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Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches
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Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches

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: closed (31 December 2021) | Viewed by 32731

Special Issue Editor

Prof. Dr. Andreas von Knethen

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Guest Editor
Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy–Experimental Unit, University Hospital Frankfurt, Theodor-Stern-Kai 7, Building 9B, 3rd Floor, 60590 Frankfurt, Germany
Interests: sepsis; ARDS; macrophages; T cells; Nrf2; PPARgamma; mouse sepsis models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

I am glad to act as a Guest Editor for a Special Issue of IJMS entitled “Sepsis: From Molecular Mechanisms and Pathophysiology to Novel Therapeutic Approaches.” Considering antibiosis, eradication of the focus, and intensive care supply as only treatment regimens for patients suffering from sepsis, it is obvious that new therapies are mandatory. Because the anamneses of the patients are very heterogeneous, characterizing mechanistic details associated with sepsis initiation or progression will be helpful to setup new therapy approaches. Therefore, manuscripts elucidating molecular mechanisms in vitro or in vivo in preclinical models as well as studies from patients providing insights into new therapy concepts to prevent or treat sepsis progression are welcome. Based on this research topic, a combination of original research manuscripts and review articles in the field of the origin of sepsis and thereof deviated therapies is planned.

Submission of review and original articles that cover, but are not limited to, the following topics are welcome:

  1. Cell culture studies, characterizing and/or identifying new factors involved in sepsis development.
  2. The role of immune cell subpopulations in sepsis progression.
  3. Animal models providing mechanistic insights of underlying principles leading to sepsis.
  4. Therapeutic approaches to prevent or cure sepsis and future perspectives.
  5. Definition of new sepsis biomarkers.
  6. Characterization of putative subgroups of sepsis patients with a similar origin of sepsis.
Prof. Dr. Andreas von Knethen
Guest Editor

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

  • animal models
  • therapy concept
  • biomarkers
  • sepsis
  • immune suppression
  • epigenetics

Related Special Issue

Published Papers (9 papers)

