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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: closed (15 July 2017) | Viewed by 77927

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Dr. Tsukasa Nakamura

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Guest Editor

Division of Nephrology, Department of Internal Medicine, Kashiwa Forest Clinic, Kashiwa, Chiba, Japan
Interests: sepsis; critical care medicine; renal replacement therapy; LDL-apheresis; diabetic nephropathy
Special Issues, Collections and Topics in MDPI journals

Dr. Eiichi Sato

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Guest Editor

Division of Nephrology, Department of Internal Medicine, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
Interests: sepsis; acute kidney injury; chronic kidney disease; hemodialysis therapy; diabetic nephropathy; aquaporin 2
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The recently modified Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) defines sepsis as “life-threatening organ dysfunction caused by a dysregulated host response to infection” and septic shock as “a subset of sepsis in which particularly profound circulatory, cellular, and metabolic abnormalities are associated with a greater risk of mortality than with sepsis alone”. Sepsis-3 guidelines still prompt debate and discussion, such as the requirement for a serum lactate level to diagnose septic shock, or use of the quick sepsis-related organ failure assessment (SOFA) score in the diagnosis of sepsis. Further detailed verification is required for reevaluation and future revision of Sepsis-3.

This Special Issue of the International Journal of Molecular Sciences will focus on sepsis, and report new insights into epidemiology, pathophysiology, diagnosis, biomarkers, and treatment. In addition, other morbidities and renal replacement therapy, including acute kidney injury and hemodiafiltration, are associated with sepsis, and submissions dealing with these conditions are welcome.

Prof. Tsukasa Nakamura
Dr. Eiichi Sato
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-3
infection
septic shock
SOFA
organ dysfunction
acute kidney injury
renal replacement therapy
hemodiafiltration
biomarkers
therapeutics

Related Special Issue

Sepsis 2019 in International Journal of Molecular Sciences (2 articles)

Published Papers (10 papers)

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Research

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The Lactate/Albumin Ratio: A Valuable Tool for Risk Stratification in Septic Patients Admitted to ICU

by Michael Lichtenauer, Bernhard Wernly, Bernhard Ohnewein, Marcus Franz, Bjoern Kabisch, Johanna Muessig, Maryna Masyuk, Alexander Lauten, Paul Christian Schulze, Uta C. Hoppe, Malte Kelm and Christian Jung

Int. J. Mol. Sci. 2017, 18(9), 1893; https://doi.org/10.3390/ijms18091893 - 02 Sep 2017

Cited by 48 | Viewed by 5882

Abstract

The lactate/albumin ratio has been reported to be associated with mortality in pediatric patients with sepsis. We aimed to evaluate the lactate/albumin ratio for its prognostic relevance in a larger collective of critically ill (adult) patients admitted to an intensive care unit (ICU). A total of 348 medical patients admitted to a German ICU for sepsis between 2004 and 2009 were included. Follow-up of patients was performed retrospectively between May 2013 and November 2013. The association of the lactate/albumin ratio (cut-off 0.15) and both in-hospital and post-discharge mortality was investigated. An optimal cut-off was calculated by means of Youden’s index. The lactate/albumin ratio was elevated in non-survivors (p < 0.001). Patients with an increased lactate/albumin ratio were of similar age, but clinically in a poorer condition and had more pronounced laboratory signs of multi-organ failure. An increased lactate/albumin ratio was associated with adverse in-hospital mortality. An optimal cut-off of 0.15 was calculated and was associated with adverse long-term outcome even after correction for APACHE2 and SAPS2. We matched 99 patients with a lactate/albumin ratio >0.15 to case-controls with a lactate/albumin ratio <0.15 corrected for APACHE2 scores: The group with a lactate/albumin ratio >0.15 evidenced adverse in-hospital outcome in a paired analysis with a difference of 27% (95%CI 10–43%; p < 0.01). Regarding long-term mortality, again, patients in the group with a lactate/albumin ratio >0.15 showed adverse outcomes (p < 0.001). An increased lactate/albumin ratio was significantly associated with an adverse outcome in critically ill patients admitted to an ICU, even after correction for confounders. The lactate/albumin ratio might constitute an independent, readily available, and important parameter for risk stratification in the critically ill. Full article

