalopathy: A Comprehensive Review

by Klaudia Krzyzaniak, Robert Krion, Aleksandra Szymczyk, Ewelina Stepniewska and Mariusz Sieminski

Int. J. Mol. Sci. 2023, 24(13), 10780; https://doi.org/10.3390/ijms241310780 - 28 Jun 2023

Cited by 3 | Viewed by 2821

Abstract

Sepsis is a life-threatening condition resulting from an inflammatory overreaction that is induced by an infectious factor, which leads to multi-organ failure. Sepsis-associated encephalopathy (SAE) is a common complication of sepsis that can lead to acute cognitive and consciousness disorders, and no strict [...] Read more.

Sepsis is a life-threatening condition resulting from an inflammatory overreaction that is induced by an infectious factor, which leads to multi-organ failure. Sepsis-associated encephalopathy (SAE) is a common complication of sepsis that can lead to acute cognitive and consciousness disorders, and no strict diagnostic criteria have been created for the complication thus far. The etiopathology of SAE is not fully understood, but plausible mechanisms include neuroinflammation, blood–brain barrier disruption, altered cerebral microcirculation, alterations in neurotransmission, changes in calcium homeostasis, and oxidative stress. SAE may also lead to long-term consequences such as dementia and post-traumatic stress disorder. This review aims to provide a comprehensive summary of substances with neuroprotective properties that have the potential to offer neuroprotection in the treatment of SAE. An extensive literature search was conducted, extracting 71 articles that cover a range of substances, including plant-derived drugs, peptides, monoclonal antibodies, and other commonly used drugs. This review may provide valuable insights for clinicians and researchers working in the field of sepsis and SAE and contribute to the development of new treatment options for this challenging condition. Full article

(This article belongs to the Special Issue Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies)

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