Beta-Blockers as an Immunologic and Autonomic Manipulator in Critically Ill Patients: A Review of the Recent Literature.

The autonomic nervous system plays a key role in maintaining body hemostasis through both the sympathetic and parasympathetic nervous systems. Sympathetic overstimulation as a reflex to multiple pathologies, such as septic shock, brain injury, cardiogenic shock, and cardiac arrest, could be harmful and lead to autonomic and immunologic dysfunction. The continuous stimulation of the beta receptors on immune cells has an inhibitory effect on these cells and may lead to immunologic dysfunction through enhancing the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), and inhibiting the production of pro-inflammatory factors, such as interleukin-1B IL-1B and tissue necrotizing factor-alpha (TNF-alpha). Sympathetic overstimulation-induced autonomic dysfunction may also happen due to adrenergic receptor insensitivity or downregulation. Administering anti-adrenergic medication, such as beta-blockers, is a promising treatment to compensate against the undesired effects of adrenergic surge. Despite many misconceptions about beta-blockers, beta-blockers have shown a promising effect in decreasing mortality in patients with critical illness. In this review, we summarize the recently published articles that have discussed using beta-blockers as a promising treatment to decrease mortality in critically ill patients, such as patients with septic shock, traumatic brain injury, cardiogenic shock, acute decompensated heart failure, and electrical storm. We also discuss the potential pathophysiology of beta-blockers in various types of critical illness. More clinical trials are encouraged to evaluate the safety and effectiveness of beta-blockers in improving mortality among critically ill patients.

Loss-of-function/gain-of-function polymorphisms of the ATP sensitive P2X7R influence sepsis, septic shock, pneumonia, and survival outcomes.

Introduction: Extracellular ATP (eATP) released from damaged cells activates the P2X7 receptor (P2X7R) ion channel on the surface of surrounding cells, resulting in calcium influx, potassium efflux and inflammasome activation. Inherited changes in the P2X7R gene (P2RX7) influence eATP induced responses. Single nucleotide polymorphisms (SNPs) of P2RX7 influence both function and signaling of the receptor, that in addition to ion flux includes pathogen control and immunity. Methods: Subjects (n = 105) were admitted to the ICU at the University Hospital Ulm, Germany between June 2018 and August 2019. Of these, subjects with a diagnosis of sepsis (n = 75), were also diagnosed with septic shock (n = 24), and/or pneumonia (n = 42). Subjects with pneumonia (n = 43) included those without sepsis (n = 1), sepsis without shock (n = 29) and pneumonia with septic shock (n = 13). Out of the 75 sepsis/septic shock patients, 33 patients were not diagnosed with pneumonia. Controls (n = 30) were recruited to the study from trauma patients and surgical patients without sepsis, septic shock, or pneumonia. SNP frequencies were determined for 16 P2RX7 SNPs known to affect P2X7R function, and association studies were performed between frequencies of these SNPs in sepsis, septic shock, and pneumonia compared to controls. Results: The loss-of-function (LOF) SNP rs17525809 (T253C) was found more frequently in patients with septic shock, and non-septic trauma patients when compared to sepsis. The LOF SNP rs2230911 (C1096G) was found to be more frequent in patients with sepsis and septic shock than in non-septic trauma patients. The frequencies of these SNPs were even higher in sepsis and septic patients with pneumonia. The current study also confirmed a previous study by our group that showed a five SNP combination that included the GOF SNPs rs208294 (C489T) and rs2230912 (Q460R) that was designated #21211 was associated with increased odds of survival in severe sepsis. Discussion: The results found an association between expression of LOF P2RX7 SNPs and presentation to the ICU with sepsis, and septic shock compared to control ICU patients. Furthermore, frequencies of LOF SNPs were found to be higher in sepsis patients with pneumonia compared to those without pneumonia. In addition, a five SNP GOF combination was associated with increased odds of survival in severe sepsis. These results suggest that P2RX7 is required to control infection in pneumonia and that inheritance of LOF variants increases the risk of sepsis when associated with pneumonia. This study confirms that P2RX7 genotyping in pneumonia may identify patients at risk of developing sepsis. The study also identifies P2X7R as a target in sepsis associated with an excessive immune response in subjects with GOF SNP combinations.