(This article belongs to the Special Issue Sepsis)

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Immune-Response Patterns and Next Generation Sequencing Diagnostics for the Detection of Mycoses in Patients with Septic Shock—Results of a Combined Clinical and Experimental Investigation

by Sebastian O. Decker, Annette Sigl, Christian Grumaz, Philip Stevens, Yevhen Vainshtein, Stefan Zimmermann, Markus A. Weigand, Stefan Hofer, Kai Sohn and Thorsten Brenner

Int. J. Mol. Sci. 2017, 18(8), 1796; https://doi.org/10.3390/ijms18081796 - 18 Aug 2017

Cited by 45 | Viewed by 9748

Abstract

Fungi are of increasing importance in sepsis. However, culture-based diagnostic procedures are associated with relevant weaknesses. Therefore, culture- and next-generation sequencing (NGS)-based fungal findings as well as corresponding plasma levels of β-d-glucan, interferon gamma (INF-γ), tumor necrosis factor alpha (TNF-α), interleukin (IL)-2, -4, -6, -10, -17A, and mid-regional proadrenomedullin (MR-proADM) were evaluated in 50 septic patients at six consecutive time points within 28 days after sepsis onset. Furthermore, immune-response patterns during infections with Candida spp. were studied in a reconstituted human epithelium model. In total, 22% (n = 11) of patients suffered from a fungal infection. An NGS-based diagnostic approach appeared to be suitable for the identification of fungal pathogens in patients suffering from fungemia as well as in patients with negative blood cultures. Moreover, MR-proADM and IL-17A in plasma proved suitable for the identification of patients with a fungal infection. Using RNA-seq., adrenomedullin (ADM) was shown to be a target gene which is upregulated early after an epithelial infection with Candida spp. In summary, an NGS-based diagnostic approach was able to close the diagnostic gap of routinely used culture-based diagnostic procedures, which can be further facilitated by plasmatic measurements of MR-proADM and IL-17A. In addition, ADM was identified as an early target gene in response to epithelial infections with Candida spp. Full article

(This article belongs to the Special Issue Sepsis)

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A Murine Model of Persistent Inflammation, Immune Suppression, and Catabolism Syndrome

by Amanda M. Pugh, Nicholas J. Auteri, Holly S. Goetzman, Charles C. Caldwell and Vanessa Nomellini

Int. J. Mol. Sci. 2017, 18(8), 1741; https://doi.org/10.3390/ijms18081741 - 10 Aug 2017

Cited by 22 | Viewed by 4193

Abstract

Critically ill patients that survive sepsis can develop a Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS), which often leads to extended recovery periods and multiple complications. Here, we utilized a cecal ligation and puncture (CLP) method in mice with the goal of creating a model that concurrently displays all the characteristics of PICS. We observed that, after eight days, mice that survive the CLP develop persistent inflammation with significant myelopoiesis in the bone marrow and spleen. These mice also demonstrate ongoing immune suppression, as evidenced by the decreased total and naïve splenic CD4 and CD8 T cells with a concomitant increase in immature myeloid cells. The mice further display significant weight loss and decreased muscle mass, indicating a state of ongoing catabolism. When PICS mice are challenged with intranasal Pseudomonas aeruginosa, mortality is significantly elevated compared to sham mice. This mortality difference is associated with increased bacterial loads in the lung, as well as impaired neutrophil migration and neutrophil dysfunction in the PICS mice. Altogether, we have created a sepsis model that concurrently exhibits PICS characteristics. We postulate that this will help determine the mechanisms underlying PICS and identify potential therapeutic targets to improve outcomes for this patient population. Full article

