International Journal of Molecular Sciences

Research

12 pages, 2079 KiB

Open AccessArticle

The Cytotoxic Effect of Septic Plasma on Healthy RBCs: Is Eryptosis a New Mechanism for Sepsis?

by Matteo Marcello, Grazia Maria Virzì, Davide Marturano, Massimo de Cal, Nicola Marchionna, Luca Sgarabotto, Silvia De Rosa, Claudio Ronco and Monica Zanella

Int. J. Mol. Sci. 2023, 24(18), 14176; https://doi.org/10.3390/ijms241814176 - 16 Sep 2023

Cited by 2 | Viewed by 964

Abstract

Sepsis is a life-threatening multiple-organ dysfunction induced by infection and is one of the leading causes of mortality and critical illness worldwide. The pathogenesis of sepsis involves the alteration of several biochemical pathways such as immune response, coagulation, dysfunction of endothelium and tissue [...] Read more.

Sepsis is a life-threatening multiple-organ dysfunction induced by infection and is one of the leading causes of mortality and critical illness worldwide. The pathogenesis of sepsis involves the alteration of several biochemical pathways such as immune response, coagulation, dysfunction of endothelium and tissue damage through cellular death and/or apoptosis. Recently, in vitro and in vivo studies reported changes in the morphology and in the shape of human red blood cells (RBCs) causing erythrocyte death (eryptosis) during sepsis. Characteristics of eryptosis include cell shrinkage, membrane blebbing, and surface exposure to phosphatidylserine (PS), which attract macrophages. The aim of this study was to evaluate the in vitro induction of eryptosis on healthy RBCs exposed to septic plasma at different time points. Furthermore, we preliminary investigated the in vivo levels of eryptosis in septic patients and its relationship with Endotoxin Activity Assay (EAA), mortality and other biological markers of inflammation and oxidative stress. We enrolled 16 septic patients and 16 healthy subjects (no systemic inflammation in the last 3 months) as a control group. At diagnosis, we measured Interleukin-6 (IL-6) and Myeloperoxidase (MPO). For in vitro study, healthy RBCs were exposed to the plasma of septic patients and CTR for 15 min, 1, 2, 4 and 24 h. Morphological markers of death and eryptosis were evaluated by flow cytometric analyses. The cytotoxic effect of septic plasma on RBCs was studied in vitro at 15 min, 1, 2, 4 and 24 h. Healthy RBCs incubated with plasma from septic patients went through significant morphological changes and eryptosis compared to those exposed to plasma from the control group at all time points (all, p < 0.001). IL-6 and MPO levels were significantly higher in septic patients than in controls (both, p < 0.001). The percentage of AnnexinV-binding RBCs was significantly higher in septic patients with EAA level ≥0.60 (positive EAA: 32.4%, IQR 27.6–36.2) compared to septic patients with EAA level <0.60 (negative EAA: 14.7%, IQR 5.7–30.7) (p = 0.04). Significant correlations were observed between eryptosis and EAA levels (Spearman rho2 = 0.50, p < 0.05), IL-6 (Spearman rho2 = 0.61, p < 0.05) and MPO (Spearman rho2 = 0.70, p < 0.05). In conclusion, we observed a quick and great cytotoxic effect of septic plasma on healthy RBCs and a strong correlation with other biomarkers of severity of sepsis. Based on these results, we confirmed the pathological role of eryptosis in sepsis and we hypothesized its use as a biomarker of sepsis, potentially helping physicians to face important treatment decisions. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Advances in the Management of Sepsis and Septic Shock)

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21 pages, 3956 KiB

Open AccessArticle

Clinical Significance of Elevated Xanthine Dehydrogenase Levels and Hyperuricemia in Patients with Sepsis

by Masaru Matsuoka, Junko Yamaguchi and Kosaku Kinoshita

Int. J. Mol. Sci. 2023, 24(18), 13857; https://doi.org/10.3390/ijms241813857 - 08 Sep 2023

Viewed by 1616

Abstract

Patient outcomes for severe sepsis and septic shock remain poor. Excessive oxidative stress accelerates organ dysfunction in severe acute illnesses. Uric acid (UA) is the most abundant antioxidant. We hypothesized that UA and related molecules, which play a critical role in antioxidant activity, [...] Read more.