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Research

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16 pages, 28696 KiB  
Article
ATRvD1 Attenuates Renal Tubulointerstitial Injury Induced by Albumin Overload in Sepsis-Surviving Mice
by José Bruno N. F. Silva, Thayanne B. B. Calcia, Cyntia P. Silva, Rafael F. Guilherme, Fernando Almeida-Souza, Felipe S. Lemos, Kátia S. Calabrese, Celso Caruso-Neves, Josiane S. Neves and Claudia F. Benjamim
Int. J. Mol. Sci. 2021, 22(21), 11634; https://doi.org/10.3390/ijms222111634 - 27 Oct 2021
Cited by 2 | Viewed by 2625
Abstract
Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution [...] Read more.
Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called the subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, the urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing proteinuria excretion, the UPC ratio, the glomerular cell number, and extracellular matrix deposition. Pro-fibrotic markers, such as transforming growth factor β (TGFβ), type 3 collagen, and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from the recruitment of IBA1+ cells. The interleukin-1β (IL-1β) levels were increased in the subAKI animal model, being attenuated by ATRvD1. Tumor necrosis factor-α (TNF-α), IL-10, and IL-4 mRNA expression were increased in the kidney of BSA-challenged post-septic mice, and it was also reduced after ATRvD1. These results suggest that ATRvD1 protects the kidney against a second insult such as BSA-induced tubulointerstitial injury and fibrosis by suppressing inflammatory and pro-fibrotic mediators in renal dysfunction after sepsis. Full article
(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)
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17 pages, 2321 KiB  
Article
Selective Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibition by the SCH772984 Compound Attenuates In Vitro and In Vivo Inflammatory Responses and Prolongs Survival in Murine Sepsis Models
by Michal Kopczynski, Izabela Rumienczyk, Maria Kulecka, Małgorzata Statkiewicz, Kazimiera Pysniak, Zuzanna Sandowska-Markiewicz, Urszula Wojcik-Trechcinska, Krzysztof Goryca, Karolina Pyziak, Eliza Majewska, Magdalena Masiejczyk, Katarzyna Wojcik-Jaszczynska, Tomasz Rzymski, Karol Bomsztyk, Jerzy Ostrowski and Michal Mikula
Int. J. Mol. Sci. 2021, 22(19), 10204; https://doi.org/10.3390/ijms221910204 - 22 Sep 2021
Cited by 7 | Viewed by 3158
Abstract
Sepsis is the leading cause of death in intensive care units worldwide. Current treatments of sepsis are largely supportive and clinical trials using specific pharmacotherapy for sepsis have failed to improve outcomes. Here, we used the lipopolysaccharide (LPS)-stimulated mouse RAW264.7 cell line and [...] Read more.
Sepsis is the leading cause of death in intensive care units worldwide. Current treatments of sepsis are largely supportive and clinical trials using specific pharmacotherapy for sepsis have failed to improve outcomes. Here, we used the lipopolysaccharide (LPS)-stimulated mouse RAW264.7 cell line and AlphaLisa assay for TNFa as a readout to perform a supervised drug repurposing screen for sepsis treatment with compounds targeting epigenetic enzymes, including kinases. We identified the SCH772984 compound, an extracellular signal-regulated kinase (ERK) 1/2 inhibitor, as an effective blocker of TNFa production in vitro. RNA-Seq of the SCH772984-treated RAW264.7 cells at 1, 4, and 24 h time points of LPS challenge followed by functional annotation of differentially expressed genes highlighted the suppression of cellular pathways related to the immune system. SCH772984 treatment improved survival in the LPS-induced lethal endotoxemia and cecal ligation and puncture (CLP) mouse models of sepsis, and reduced plasma levels of Ccl2/Mcp1. Functional analyses of RNA-seq datasets for kidney, lung, liver, and heart tissues from SCH772984-treated animals collected at 6 h and 12 h post-CLP revealed a significant downregulation of pathways related to the immune response and platelets activation but upregulation of the extracellular matrix organization and retinoic acid signaling pathways. Thus, this study defined transcriptome signatures of SCH772984 action in vitro and in vivo, an agent that has the potential to improve sepsis outcome. Full article
(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)
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12 pages, 1306 KiB  
Article
Fibrin Network Formation and Lysis in Septic Shock Patients
by Julie Brogaard Larsen, Mathies Appel Aggerbeck, Kim Michael Larsen, Christine Lodberg Hvas and Anne-Mette Hvas
Int. J. Mol. Sci. 2021, 22(17), 9540; https://doi.org/10.3390/ijms22179540 - 2 Sep 2021
Cited by 6 | Viewed by 2066
Abstract
