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Sepsis and Septic Shock: From Molecular Mechanisms to Novel Therapies

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 May 2024 | Viewed by 14231

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Special Issue Editors

Prof. Dr. Markus A. Weigand

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Guest Editor

Department of Anesthesiology, Heidelberg University Hospital, 69120 Heidelberg, Germany
Interests: sepsis; septic shock; severe infection; hemodynamic management; inflammation; immunology
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Michael Adamzik

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Guest Editor

Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, 44892 Bochum, Germany
Interests: sepsis

Special Issue Information

Dear Colleagues,

Today, knowledge about the prevention and early detection of sepsis and septic shock is still lacking.

In sepsis and septic shock there is ongoing controversy regarding the number and importance of activated or repressed pathways and which are relevant in the progression from health to death.

In addition to the classic inflammatory mechanisms, the focus is now also increasingly placed on, e.g., metabolic changes (such as the formation of reactive metabolites), new biomarkers, and epigenetics (including DNA methylation, histone modifications, and non-coding RNAs).

However, of the more than one hundred proposed therapy concepts for sepsis and septic shock, only a few have been adequately investigated and have found their way into everyday clinical practice.

Due to the heterogeneity of septic patients, it could be very helpful to move from the classic therapeutic approaches such as antibiotics, volume therapy, or catecholamine administration to individual therapies tailored to the patient. A deeper understanding of the molecular mechanisms will be the basis for these new treatment options.

Therefore, for this Special Issue, we invite researchers and clinicians to present their original research manuscripts and review articles providing insights into new therapy concepts to prevent or treat the progression of sepsis and septic shock based on new molecular findings.

Prof. Dr. Markus A. Weigand
Prof. Dr. Michael Adamzik
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

sepsis
septic shock
mechanistic insight
epigenetics
immunometabolism
biomarkers
therapy approach
stratification
precision diagnostics

Published Papers (10 papers)

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Research

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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 - 04 Mar 2024

Viewed by 602

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 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

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 - 06 Jan 2024

Viewed by 974

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 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 1 | Viewed by 612

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 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

Viewed by 975

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 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 1 | Viewed by 1188

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. 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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Graphical abstract

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 1361

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 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

Jump to: Research

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 - 08 Mar 2024

Viewed by 1324

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 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

Viewed by 2410

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 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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11 pages, 1539 KiB

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 2 | Viewed by 1920

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 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 1 | Viewed by 1977

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 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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