Tofacitinib Treatment Suppresses CD4+ T-Cell Activation and Th1 Response, Contributing to Protection against Staphylococcal Toxic Shock.

Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by Staphylococcus aureus (S. aureus) enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against S. aureus sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS.

A highly neutralizing human monoclonal antibody targeting a novel linear epitope on staphylococcal enterotoxin B.

Staphylococcal Enterotoxin B (SEB), produced by Staphylococcus aureus (S. aureus), is a powerful superantigen that induces severe immune disruption and toxic shock syndrome (TSS) upon binding to MHC-II and TCR. Despite its significant impact on the pathogenesis of S. aureus, there are currently no specific therapeutic interventions available to counteract the mechanism of action exerted by this toxin. In this study, we have identified a human monoclonal antibody, named Hm0487, that specifically targets SEB by single-cell sequencing using PBMCs isolated from volunteers enrolled in a phase I clinical trial of the five-antigen S. aureus vaccine. X-ray crystallography studies revealed that Hm0487 exhibits high affinity for a linear B cell epitope in SEB (SEB138-147), which is located distantly from the site involved in the formation of the MHC-SEB-TCR ternary complex. Furthermore, in vitro studies demonstrated that Hm0487 significantly impacts the interaction of SEB with both receptors and the binding to immune cells, probably due to an allosteric effect on SEB rather than competing with receptors for binding sites. Moreover, both in vitro and in vivo studies validated that Hm0487 displayed efficient neutralizing efficacy in models of lethal shock and sepsis induced by either SEB or bacterial challenge. Our findings unveil an alternative mechanism for neutralizing the pathogenesis of SEB by Hm0487, and this antibody provides a novel strategy for mitigating both SEB-induced toxicity and S. aureus infection.

CD5L as a promising biological therapeutic for treating sepsis.

Sepsis results from systemic, dysregulated inflammatory responses to infection, culminating in multiple organ failure. Here, we demonstrate the utility of CD5L for treating experimental sepsis caused by cecal ligation and puncture (CLP). We show that CD5L's important features include its ability to enhance neutrophil recruitment and activation by increasing circulating levels of CXCL1, and to promote neutrophil phagocytosis. CD5L-deficient mice exhibit impaired neutrophil recruitment and compromised bacterial control, rendering them susceptible to attenuated CLP. CD5L-/- peritoneal cells from mice subjected to medium-grade CLP exhibit a heightened pro-inflammatory transcriptional profile, reflecting a loss of control of the immune response to the infection. Intravenous administration of recombinant CD5L (rCD5L) in immunocompetent C57BL/6 wild-type (WT) mice significantly ameliorates measures of disease in the setting of high-grade CLP-induced sepsis. Furthermore, rCD5L lowers endotoxin and damage-associated molecular pattern (DAMP) levels, and protects WT mice from LPS-induced endotoxic shock. These findings warrant the investigation of rCD5L as a possible treatment for sepsis in humans.

Single-cell RNA sequencing reveals cell-cell communication and potential biomarker in sepsis and septic shock patients.

