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Biomedicines
Special Issues
Mechanism and Modulation in Sepsis
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Mechanism and Modulation in Sepsis

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 20257

Special Issue Editors

Dr. Waldemar Kanczkowski

E-Mail Website1 Website2
Guest Editor
Department of Medicine III, Faculty of Medicine of the Technische Universität Dresden, Dresden, Germany
Interests: hypothalamus-pituitary-adrenal gland function and dysfunction during sepsis; sepsis and septic shock; tissue-specific vascular biology; pattern recognition receptors; new forms of regulated cell death
Special Issues, Collections and Topics in MDPI journals
Dr. Koichi Yuki

E-Mail Website
Guest Editor
Department Anesthesiology Perioperative and Pain Medicine, Boston Children’s Hospital, Boston, MA, USA
Interests: sepsis; surgical site infection; perioperative complication; Integrin; neutrophil driven tissue injury; anesthetic driven immunomodulation

Special Issue Information

Dear Colleagues,

Sepsis remains to be associated with significant morbidity and mortality. The importance of organ injury was recognized in this process and is now included in the diagnostic criteria for sepsis in the most recent sepsis conference (Sepsis-3 conference), replacing the concept of sepsis as mere “systemic inflammatory diseases”. Thus, it is critical to understand the mechanism of organ injury in sepsis, thereby developing an approach to attenuate it. This Special Issue focuses on studies deciphering the mechanism and modulation of organ injury in sepsis, hoping to improve outcomes of sepsis.

Dr. Koichi Yuki
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). 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
  • organ injury
  • pathophysiology
  • sepsis modulation
  • outcome

Published Papers (7 papers)