Patient outcomes for severe sepsis and septic shock remain poor. Excessive oxidative stress accelerates organ dysfunction in severe acute illnesses. Uric acid (UA) is the most abundant antioxidant. We hypothesized that UA and related molecules, which play a critical role in antioxidant activity, might be markers of oxidative stress in sepsis. The study aimed to clarify the clinical significance of UA and the relationship between UA, molecules related to UA, and outcomes by measuring blood UA, xanthine dehydrogenase (XDH), and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels over time. Blood UA levels in septic patients were correlated with the SOFA score (ρ = 0.36, p < 0.0001) and blood XDH levels (ρ = 0.27, p < 0.0001). Blood XDH levels were correlated with the SOFA score (ρ = 0.59, p < 0.0001) and blood 8-OHdG levels (ρ = −0.32, p < 0.0001). Blood XDH levels were persistently high in fatal cases. Blood XDH level (OR 8.84, 95% CI: 1.42–91.2, p = 0.018) was an independent factor of poor outcomes. The cutoff of blood XDH level was 1.38 ng/mL (sensitivity 92.8%, specificity 61.9%), and those 1.38 ng/mL or higher were associated with a significantly reduced survival rate (blood XDH level > 1.38 ng/mL: 23.7%, blood XDH level < 1.38 ng/mL: 96.3%, respectively, p = 0.0007). Elevated UA levels due to elevated blood XDH levels in sepsis cases may reduce oxidative stress. Countermeasures against increased oxidative stress in sepsis may provide new therapeutic strategies. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Advances in the Management of Sepsis and Septic Shock)

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12 pages, 503 KiB

Open AccessArticle

Rapid Point-of-Care PCR Testing of Drug-Resistant Strains on Endotracheal Aspirate Samples: A Repurposed Effective Tool in the Stepwise Approach of Healthcare-Acquired Pneumonia—A Pilot Study

by Andrei-Mihai Bălan, Constantin Bodolea, Andrada Nemes, Rareș Crăciun and Natalia Hagău

Int. J. Mol. Sci. 2023, 24(17), 13393; https://doi.org/10.3390/ijms241713393 - 29 Aug 2023

Viewed by 915

Abstract

Healthcare-associated pneumonia (HCAP) is a common nosocomial infection with high morbidity and mortality. Culture-based detection of the etiologic agent and drug susceptibility is time-consuming, potentially leading to the inadequate use of broad-spectrum empirical antibiotic regimens. The aim was to evaluate the diagnostic capabilities [...] Read more.

Healthcare-associated pneumonia (HCAP) is a common nosocomial infection with high morbidity and mortality. Culture-based detection of the etiologic agent and drug susceptibility is time-consuming, potentially leading to the inadequate use of broad-spectrum empirical antibiotic regimens. The aim was to evaluate the diagnostic capabilities of rapid point-of-care multiplex polymerase chain reaction (PCR) assays from the endotracheal aspirate of critically ill patients with HCAP. A consecutive series of 29 intensive care unit (ICU) patients with HCAP and a control group of 28 patients undergoing elective surgical procedures were enrolled in the study. The results of the PCR assays were compared to the culture-based gold standard. The overall accuracy of the PCR assays was 95.12%, with a sensitivity of 92.31% and a specificity of 97.67%. The median time was 90 min for the rapid PCR tests (p < 0.001), while for the first preliminary results of the cultures, it was 48 h (46–72). The overall accuracy for rapid PCR testing in suggesting an adequate antibiotic adjustment was 82.98% (95% CI 69.19–92.35%), with a specificity of 90% (95% CI 55.50–99.75%), a positive predictive value of 96.77% (95% CI 83.30–99.92%), and a negative predictive value of 56.25 (95% CII 29.88–80.25%). This method of rapid point-of-care PCR could effectively guide antimicrobial stewardship in patients with healthcare-acquired pneumonia. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Advances in the Management of Sepsis and Septic Shock)

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18 pages, 1110 KiB

Open AccessArticle

S-Adenosylhomocysteine Is a Useful Metabolic Factor in the Early Prediction of Septic Disease Progression and Death in Critically Ill Patients: A Prospective Cohort Study

by Franz-Simon Centner, Jochen J. Schoettler, Kathrin Brohm, Sonani Mindt, Evelyn Jäger, Bianka Hahn, Tanja Fuderer, Holger A. Lindner, Verena Schneider-Lindner, Joerg Krebs, Michael Neumaier and Manfred Thiel

Int. J. Mol. Sci. 2023, 24(16), 12600; https://doi.org/10.3390/ijms241612600 - 09 Aug 2023

Cited by 2 | Viewed by 897

Abstract

A common final pathway of pathogenetic mechanisms in septic organ dysfunction and death is a lack or non-utilization of oxygen. Plasma concentrations of lactate serve as surrogates for the oxygen-deficiency-induced imbalance between energy supply and demand. As S-adenosylhomocysteine (SAH) was shown to reflect [...] Read more.