(This article belongs to the Special Issue Sepsis)

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The Novel HDAC8 Inhibitor WK2-16 Attenuates Lipopolysaccharide-Activated Matrix Metalloproteinase-9 Expression in Human Monocytic Cells and Improves Hypercytokinemia In Vivo

by Jing-Shiun Jan, Yung-Chen Chou, Yu-Wen Cheng, Chih-Kuang Chen, Wei-Jan Huang and George Hsiao

Int. J. Mol. Sci. 2017, 18(7), 1394; https://doi.org/10.3390/ijms18071394 - 29 Jun 2017

Cited by 16 | Viewed by 5215

Abstract

Dysregulated human monocytes/macrophages can synthesize and secrete matrix metalloproteinases (MMPs), which play important roles in the progression of sepsis. In this study, we investigated the effects and mechanism of a novel histone deacetylase (HDAC8) inhibitor, (E)-N-hydroxy-4-methoxy-2-(biphenyl-4-yl)cinnamide (WK2-16), on MMP-9 production and activation in stimulated human monocytic THP-1 cells. Our results demonstrated that the acetylation level of structural maintenance of chromosomes 3 (SMC3) was up-regulated by WK2-16 in THP-1 cells. Consistently, an in vitro enzyme study demonstrated that WK2-16 selectively inhibited HDAC8 activity. Moreover, the WK2-16 concentration dependently suppressed MMP-9-mediated gelatinolysis induced by tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS). Additionally, WK2-16 significantly inhibited both MMP-9 protein and mRNA expression without cellular toxicity. Nevertheless, WK2-16 suppressed the extracellular levels of interleukin (IL)-6 from LPS-stimulated THP-1 cells. For the signaling studies, WK2-16 had no effect on LPS/TLR4 downstream signaling pathways, such as the NF-κB and ERK/JNK/P38 MAPK pathways. On the other hand, WK2-16 enhanced the recruitment of acetylated Yin Yang 1 (YY1) with HDAC1. Finally, in vivo studies indicated that WK2-16 could reduce the serum levels of TNF-α and IL-6 in endotoxemic mice. These results suggested that HDAC8 inhibition might provide a novel therapeutic strategy of hypercytokinemia in sepsis. Full article

(This article belongs to the Special Issue Sepsis)

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Hypoxia Inducible Factor-2 Alpha and Prolinhydroxylase 2 Polymorphisms in Patients with Acute Respiratory Distress Syndrome (ARDS)

by Annika Dötsch, Lewin Eisele, Miriam Rabeling, Katharina Rump, Kai Walstein, Alexandra Bick, Linda Cox, Andrea Engler, Hagen S. Bachmann, Karl-Heinz Jöckel, Michael Adamzik, Jürgen Peters and Simon T. Schäfer

Int. J. Mol. Sci. 2017, 18(6), 1266; https://doi.org/10.3390/ijms18061266 - 14 Jun 2017

Cited by 11 | Viewed by 4719

Abstract

Hypoxia-inducible-factor-2α (HIF-2α) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902) are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs’ prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2α or PHD2 genes are (1) common, and (2) independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay) and HIF-2α-polymorphism (restriction digest + agarose-gel visualization), and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2α CC-carriers (CG: 0.38%; GG: 0%), 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%; CC: 78.8%), and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%; CC: 52.4%). PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09–10.22; p = 0.034) within 30-days, whereas the other SNPs had no significant impact (p = ns). The homozygous HIF-2α GG-genotype was not present in our Caucasian ARDS cohort; however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS. Full article

(This article belongs to the Special Issue Sepsis)

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Adjustment of Dysregulated Ceramide Metabolism in a Murine Model of Sepsis-Induced Cardiac Dysfunction

by Ha-Yeun Chung, Anna S. Kollmey, Andrea Schrepper, Matthias Kohl, Markus F. Bläss, Sebastian N. Stehr, Amelie Lupp, Markus H. Gräler and Ralf A. Claus