Background: Septic shock patients are prone to altered fibrinolysis, which contributes to microthrombus formation, organ failure and mortality. However, characterisation of the individual patient’s fibrinolytic capacity remains a challenge due to a lack of global fibrinolysis biomarkers. We aimed to assess fibrinolysis in [...] Read more.
Background: Septic shock patients are prone to altered fibrinolysis, which contributes to microthrombus formation, organ failure and mortality. However, characterisation of the individual patient’s fibrinolytic capacity remains a challenge due to a lack of global fibrinolysis biomarkers. We aimed to assess fibrinolysis in septic shock patients using a plasma-based fibrin clot formation and lysis (clot–lysis) assay and investigate the association between clot–lysis parameters and other haemostatic markers, organ dysfunction and mortality. Methods: This was a prospective cohort study including adult septic shock patients (n = 34). Clot–lysis was assessed using our plasma-based in-house assay. Platelet count, activated partial thromboplastin time (aPTT), international normalised ratio (INR), fibrinogen, fibrin D-dimer, antithrombin, thrombin generation, circulating fibrinolysis markers and organ dysfunction markers were analysed. Disseminated intravascular coagulation score, Sequential Organ Failure Assessment (SOFA) score and 30-day mortality were registered. Results: Three distinct clot–lysis profiles emerged in the patients: (1) severely decreased fibrin formation (flat clot–lysis curve), (2) normal fibrin formation and lysis and (3) pronounced lysis resistance. Patients with abnormal curves had lower platelet counts (p = 0.05), more prolonged aPTT (p = 0.04), higher lactate (p < 0.01) and a tendency towards higher SOFA scores (p = 0.09) than patients with normal clot–lysis curves. Fibrinogen and fibrin D-dimer were not associated with clot–lysis profile (p ≥ 0.37). Conclusion: Septic shock patients showed distinct and abnormal clot–lysis profiles that were associated with markers of coagulation and organ dysfunction. Our results provide important new insights into sepsis-related fibrinolysis disturbances and support the importance of assessing fibrinolytic capacity in septic shock. Full article
(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)
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15 pages, 1591 KiB  
Article
Embryonic-Derived Myb− Macrophages Enhance Bacterial Clearance and Improve Survival in Rat Sepsis
by Mirjana Jerkic, Michael L. Litvack, Stéphane Gagnon, Gail Otulakowski, Haibo Zhang, Ori Rotstein, Brian P. Kavanagh, Martin Post and John G. Laffey
Int. J. Mol. Sci. 2021, 22(6), 3190; https://doi.org/10.3390/ijms22063190 - 20 Mar 2021
Cited by 8 | Viewed by 2578
Abstract
Peritoneal resident macrophages play a key role in combating sepsis in the peritoneal cavity. We sought to determine if peritoneal transplantation of embryonic Myb− “peritoneal-like” macrophages attenuate abdominal fecal sepsis. Directed differentiation of rodent pluripotent stem cells (PSCs) was used in factor-defined [...] Read more.
Peritoneal resident macrophages play a key role in combating sepsis in the peritoneal cavity. We sought to determine if peritoneal transplantation of embryonic Myb− “peritoneal-like” macrophages attenuate abdominal fecal sepsis. Directed differentiation of rodent pluripotent stem cells (PSCs) was used in factor-defined media to produce embryonic-derived large “peritoneal-like” macrophages (Ed-LPM) that expressed peritoneal macrophage markers and demonstrated phagocytic capacity. Preclinical in vivo studies determined Ed-LPM efficacy in rodent abdominal fecal sepsis with or without Meropenem. Ex vivo studies explored the mechanism and effects of Ed-LPM on host immune cell number and function, including phagocytosis, reactive oxygen species (ROS) production, efferocytosis and apoptosis. Ed-LPM reduced sepsis severity by decreasing bacterial load in the liver, spleen and lungs. Ed-LPM therapy significantly improved animal survival by ~30% and reduced systemic bacterial burden to levels comparable to Meropenem therapy. Ed-LPM therapy decreased peritoneal TNFα while increasing IL-10 concentrations. Ed-LPMs enhanced peritoneal macrophage phagocytosis of bacteria, increased macrophage production of ROS and restored homeostasis via apoptosis and efferocytosis-induced clearance of neutrophils. In conclusion, Ed-LPM reduced systemic sepsis severity, improved survival and reduced bacterial load by enhancing peritoneal macrophage bacterial phagocytosis and killing and clearance of intra-peritoneal neutrophils. Macrophage therapy may be a potential strategy to address sepsis. Full article
(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)
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Review