A common final pathway of pathogenetic mechanisms in septic organ dysfunction and death is a lack or non-utilization of oxygen. Plasma concentrations of lactate serve as surrogates for the oxygen-deficiency-induced imbalance between energy supply and demand. As S-adenosylhomocysteine (SAH) was shown to reflect tissue hypoxia, we compared the ability of SAH versus lactate to predict the progression of inflammatory and septic disease to septic organ dysfunction and death. Using univariate and multiple logistic regression, we found that SAH but not lactate, taken upon patients’ inclusion in the study close to ICU admission, significantly and independently contributed to the prediction of disease progression and death. Due to the stronger increase in SAH in relation to S-adenosylmethionine (SAM), the ratio of SAM to SAH, representing methylation potential, was significantly decreased in patients with septic organ dysfunction and non-survivors compared with SIRS/sepsis patients (2.8 (IQR 2.3–3.9) vs. 8.8 (4.9–13.8); p = 0.003) or survivors (4.9 (2.8–9.5) vs. 8.9 (5.1–14.3); p = 0.026), respectively. Thus, SAH appears to be a better contributor to the prediction of septic organ dysfunction and death than lactate in critically ill patients. As SAH is a potent inhibitor of SAM-dependent methyltransferases involved in numerous vital biochemical processes, the impairment of the SAM-to-SAH ratio in severely critically ill septic patients and non-survivors warrants further studies on the pathogenetic role of SAH in septic multiple organ failure. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Advances in the Management of Sepsis and Septic Shock)

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15 pages, 2858 KiB

Open AccessArticle

Development of Procathepsin L (pCTS-L)-Inhibiting Lanosterol-Carrying Liposome Nanoparticles to Treat Lethal Sepsis

by Weiqiang Chen, Cassie Shu Zhu, Xiaoling Qiang, Shujin Chen, Jianhua Li, Ping Wang, Kevin J. Tracey and Haichao Wang

Int. J. Mol. Sci. 2023, 24(10), 8649; https://doi.org/10.3390/ijms24108649 - 12 May 2023

Cited by 4 | Viewed by 1555

Abstract

The pathogenesis of microbial infections and sepsis is partly attributable to dysregulated innate immune responses propagated by late-acting proinflammatory mediators such as procathepsin L (pCTS-L). It was previously not known whether any natural product could inhibit pCTS-L-mediated inflammation or could be strategically developed [...] Read more.

The pathogenesis of microbial infections and sepsis is partly attributable to dysregulated innate immune responses propagated by late-acting proinflammatory mediators such as procathepsin L (pCTS-L). It was previously not known whether any natural product could inhibit pCTS-L-mediated inflammation or could be strategically developed into a potential sepsis therapy. Here, we report that systemic screening of a NatProduct Collection of 800 natural products led to the identification of a lipophilic sterol, lanosterol (LAN), as a selective inhibitor of pCTS-L-induced production of cytokines [e.g., Tumor Necrosis Factor (TNF) and Interleukin-6 (IL-6)] and chemokines [e.g., Monocyte Chemoattractant Protein-1 (MCP-1) and Epithelial Neutrophil-Activating Peptide (ENA-78)] in innate immune cells. To improve its bioavailability, we generated LAN-carrying liposome nanoparticles and found that these LAN-containing liposomes (LAN-L) similarly inhibited pCTS-L-induced production of several chemokines [e.g., MCP-1, Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted (RANTES) and Macrophage Inflammatory Protein-2 (MIP-2)] in human blood mononuclear cells (PBMCs). In vivo, these LAN-carrying liposomes effectively rescued mice from lethal sepsis even when the first dose was given at 24 h post the onset of this disease. This protection was associated with a significant attenuation of sepsis-induced tissue injury and systemic accumulation of serval surrogate biomarkers [e.g., IL-6, Keratinocyte-derived Chemokine (KC), and Soluble Tumor Necrosis Factor Receptor I (sTNFRI)]. These findings support an exciting possibility to develop liposome nanoparticles carrying anti-inflammatory sterols as potential therapies for human sepsis and other inflammatory diseases. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Advances in the Management of Sepsis and Septic Shock)

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Graphical abstract

14 pages, 1751 KiB

Open AccessArticle

Hematological Parameters and Procalcitonin as Discriminants between Bacterial Pneumonia-Induced Sepsis and Viral Sepsis Secondary to COVID-19: A Retrospective Single-Center Analysis

by Emanuel Moisa, Madalina Dutu, Dan Corneci, Ioana Marina Grintescu and Silvius Negoita

Int. J. Mol. Sci. 2023, 24(6), 5146; https://doi.org/10.3390/ijms24065146 - 07 Mar 2023

Cited by 2 | Viewed by 1749

Abstract

Bacterial and viral sepsis induce alterations of all hematological parameters and procalcitonin is used as a biomarker of infection and disease severity. Our aim was to study the hematological patterns associated with pulmonary sepsis triggered by bacteria and Severe Acute Respiratory Syndrome–Coronavirus–type-2 (SARS-CoV-2) [...] Read more.