Int. J. Mol. Sci. 2017, 18(4), 839; https://doi.org/10.3390/ijms18040839 - 15 Apr 2017

Cited by 22 | Viewed by 5253

Abstract

Cardiac dysfunction, in particular of the left ventricle, is a common and early event in sepsis, and is strongly associated with an increase in patients’ mortality. Acid sphingomyelinase (SMPD1)—the principal regulator for rapid and transient generation of the lipid mediator ceramide—is involved in both the regulation of host response in sepsis as well as in the pathogenesis of chronic heart failure. This study determined the degree and the potential role to which SMPD1 and its modulation affect sepsis-induced cardiomyopathy using both genetically deficient and pharmacologically-treated animals in a polymicrobial sepsis model. As surrogate parameters of sepsis-induced cardiomyopathy, cardiac function, markers of oxidative stress as well as troponin I levels were found to be improved in desipramine-treated animals, desipramine being an inhibitor of ceramide formation. Additionally, ceramide formation in cardiac tissue was dysregulated in SMPD1^+/+ as well as SMPD1^−/− animals, whereas desipramine pretreatment resulted in stable, but increased ceramide content during host response. This was a result of elevated de novo synthesis. Strikingly, desipramine treatment led to significantly improved levels of surrogate markers. Furthermore, similar results in desipramine-pretreated SMPD1^−/− littermates suggest an SMPD1-independent pathway. Finally, a pattern of differentially expressed transcripts important for regulation of apoptosis as well as antioxidative and cytokine response supports the concept that desipramine modulates ceramide formation, resulting in beneficial myocardial effects. We describe a novel, protective role of desipramine during sepsis-induced cardiac dysfunction that controls ceramide content. In addition, it may be possible to modulate cardiac function during host response by pre-conditioning with the Food and Drug Administration (FDA)-approved drug desipramine. Full article

(This article belongs to the Special Issue Sepsis)

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Review

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Platelets and Multi-Organ Failure in Sepsis

by Elisabetta Greco, Enrico Lupia, Ornella Bosco, Barbara Vizio and Giuseppe Montrucchio

Int. J. Mol. Sci. 2017, 18(10), 2200; https://doi.org/10.3390/ijms18102200 - 20 Oct 2017

Cited by 118 | Viewed by 9971

Abstract

Platelets have received increasing attention for their role in the pathophysiology of infectious disease, inflammation, and immunity. In sepsis, a low platelet count is a well-known biomarker for disease severity and more recently authors have focused their attention on the active role of platelets in the pathogenesis of multi-organ failure. Septic shock is characterised by a dysregulated inflammatory response, which can impair the microcirculation and lead to organ injury. Being at the crossroads between the immune system, clotting cascade, and endothelial cells, platelets seem to be an appealing central mediator and possible therapeutic target in sepsis. This review focuses on the pathogenic role of platelets in septic organ dysfunction in humans and animal models. Full article

(This article belongs to the Special Issue Sepsis)

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Transfusion of Red Blood Cells to Patients with Sepsis

by Yi-Ling Chan, Shih-Tsung Han, Chih-Huang Li, Chin-Chieh Wu and Kuan-Fu Chen

Int. J. Mol. Sci. 2017, 18(9), 1946; https://doi.org/10.3390/ijms18091946 - 11 Sep 2017

Cited by 14 | Viewed by 6415

Abstract

Sepsis is one of the major causes of death worldwide, and is the host response to infection which renders our organs malfunctioning. Insufficient tissue perfusion and oxygen delivery have been implicated in the pathogenesis of sepsis-related organ dysfunction, making transfusion of packed red blood cells (pRBCs) a reasonable treatment modality. However, clinical trials have generated controversial results. Even the notion that transfused pRBCs increase the oxygen-carrying capacity of blood has been challenged. Meanwhile, during sepsis, the ability of our tissues to utilize oxygen may also be reduced, and the increased blood concentrations of lactate may be the results of strong inflammation and excessive catecholamine release, rather than impaired cell respiration. Leukodepleted pRBCs more consistently demonstrated improvement in microcirculation, and the increase in blood viscosity brought about by pRBC transfusion helps maintain functional capillary density. A restrictive strategy of pRBC transfusion is recommended in treating septic patients. Full article