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18 pages, 1126 KiB  
Review
Renal Replacement Techniques in Septic Shock
by Tapio Hellman, Panu Uusalo and Mikko J. Järvisalo
Int. J. Mol. Sci. 2021, 22(19), 10238; https://doi.org/10.3390/ijms221910238 - 23 Sep 2021
Cited by 24 | Viewed by 7384
Abstract
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection; it carries a risk for mortality, considerably exceeding that of a mere infection. Sepsis is the leading cause for acute kidney injury (AKI) and the requirement [...] Read more.
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection; it carries a risk for mortality, considerably exceeding that of a mere infection. Sepsis is the leading cause for acute kidney injury (AKI) and the requirement for renal replacement therapy (RRT) in intensive care unit (ICU) patients. Almost every second critically ill patient with sepsis will develop AKI. In septic shock, the dysregulated host response to infectious pathogens leads to a cytokine storm with uncontrolled production and release of humoral proinflammatory mediators that evoke cellular toxicity and promote the development of organ dysfunction and increased mortality. In addition to treating AKI, RRT techniques can be employed for extracorporeal adsorption of inflammatory mediators using specifically developed adsorption membranes, hemoperfusion sorbent cartridges or columns; these techniques are intended to decrease the level and early deleterious effects of circulating proinflammatory cytokines and endotoxins during the first hours and days of septic shock treatment, in order to improve patient outcomes. Several methods and devices, such as high cut-off membranes, the Oxiris®-AN69 membrane, CytoSorb® and HA380 cytokine hemoadsorption, polymyxin B endotoxin adsorption, and plasmapheresis have been examined in small study series or are under evaluation as ways of improving patient outcomes in septic shock. However, to date, the data on actual outcome benefits have remained controversial, as discussed in this review. Full article
(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)
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15 pages, 1191 KiB  
Review
Endothelial Dysfunction and Neutrophil Degranulation as Central Events in Sepsis Physiopathology
by Marta Martín-Fernández, Álvaro Tamayo-Velasco, Rocío Aller, Hugo Gonzalo-Benito, Pedro Martínez-Paz and Eduardo Tamayo
Int. J. Mol. Sci. 2021, 22(12), 6272; https://doi.org/10.3390/ijms22126272 - 10 Jun 2021
Cited by 21 | Viewed by 3716
Abstract
Sepsis is a major health problem worldwide. It is a time-dependent disease, with a high rate of morbidity and mortality. In this sense, an early diagnosis is essential to reduce these rates. The progressive increase of both the incidence and prevalence of sepsis [...] Read more.
Sepsis is a major health problem worldwide. It is a time-dependent disease, with a high rate of morbidity and mortality. In this sense, an early diagnosis is essential to reduce these rates. The progressive increase of both the incidence and prevalence of sepsis has translated into a significant socioeconomic burden for health systems. Currently, it is the leading cause of noncoronary mortality worldwide and represents one of the most prevalent pathologies both in hospital emergency services and in intensive care units. In this article, we review the role of both endothelial dysfunction and neutrophil dysregulation in the physiopathology of this disease. The lack of a key symptom in sepsis makes it difficult to obtain a quick and accurate diagnosis of this condition. Thus, it is essential to have fast and reliable diagnostic tools. In this sense, the use of biomarkers can be a very important alternative when it comes to achieving these goals. Both new biomarkers and treatments related to endothelial dysfunction and neutrophil dysregulation deserve to be further investigated in order to open new venues for the diagnosis, treatment and prognosis of sepsis. Full article
(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)
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17 pages, 607 KiB  
Review
Humanized Mice as a Tool to Study Sepsis—More Than Meets the Eye
by Krzysztof Laudanski
Int. J. Mol. Sci. 2021, 22(5), 2403; https://doi.org/10.3390/ijms22052403 - 27 Feb 2021
Cited by 8 | Viewed by 3204
Abstract
(1) Background. Repetitive animal studies that have disappointed upon translation into clinical therapies have led to an increased appreciation of humanized mice as a remedy to the shortcomings of rodent-based models. However, their limitations have to be understood in depth. (2) Methods. This [...] Read more.
(1) Background. Repetitive animal studies that have disappointed upon translation into clinical therapies have led to an increased appreciation of humanized mice as a remedy to the shortcomings of rodent-based models. However, their limitations have to be understood in depth. (2) Methods. This is a narrative, comprehensive review of humanized mice and sepsis literature to understand the model’s benefits and shortcomings. (3) Results: Studies involving humanized models of sepsis include bacterial, viral, and protozoan etiology. Humanized mice provided several unique insights into the etiology and natural history of sepsis and are particularly useful in studying Ebola, and certain viral and protozoan infections. However, studies are relatively sparse and based on several different models of sepsis and humanized animals. (4) Conclusions. The utilization of humanized mice as a model for sepsis presents complex limitations that, once surpassed, hold some potential for the advancement of sepsis etiology and treatment. Full article
(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)
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21 pages, 1279 KiB  
Review
Ion and Water Transport in Neutrophil Granulocytes and Its Impairment during Sepsis
by David Alexander Christian Messerer, Hanna Schmidt, Manfred Frick and Markus Huber-Lang
Int. J. Mol. Sci. 2021, 22(4), 1699; https://doi.org/10.3390/ijms22041699 - 8 Feb 2021
Cited by 9 | Viewed by 4497
Abstract
Neutrophil granulocytes are the vanguard of innate immunity in response to numerous pathogens. Their activity drives the clearance of microbe- and damage-associated molecular patterns, thereby contributing substantially to the resolution of inflammation. However, excessive stimulation during sepsis leads to cellular unresponsiveness, immunological dysfunction, [...] Read more.
Neutrophil granulocytes are the vanguard of innate immunity in response to numerous pathogens. Their activity drives the clearance of microbe- and damage-associated molecular patterns, thereby contributing substantially to the resolution of inflammation. However, excessive stimulation during sepsis leads to cellular unresponsiveness, immunological dysfunction, bacterial expansion, and subsequent multiple organ dysfunction. During the short lifespan of neutrophils, they can become significantly activated by complement factors, cytokines, and other inflammatory mediators. Following stimulation, the cells respond with a defined (electro-)physiological pattern, including depolarization, calcium influx, and alkalization as well as with increased metabolic activity and polarization of the actin cytoskeleton. Activity of ion transport proteins and aquaporins is critical for multiple cellular functions of innate immune cells, including chemotaxis, generation of reactive oxygen species, and phagocytosis of both pathogens and tissue debris. In this review, we first describe the ion transport proteins and aquaporins involved in the neutrophil ion–water fluxes in response to chemoattractants. We then relate ion and water flux to cellular functions with a focus on danger sensing, chemotaxis, phagocytosis, and oxidative burst and approach the role of altered ion transport protein expression and activity in impaired cellular functions and cell death during systemic inflammation as in sepsis. Full article
(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)
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Other