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Research

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20 pages, 10853 KiB  
Article
The Actin-Binding Protein Cortactin Promotes Sepsis Severity by Supporting Excessive Neutrophil Infiltration into the Lung
by Nathaniel L. Lartey, Hilda Vargas-Robles, Idaira M. Guerrero-Fonseca, Alexander García-Ponce, Citlaltepetl Salinas-Lara, Klemens Rottner and Michael Schnoor
Biomedicines 2022, 10(5), 1019; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051019 - 28 Apr 2022
Cited by 4 | Viewed by 2082
Abstract
Sepsis is a systemic infection that can lead to multi-organ failure. It is characterised by an uncontrolled immune response with massive neutrophil influx into peripheral organs. Neutrophil extravasation into tissues depends on actin remodeling and actin-binding proteins such as cortactin, which is expressed [...] Read more.
Sepsis is a systemic infection that can lead to multi-organ failure. It is characterised by an uncontrolled immune response with massive neutrophil influx into peripheral organs. Neutrophil extravasation into tissues depends on actin remodeling and actin-binding proteins such as cortactin, which is expressed ubiquitously, except for neutrophils. Endothelial cortactin is necessary for proper regulation of neutrophil transendothelial migration and recruitment to sites of infection. We therefore hypothesised that cortactin plays a crucial role in sepsis development by regulating neutrophil trafficking. Using a murine model of sepsis induced by cecal ligation and puncture (CLP), we showed that cortactin-deficient (KO) mice survive better due to reduced lung injury. Histopathological analysis of lungs from septic KO mice revealed absence of oedema, reduced vascular congestion and mucus deposition, and better-preserved alveoli compared to septic wild-type (WT) mice. Additionally, sepsis-induced cytokine storm, excessive neutrophil infiltration into the lung and oxidative stress were significantly reduced in KO mice. Neutrophil depletion 12 h after sepsis improved survival in WT mice by averting lung injury, similar to both neutrophil-depleted and non-depleted KO mice. Our findings highlight a critical role of cortactin for lung neutrophil infiltration and sepsis severity. Full article
(This article belongs to the Special Issue Mechanism and Modulation in Sepsis)
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19 pages, 19427 KiB  
Article
Characterization of Early Peripheral Immune Responses in Patients with Sepsis and Septic Shock
by Jesús Beltrán-García, Rebeca Osca-Verdegal, Beatriz Jávega, Guadalupe Herrera, José-Enrique O’Connor, Eva García-López, Germán Casabó-Vallés, María Rodriguez-Gimillo, José Ferreres, Nieves Carbonell, Federico V. Pallardó and José Luis García-Giménez
Biomedicines 2022, 10(3), 525; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10030525 - 23 Feb 2022
Cited by 8 | Viewed by 2211
Abstract
(1) Background: Sepsis is a life-threatening condition caused by an abnormal host response to infection that produces altered physiological responses causing tissue damage and can result in organ dysfunction and, in some cases, death. Although sepsis is characterized by a malfunction of the [...] Read more.
(1) Background: Sepsis is a life-threatening condition caused by an abnormal host response to infection that produces altered physiological responses causing tissue damage and can result in organ dysfunction and, in some cases, death. Although sepsis is characterized by a malfunction of the immune system leading to an altered immune response and immunosuppression, the high complexity of the pathophysiology of sepsis requires further investigation to characterize the immune response in sepsis and septic shock. (2) Methods: This study analyzes the immune-related responses occurring during the early stages of sepsis by comparing the amounts of cytokines, immune modulators and other endothelial mediators of a control group and three types of severe patients: critically ill non-septic patients, septic and septic shock patients. (3) Results: We showed that in the early stages of sepsis the innate immune system attempts to counteract infection, probably via neutrophils. Conversely, the adaptive immune system is not yet fully activated, either in septic or in septic shock patients. In addition, immunosuppressive responses and pro-coagulation signals are active in patients with septic shock. (4) Conclusions: The highest levels of IL-6 and pyroptosis-related cytokines (IL-18 and IL-1α) were found in septic shock patients, which correlated with D-dimer. Moreover, endothelial function may be affected as shown by the overexpression of adhesion molecules such as s-ICAM1 and E-Selectin during septic shock. Full article
(This article belongs to the Special Issue Mechanism and Modulation in Sepsis)
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9 pages, 1306 KiB  
Article
Neutrophil to Lymphocyte Ratio (NLR)—A Useful Tool for the Prognosis of Sepsis in the ICU
by Alice Nicoleta Drăgoescu, Vlad Pădureanu, Andreea Doriana Stănculescu, Luminița Cristina Chiuțu, Paul Tomescu, Cristiana Geormăneanu, Rodica Pădureanu, Vlad Florin Iovănescu, Bogdan Silviu Ungureanu, Andrei Pănuș and Octavian Petru Drăgoescu
Biomedicines 2022, 10(1), 75; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10010075 - 30 Dec 2021
Cited by 35 | Viewed by 2834
Abstract
Sepsis is a life-threatening medical emergency induced by the body′s extreme response to an infection. Despite well-defined and constantly updated criteria for diagnosing sepsis, it is still underdiagnosed worldwide. Among various markers studied over time, the neutrophil to lymphocyte ratio (NLR) recently emerged [...] Read more.
Sepsis is a life-threatening medical emergency induced by the body′s extreme response to an infection. Despite well-defined and constantly updated criteria for diagnosing sepsis, it is still underdiagnosed worldwide. Among various markers studied over time, the neutrophil to lymphocyte ratio (NLR) recently emerged as a good marker to predict sepsis severity. Our study was a single-center prospective observational study performed in our ICU and included 114 patients admitted for sepsis or septic shock. Neutrophil to lymphocyte ratio (NLR) is easy to perform, CBC being one of the standard blood tests routinely performed upon admission for all ICU patients. We found that NLR was increased in all patients with sepsis and significantly raised in those with septic shock. NLR correlates significantly with sepsis severity evaluated by the SOFA score (R = 0.65) and also with extensively studied sepsis prognosis marker presepsin (R = 0.56). Additionally, NLR showed good sensitivity (47%) and specificity (78%) with AUC = 0.631 (p < 0.05). NLR is less expensive and easier to perform compared with other specific markers and may potentially become a good alternate option for evaluation of sepsis severity. Larger studies are needed in the future to demonstrate the prognosis value of NLR. Full article