(This article belongs to the Special Issue Sepsis)

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The Effect of Sepsis on the Erythrocyte

by Ryon M. Bateman, Michael D. Sharpe, Mervyn Singer and Christopher G. Ellis

Int. J. Mol. Sci. 2017, 18(9), 1932; https://doi.org/10.3390/ijms18091932 - 08 Sep 2017

Cited by 102 | Viewed by 10520

Abstract

Sepsis induces a wide range of effects on the red blood cell (RBC). Some of the effects including altered metabolism and decreased 2,3-bisphosphoglycerate are preventable with appropriate treatment, whereas others, including decreased erythrocyte deformability and redistribution of membrane phospholipids, appear to be permanent, and factors in RBC clearance. Here, we review the effects of sepsis on the erythrocyte, including changes in RBC volume, metabolism and hemoglobin’s affinity for oxygen, morphology, RBC deformability (an early indicator of sepsis), antioxidant status, intracellular Ca²⁺ homeostasis, membrane proteins, membrane phospholipid redistribution, clearance and RBC O₂-dependent adenosine triphosphate efflux (an RBC hypoxia signaling mechanism involved in microvascular autoregulation). We also consider the causes of these effects by host mediated oxidant stress and bacterial virulence factors. Additionally, we consider the altered erythrocyte microenvironment due to sepsis induced microvascular dysregulation and speculate on the possible effects of RBC autoxidation. In future, a better understanding of the mechanisms involved in sepsis induced erythrocyte pathophysiology and clearance may guide improved sepsis treatments. Evidence that small molecule antioxidants protect the erythrocyte from loss of deformability, and more importantly improve septic patient outcome suggest further research in this area is warranted. While not generally considered a critical factor in sepsis, erythrocytes (and especially a smaller subpopulation) appear to be highly susceptible to sepsis induced injury, provide an early warning signal of sepsis and are a factor in the microvascular dysfunction that has been associated with organ dysfunction. Full article

(This article belongs to the Special Issue Sepsis)

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Issues of Acute Kidney Injury Staging and Management in Sepsis and Critical Illness: A Narrative Review

by Christian Nusshag, Markus A. Weigand, Martin Zeier, Christian Morath and Thorsten Brenner

Int. J. Mol. Sci. 2017, 18(7), 1387; https://doi.org/10.3390/ijms18071387 - 28 Jun 2017

Cited by 26 | Viewed by 14814

Abstract

Acute kidney injury (AKI) has a high incidence on intensive care units around the world and is a major complication in critically ill patients suffering from sepsis or septic shock. The short- and long-term complications are thereby devastating and impair the quality of life. Especially in terms of AKI staging, the determination of kidney function and the timing of dialytic AKI management outside of life-threatening indications are ongoing matters of debate. Despite several studies, a major problem remains in distinguishing between beneficial and unnecessary “early” or even harmful renal replacement therapy (RRT). The latter might prolong disease course and renal recovery. AKI scores, however, provide an insufficient outcome-predicting ability and the related estimation of kidney function via serum creatinine or blood urea nitrogen (BUN)/urea is not reliable in AKI and critical illness. Kidney independent alterations of creatinine- and BUN/urea-levels further complicate the situation. This review critically assesses the current AKI staging, issues and pitfalls of the determination of kidney function and RRT timing, as well as the potential harm reflected by unnecessary RRT. A better understanding is mandatory to improve future study designs and avoid unnecessary RRT for higher patient safety and lower health care costs. Full article

(This article belongs to the Special Issue Sepsis)

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