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9 pages, 1827 KiB  
Brief Report
Prolonged Transcriptional Consequences in Survivors of Sepsis
by Krzysztof Laudanski, James Soh, Matthew DiMeglio and Kathleen E. Sullivan
Int. J. Mol. Sci. 2021, 22(11), 5422; https://doi.org/10.3390/ijms22115422 - 21 May 2021
Cited by 3 | Viewed by 1985
Abstract
Survivors of sepsis often suffer from prolonged post-critical illness syndrome secondary to the immune system’s reprogramming. It is unclear if this process is static and pervasive due to methodological difficulties studying long-term outcomes of sepsis. The purpose of this study is to evaluate [...] Read more.
Survivors of sepsis often suffer from prolonged post-critical illness syndrome secondary to the immune system’s reprogramming. It is unclear if this process is static and pervasive due to methodological difficulties studying long-term outcomes of sepsis. The purpose of this study is to evaluate transcriptional profiles longitudinally in Drosophila melanogaster in the aftermath of sepsis to provide preliminary data for targets playing a role in post-sepsis immunostasis. Adult Drosophila melanogaster were infected with E. coli, and survivors were euthanized at 7, 14, and 21 days. Control flies were subjected to sham stress. Gene profiling was done with RNA-seq, and potential miRNA factors were computed. Profiling identified 55 unique genes at seven days, 61 unique genes at 14 days, and 78 genes at 21 days in sepsis survivors vs. sham control. Each post-sepsis timepoint had a distinctive transcriptional pattern with a signature related to oxidative stress at seven days, neuronal signal transduction at 14 days, and metabolism at 21 days. Several potential miRNA patterns were computed as potentially affecting several of the genes expressed in sepsis survivors. Our study demonstrated that post-sepsis changes in the transcriptome profile are dynamic and extend well into the Drosophila melanogaster natural life span. Full article
(This article belongs to the Special Issue Sepsis: From Molecular Mechanisms, Pathophysiology to Novel Therapeutic Approaches)
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