(This article belongs to the Special Issue Mechanism and Modulation in Sepsis)
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9 pages, 1070 KiB  
Article
A Comparison between Endostatin and Conventional Biomarkers on 30-Day Mortality and Renal Replacement Therapy in Unselected Intensive Care Patients
by Toralph Ruge, Anders Larsson, Miklós Lipcsey, Jonas Tydén, Joakim Johansson and Mats Eriksson
Biomedicines 2021, 9(11), 1603; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9111603 - 03 Nov 2021
Cited by 1 | Viewed by 1460
Abstract
Endostatin may predict mortality and kidney impairment in general populations as well as in critically ill patients. We decided to explore the possible role of endostatin as a predictor of 30-day mortality, acute kidney injury (AKI), and renal replacement therapy (RRT) in a [...] Read more.
Endostatin may predict mortality and kidney impairment in general populations as well as in critically ill patients. We decided to explore the possible role of endostatin as a predictor of 30-day mortality, acute kidney injury (AKI), and renal replacement therapy (RRT) in a cohort of unselected intensive care unit (ICU) patients. Endostatin and creatinine in plasma were analyzed and SAPS3 was determined in 278 patients on ICU arrival at admission to a Swedish medium-sized hospital. SAPS3 had the highest predictive value, 0.85 (95% C.I.: 0.8–0.90), for 30-day mortality. Endostatin, in combination with age, predicted 30-day mortality by 0.76 (95% C.I.: 0.70–0.82). Endostatin, together with age and creatinine, predicted AKI with 0.87 (95% C.I.: 0.83–0.91). Endostatin predicted AKI with [0.68 (0.62–0.74)]. Endostatin predicted RRT, either alone [0.82 (95% C.I.: 0.72–0.91)] or together with age [0.81 (95% C.I.: 0.71–0.91)]. The predicted risk for 30-day mortality, AKI, or RRT during the ICU stay, predicted by plasma endostatin, was not influenced by age. Compared to the complex severity score SAPS3, circulating endostatin, combined with age, offers an easily managed option to predict 30-day mortality. Additionally, circulating endostatin combined with creatinine was closely associated with AKI development. Full article
(This article belongs to the Special Issue Mechanism and Modulation in Sepsis)
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16 pages, 2690 KiB  
Article
Reverse Engineering of the Pediatric Sepsis Regulatory Network and Identification of Master Regulators
by Raffael Azevedo de Carvalho Oliveira, Danilo Oliveira Imparato, Vítor Gabriel Saldanha Fernandes, João Vitor Ferreira Cavalcante, Ricardo D’Oliveira Albanus and Rodrigo Juliani Siqueira Dalmolin
Biomedicines 2021, 9(10), 1297; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101297 - 23 Sep 2021
Cited by 2 | Viewed by 2920
Abstract
Sepsis remains a leading cause of death in ICUs all over the world, with pediatric sepsis accounting for a high percentage of mortality in pediatric ICUs. Its complexity makes it difficult to establish a consensus on genetic biomarkers and therapeutic targets. A promising [...] Read more.
Sepsis remains a leading cause of death in ICUs all over the world, with pediatric sepsis accounting for a high percentage of mortality in pediatric ICUs. Its complexity makes it difficult to establish a consensus on genetic biomarkers and therapeutic targets. A promising strategy is to investigate the regulatory mechanisms involved in sepsis progression, but there are few studies regarding gene regulation in sepsis. This work aimed to reconstruct the sepsis regulatory network and identify transcription factors (TFs) driving transcriptional states, which we refer to here as master regulators. We used public gene expression datasets to infer the co-expression network associated with sepsis in a retrospective study. We identified a set of 15 TFs as potential master regulators of pediatric sepsis, which were divided into two main clusters. The first cluster corresponded to TFs with decreased activity in pediatric sepsis, and GATA3 and RORA, as well as other TFs previously implicated in the context of inflammatory response. The second cluster corresponded to TFs with increased activity in pediatric sepsis and was composed of TRIM25, RFX2, and MEF2A, genes not previously described as acting in a coordinated way in pediatric sepsis. Altogether, these results show how a subset of master regulators TF can drive pathological transcriptional states, with implications for sepsis biology and treatment. Full article
(This article belongs to the Special Issue Mechanism and Modulation in Sepsis)
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21 pages, 6299 KiB  
Article
Serum Perilipin 2 (PLIN2) Predicts Multiple Organ Dysfunction in Critically Ill Patients
by Berkan Kurt, Lukas Buendgens, Theresa H. Wirtz, Sven H. Loosen, Maximilian Schulze-Hagen, Daniel Truhn, Jonathan F. Brozat, Samira Abu Jhaisha, Philipp Hohlstein, Ger Koek, Ralf Weiskirchen, Christian Trautwein, Frank Tacke, Karim Hamesch and Alexander Koch
Biomedicines 2021, 9(9), 1210; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9091210 - 13 Sep 2021
Cited by 4 | Viewed by 2461
Abstract
Perilipin 2 (PLIN2) is a lipid droplet protein with various metabolic functions. However, studies investigating PLIN2 in the context of inflammation, especially in systemic and acute inflammation, are lacking. Hence, we assessed the relevance of serum PLIN2 in critically ill patients. We measured [...] Read more.
Perilipin 2 (PLIN2) is a lipid droplet protein with various metabolic functions. However, studies investigating PLIN2 in the context of inflammation, especially in systemic and acute inflammation, are lacking. Hence, we assessed the relevance of serum PLIN2 in critically ill patients. We measured serum PLIN2 serum in 259 critically ill patients (166 with sepsis) upon admission to a medical intensive care unit (ICU) compared to 12 healthy controls. A subset of 36 patients underwent computed tomography to quantify body composition. Compared to controls, serum PLIN2 concentrations were elevated in critically ill patients at ICU admission. Interestingly, PLIN2 independently indicated multiple organ dysfunction (MOD), defined as a SOFA score > 9 points, at ICU admission, and was also able to independently predict MOD after 48 h. Moreover, serum PLIN2 levels were associated with severe respiratory failure potentially reflecting a moribund state. However, PLIN2 was neither a predictor of ICU mortality nor did it reflect metabolic dysregulation. Conclusively, the first study assessing serum PLIN2 in critical illness proved that it may assist in risk stratification because it is capable of independently indicating MOD at admission and predicting MOD 48 h after PLIN2 measurement. Further evaluation regarding the underlying mechanisms is warranted. Full article
(This article belongs to the Special Issue Mechanism and Modulation in Sepsis)
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Review