BACKGROUND: Sepsis is a disease characterized by infection-induced multiorgan dysfunction, which can progress to septic shock if not promptly treated. Early identification of sepsis is crucial for its treatment. However, there are currently limited specific biomarkers for sepsis or septic shock. This study aims to identify potential biomarkers for sepsis and septic shock. METHODS: We analyzed single-cell transcriptomic data of peripheral blood mononuclear cells (PBMCs) from healthy individuals, sepsis and septic shock patients, identified differences in gene expression and cell-cell communication between different cell types during disease progression. Moreover, our analyses were further validated with flow cytometry and bulk RNA-seq data. RESULTS: Our study elucidates the alterations in cellular proportions and cell-cell communication among healthy controls, sepsis, and septic shock patients. We identified a specific augmentation in the Resistin signaling within sepsis monocytes, mediated via RETN-CAP1 ligand-receptor pairs. Additionally, we observed enhanced IL16 signaling within monocytes from septic shock patients, mediated through IL16-CD4 ligand-receptor pairs. Subsequently, we confirmed our findings by validating the increase in CAP-1+ monocytes in sepsis and IL16+ monocytes in septic shock in mouse models. And a significant upregulation of CAP-1 and IL16 was also observed in the bulk RNA-seq data from patients with sepsis and septic shock. Furthermore, we identified four distinct clusters of CD14+ monocytes, highlighting the heterogeneity of monocytes in the progress of sepsis. CONCLUSIONS: In summary, our work demonstrates changes in cell-cell communication of healthy controls, sepsis and septic shock, confirming that the molecules CAP-1 and IL16 on monocytes may serve as potential diagnostic markers for sepsis and septic shock, respectively. These findings provide new insights for early diagnosis and stratified treatment of the disease.

EFFECT OF STRATIFIED DOSE OF NOREPINEPHRINE ON CELLULAR IMMUNE RESPONSE IN PATIENTS WITH SEPTIC SHOCK AND THE CONSTRUCTION OF A PROGNOSTIC RISK MODEL.

ABSTRACT: Objective: To explore the effect of a stratified dose of norepinephrine (NE) on cellular immune response in patients with septic shock, and to construct a prognostic model of septic shock. Methods: A total of 160 patients with septic shock (B group) and 58 patients with sepsis (A group) were given standard cluster therapy. Patients with septic shock were divided into four groups (B1-B4 groups: 0.01-0.2, 0.2-0.5, 0.5-1.0, and >1 µg/kg/min) according to the quartile method of the early (72 h) time-weighted average dose of NE and clinical application. The cellular immune indexes at 24 h (T0) and 4-7 days (T1) after admission were collected. The difference method was used to explore the effect of NE stratified dose on cellular immune effect in patients with septic shock. A multivariate COX proportional risk regression model was used to analyze the independent prognostic risk factors, and a prognostic risk model was constructed. Results: The differences of ΔIL-1ß, ΔIL-6, ΔIL-10, absolute value difference of T lymphocyte (ΔCD3+/CD45+#) and Th helper T cell (ΔCD3+ CD4+/CD45+#), CD64 infection index difference, ΔmHLA-DR, regulatory T lymphocyte ratio difference (ΔTregs%) between group A, B1, B2, B3, and B4 were statistically significant ( P < 0.05). There was a nonlinear relation between the stratified dose of NE and ΔIL-6, ΔIL-10, ΔCD3+/CD45+#, ΔmHLA-DR%. The threshold periods of NE-induced proinflammatory and anti-inflammatory immune changes were 0.3-0.5 µg/kg/min. Multivariate COX model regression analysis showed that age, nutritional patterns, weighted average dose of norepinephrine, IL-6, absolute value of T lymphocytes, and mHLA-DR were independent risk factors affecting the prognosis of patients with septic shock ( P < 0.05). The prognostic risk model was constructed (AUC value = 0.813, 95% CI: 0.752-0.901). Conclusion: NE has a certain inhibitory effect on cellular immune function in patients with septic shock. A prognostic risk model was constructed with stronger prediction efficiency for the prognosis of patients with septic shock.

TLRs1-10 Protein Expression in Circulating Human White Blood Cells during Bacterial and COVID-19 Infections.