Bacterial and viral sepsis induce alterations of all hematological parameters and procalcitonin is used as a biomarker of infection and disease severity. Our aim was to study the hematological patterns associated with pulmonary sepsis triggered by bacteria and Severe Acute Respiratory Syndrome–Coronavirus–type-2 (SARS-CoV-2) and to identify the discriminants between them. We performed a retrospective, observational study including 124 patients with bacterial sepsis and 138 patients with viral sepsis. Discriminative ability of hematological parameters and procalcitonin between sepsis types was tested using receiver operating characteristic (ROC) analysis. Sensitivity (Sn%), specificity (Sp%), positive and negative likelihood ratios were calculated for the identified cut-off values. Patients with bacterial sepsis were older than patients with viral sepsis (p < 0.001), with no differences regarding gender. Subsequently to ROC analysis, procalcitonin had excellent discriminative ability for bacterial sepsis diagnosis with an area under the curve (AUC) of 0.92 (cut-off value of >1.49 ng/mL; Sn = 76.6%, Sp = 94.2%), followed by RDW% with an AUC = 0.87 (cut-off value >14.8%; Sn = 80.7%, Sp = 85.5%). Leukocytes, monocytes and neutrophils had good discriminative ability with AUCs between 0.76–0.78 (p < 0.001), while other hematological parameters had fair or no discriminative ability. Lastly, procalcitonin value was strongly correlated with disease severity in both types of sepsis (p < 0.001). Procalcitonin and RDW% had the best discriminative ability between bacterial and viral sepsis, followed by leukocytes, monocytes and neutrophils. Procalcitonin is a marker of disease severity regardless of sepsis type. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Advances in the Management of Sepsis and Septic Shock)

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Review

Jump to: Research, Other

21 pages, 791 KiB

Open AccessReview

Plasminogen System in the Pathophysiology of Sepsis: Upcoming Biomarkers

by Filomena Napolitano, Valentina Giudice, Carmine Selleri and Nunzia Montuori

Int. J. Mol. Sci. 2023, 24(15), 12376; https://doi.org/10.3390/ijms241512376 - 03 Aug 2023

Cited by 3 | Viewed by 1504

Abstract

Severe hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock, disseminated intravascular coagulation (DIC), and death. Therefore, an analysis of circulating concentrations of pro- and anti-fibrinolytic mediators could be a winning [...] Read more.

Severe hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock, disseminated intravascular coagulation (DIC), and death. Therefore, an analysis of circulating concentrations of pro- and anti-fibrinolytic mediators could be a winning strategy in both the diagnosis and the treatment of sepsis. However, the optimal cutoff value, the timing of the measurements, and their combination with coagulation indicators should be further investigated. The purpose of this review is to summarize all relevant publications regarding the role of the main components of the plasminogen activation system (PAS) in the pathophysiology of sepsis. In addition, the clinical value of PAS-associated biomarkers in the diagnosis and the outcomes of patients with septic syndrome will be explored. In particular, experimental and clinical trials performed in emergency departments highlight the validity of soluble urokinase plasminogen activator receptor (suPAR) as a predictive and prognostic biomarker in patients with sepsis. The measurements of PAI-I may also be useful, as its increase is an early manifestation of sepsis and may precede the development of thrombocytopenia. The upcoming years will undoubtedly see progress in the use of PAS-associated laboratory parameters. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Advances in the Management of Sepsis and Septic Shock)

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Other

Jump to: Research, Review

2 pages, 183 KiB

Open AccessComment

Comment on Vidart et al. Relationship among Low T3 Levels, Type 3 Deiodinase, Oxidative Stress, and Mortality in Sepsis and Septic Shock: Defining Patient Outcomes. Int. J. Mol. Sci. 2023, 24, 3935

by I-Shiang Tzeng

Int. J. Mol. Sci. 2023, 24(18), 13940; https://doi.org/10.3390/ijms241813940 - 11 Sep 2023

Viewed by 470

Abstract

In a previously published article, Vidart and colleagues conducted a prospective cohort study to explore the correlation between T3 levels and the risk of sepsis and septic shock in patients, with a follow-up period of 28 days or until deceased. The authors concluded [...] Read more.

In a previously published article, Vidart and colleagues conducted a prospective cohort study to explore the correlation between T3 levels and the risk of sepsis and septic shock in patients, with a follow-up period of 28 days or until deceased. The authors concluded that patients with sepsis and septic shock exhibited a significantly high risk of having low T3 levels. This research provides valuable insights into the clinical perspective in this particular field. However, certain clinical considerations should be addressed to enhance the study’s merit for researchers. Full article

(This article belongs to the Special Issue Diagnostic and Therapeutic Advances in the Management of Sepsis and Septic Shock)

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