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17 pages, 1327 KiB  
Review
The Potential Role of Extracorporeal Cytokine Removal in Hemodynamic Stabilization in Hyperinflammatory Shock
by Fatime Hawchar, Cristina Rao, Ali Akil, Yatin Mehta, Christopher Rugg, Joerg Scheier, Harriet Adamson, Efthymios Deliargyris and Zsolt Molnar
Biomedicines 2021, 9(7), 768; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9070768 - 01 Jul 2021
Cited by 20 | Viewed by 4844
Abstract
Hemodynamic instability due to dysregulated host response is a life-threatening condition requiring vasopressors and vital organ support. Hemoadsorption with Cytosorb has proven to be effective in reducing cytokines and possibly in attenuating the devastating effects of the cytokine storm originating from the immune [...] Read more.
Hemodynamic instability due to dysregulated host response is a life-threatening condition requiring vasopressors and vital organ support. Hemoadsorption with Cytosorb has proven to be effective in reducing cytokines and possibly in attenuating the devastating effects of the cytokine storm originating from the immune over-response to the initial insult. We reviewed the PubMed database to assess evidence of the impact of Cytosorb on norepinephrine needs in the critically ill. We further analyzed those studies including data on control cohorts in a comparative pooled analysis, defining a treatment effect as the standardized mean differences in relative reductions in vasopressor dosage at 24 h. The literature search returned 33 eligible studies. We found evidence of a significant reduction in norepinephrine requirement after treatment: median before, 0.55 (IQR: 0.39–0.90); after, 0.09 (0.00–0.25) μg/kg/min, p < 0.001. The pooled effect size at 24 h was large, though characterized by high heterogeneity. In light of the importance of a quick resolution of hemodynamic instability in the critically ill, further research is encouraged to enrich knowledge on the potentials of the therapy. Full article
(This article belongs to the Special Issue Mechanism and Modulation in Sepsis)
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