INTRODUCTION: Toll-like receptors play crucial roles in the sepsis-induced systemic inflammatory response. Septic shock mortality correlates with overexpression of neutrophilic TLR2 and TLR9, while the role of TLR4 overexpression remains a debate. In addition, TLRs are involved in the pathogenesis of viral infections such as COVID-19, where the single-stranded RNA of SARS-CoV-2 is recognized by TLR7 and TLR8, and the spike protein activates TLR4. METHODS: In this study, we conducted a comprehensive analysis of TLRs 1-10 expressions in white blood cells from 71 patients with bacterial and viral infections. Patients were divided into 4 groups based on disease type and severity (sepsis, septic shock, moderate, and severe COVID-19) and compared to 7 healthy volunteers. RESULTS: We observed a significant reduction in the expression of TLR4 and its co-receptor CD14 in septic shock neutrophils compared to the control group (p < 0.001). Severe COVID-19 patients exhibited a significant increase in TLR3 and TLR7 levels in neutrophils compared to controls (p < 0.05). Septic shock patients also showed a similar increase in TLR7 in neutrophils along with elevated intermediate monocytes (CD14+CD16+) compared to the control group (p < 0.005 and p < 0.001, respectively). However, TLR expression remained unchanged in lymphocytes. CONCLUSION: This study provides further insights into the mechanisms of TLR activation in various infectious conditions. Additional analysis is needed to assess their correlation with patient outcome and to evaluate the impact of TLR-pathway modulation during septic shock and severe COVID-19.

High mortality rate of septic patients with high blood granzyme B concentrations.

Granzyme B could be released from cytotoxic T lymphocytes producing apoptosis activation. The objective of our study was to determine whether an association between septic patient mortality and blood granzyme B concentrations exist. We recruited septic patients admitted in 3 Intensive Care Units. We recorded mortality at 30 days and we determined serum granzyme B concentrations at moment of sepsis diagnosis. We found higher rate of history of diabetes mellitus (P = 0.02), serum granzyme B concentrations (P < 0.001), age (P = 0.001), serum lactic acid levels (P = 0.001) and sepsis-related organ failure assessment (P < 0.001) exhibited non-surviving patients (n = 67) than surviving ones (n = 110). We found in multiple logistic regression analysis an association of serum granzyme B concentrations with mortality (odds ratio = 1.223; 95% confidence interval = 1.104-1.355; P < 0.001) controlling for diabetes mellitus, sepsis-related organ failure assessment, lactic acid and age. That we know, our study is the first reporting the existence of an association of high serum granzyme B concentrations with high septic patients mortality.

Emergence of immunosuppressive LOX-1+ PMN-MDSC in septic shock and severe COVID-19 patients with acute respiratory distress syndrome.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with immunosuppressive properties. In cancer patients, the expression of lectin-type oxidized LDL receptor 1 (LOX-1) on granulocytic MDSC identifies a subset of MDSC that retains the most potent immunosuppressive properties. The main objective of the present work was to explore the presence of LOX-1+ MDSC in bacterial and viral sepsis. To this end, whole blood LOX-1+ cells were phenotypically, morphologically, and functionally characterized. They were monitored in 39 coronavirus disease-19 (COVID-19, viral sepsis) and 48 septic shock (bacterial sepsis) patients longitudinally sampled five times over a 3 wk period in intensive care units (ICUs). The phenotype, morphology, and immunosuppressive functions of LOX-1+ cells demonstrated that they were polymorphonuclear MDSC. In patients, we observed the significant emergence of LOX-1+ MDSC in both groups. The peak of LOX-1+ MDSC was 1 wk delayed with respect to ICU admission. In COVID-19, their elevation was more pronounced in patients with acute respiratory distress syndrome. The persistence of these cells may contribute to long lasting immunosuppression leaving the patient unable to efficiently resolve infections.

HLA-A Locus is Associated With Sepsis and Septic Shock After Traumatic Injury.

OBJECTIVE: Determine whether variation in the HLA region is associated with the development of post-traumatic sepsis and septic shock. BACKGROUND: Sepsis-related deaths remain a major source of mortality after traumatic injury. Genetic characteristics may contribute to susceptibility to adverse outcomes including sepsis and septic shock. Recent advances in next-generation sequencing technology now allow comprehensive genotyping of the HLA region. METHODS: White adult trauma patients requiring more than 2 days of mechanical ventilation underwent HLA genotyping, and were followed for the development of sepsis and septic shock. Odds ratios (OR) for the associations between our outcomes and HLA variants were estimated, a correction for multiple comparisons was applied, and significant variants were included in regression models adjusting for potential confounders. RESULTS: A total of 1184 patients were included. Patients were severely injured (median injury severity score 33); 33% developed sepsis, 6% septic shock, and in-hospital mortality was 14%. An amino acid variant (156Q) within the HLA-A peptide-binding groove was associated with greater odds of sepsis [OR 1.50, (1.18-1.89)]. HLA-A∗02:01 was associated with lower odds of septic shock [OR 0.52, (0.32-0.82)]. These associations remained significant after adjusting for potential confounders. CONCLUSIONS: This is the first study to apply next-generation sequencing techniques to evaluate associations between immunogenetic factors and post-traumatic sepsis and septic shock. Associations with class I HLA variants are novel as they implicate adaptive immunity in post-traumatic sepsis. These findings are a step towards developing a panel of genetic markers assessing risk of infection-related complications as we move towards more personalized medicine.

Therapeutic Modulation of the Host Defense by Hemoadsorption with CytoSorb®-Basics, Indications and Perspectives-A Scoping Review.

The "normal" immune response to an insult triggers a highly regulated response determined by the interaction of various immunocompetent cells with pro- and anti-inflammatory cytokines. Under pathologic conditions, the massive elevation of cytokine levels ("cytokine storm") could not be controlled until the recent development of hemoadsorption devices that are able to extract a variety of different DAMPs, PAMPs, and metabolic products from the blood. CytoSorb® has been approved for adjunctive sepsis therapy since 2011. This review aims to summarize theoretical knowledge, in vitro results, and clinical findings to provide the clinician with pragmatic guidance for daily practice. English-language and peer-reviewed literature identified by a selective literature search in PubMed and published between January 2016 and May 2021 was included. Hemoadsorption can be used successfully as adjunct to a complex therapeutic regimen for various conditions. To the contrary, this nonspecific intervention may potentially worsen patient outcomes in complex immunological processes. CytoSorb® therapy appears to be safe and useful in various diseases (e.g., rhabdomyolysis, liver failure, or intoxications) as well as in septic shock or cytokine release syndrome, although a conclusive assessment of treatment benefit is not possible and no survival benefit has yet been demonstrated in randomized controlled trials.

Transcriptomic Profiles in Children With Septic Shock With or Without Immunoparalysis.

Background: Severe innate immune suppression, termed immunoparalysis, is associated with increased risks of nosocomial infection and mortality in children with septic shock. Currently, immunoparalysis cannot be clinically diagnosed in children, and mechanisms remain unclear. Transcriptomic studies identify subsets of septic children with downregulation of genes within adaptive immune pathways, but assays of immune function have not been performed as part of these studies, and little is known about transcriptomic profiles of children with immunoparalysis. Methods: We performed a nested case-control study to identify differences in RNA expression patterns between children with septic shock with immunoparalysis (defined as lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)α response < 200 pg/ml) vs those with normal LPS-induced TNFα response. Children were enrolled within 48 hours of the onset of septic shock and divided into two groups based on LPS-induced TNFα response. RNA was extracted from whole blood for RNAseq, differential expression analyses using DESeq2 software, and pathway analyses using Ingenuity Pathway Analysis. Results: 32 children were included in analyses. Comparing those with immunoparalysis (n =19) to those with normal TNFα response (n = 13), 2,303 transcripts were differentially expressed with absolute value fold change ≥ 1.5 and false discovery rate ≤ 0.05. The majority of downregulated pathways in children with immunoparalysis were pathways that involved interactions between innate and adaptive immune cells necessary for cell-mediated immunity, crosstalk between dendritic cells and natural killer cells, and natural killer cell signaling pathways. Upregulated pathways included those involved in humoral immunity (T helper cell type 2), corticotropin signaling, platelet activation (GP6 signaling), and leukocyte migration and extravasation. Conclusions: Our study suggests that gene expression data might be useful to identify children with immunoparalysis and identifies several key differentially regulated pathways involved in both innate and adaptive immunity. Our ongoing work in this area aims to dissect interactions between innate and adaptive immunity in septic children and to more fully elucidate patient-specific immunologic pathophysiology to guide individualized immunotherapeutic targets.

Dysregulation of the renin-angiotensin system in septic shock: Mechanistic insights and application of angiotensin II in clinical management.

Synergistic physiologic mechanisms involving the renin-angiotensin system (RAS), the sympathetic nervous system, and the arginine-vasopressin system play an integral role in blood pressure homeostasis. A subset of patients with sepsis experience septic shock with attendant circulatory, cellular, and metabolic abnormalities. Septic shock is associated with increased mortality because of an inadequacy to maintain mean arterial blood pressure (MAP) despite volume resuscitation and the use of vasopressors. Vasodilatory shock raises the dose of vasopressors required to maintain a MAP of > 65 mm Hg. The diminished response to endogenous angiotensin II in sepsis-induced vasoplegia may be related to the aberrant RAS activation that stimulates a proinflammatory beneficial antibacterial response, increasing the secretion of proinflammatory cytokines that downregulate AT-1 receptors expression. Moreover, excessive systemic upregulation of nitric oxide synthase, stimulation of prostaglandin synthesis, and activation of ATP-sensitive potassium channels followed by reduced vascular entry of calcium ions are putative mechanisms in the reduced responsiveness to vasopressors. However, intravenous angiotensin II in catecholamine-resistant septic shock patients showed substantial evidence of raising the MAP to target hemodynamic levels, thus allowing time to treat underlying conditions. Nevertheless, evidence of catecholamine-sparing effect by adding angiotensin II, aimed at increasing the therapeutic index of vasopressor therapy, does not show an attenuation of end-organ damage. The use of angiotensin II in septic shock has not been evaluated in patients who are not catecholamine resistant. This, in conjunction with an evolving definition of catecholamine resistance, provides an opportunity for further evaluation of exogenous angiotensin II in septic shock.

Cytokine Drizzle-The Rationale for Abandoning "Cytokine Storm".

BACKGROUND: "Cytokine storm" has been used to implicate increased cytokine levels in the pathogenesis of serious clinical conditions. Similarities with Severe Acute Respiratory Syndrome Coronoavirus-2 (SARS CoV-2) and the 2012 Middle Eastern Respiratory Syndrome led early investigators to suspect a "cytokine storm" resulting in an unregulated inflammatory response associated with the significant morbidity and mortality induced by SARS CoV-2. The threshold of blood cytokines necessary to qualify as a "cytokine storm" has yet to be defined. METHODS: A literature review was conducted to identify cytokine levels released during 11 assorted clinical conditions or diseases. Weighted averages for various cytokines were calculated by multiplying the number of patients in the paper by the average concentration of each cytokine. Correlation between cytokine levels for individual conditions or diseases were assessed using Pearson correlation coefficient. RESULTS: The literature was reviewed to determine blood levels of cytokines in a wide variety of clinical conditions. These conditions ranged from exercise and autoimmune disease to septic shock and therapy with chimeric antigen receptor T cells. The most frequently measured cytokine was IL-6 which ranged from 24,123 pg/mL in septic shock to 11 pg/mL after exercise. In patients with severe SARS CoV-2 infections, blood levels of IL-6 were only 43 pg/mL, nearly three magnitudes lower than IL-6 levels in patients with septic shock. The clinical presentations of these different diseases do not correlate with blood levels of cytokines. Additionally, there is poor correlation between the concentrations of different cytokines among the different diseases. Specifically, blood levels of IL-6 did not correlate with levels of IL-8, IL-10, or TNF. Septic shock had the highest concentrations of cytokines, yet multiple cytokine inhibitors have failed to demonstrate improved outcomes in multiple clinical trials. Patients with autoimmune diseases have very low blood levels of cytokines (rheumatoid arthritis, IL-6 = 34 pg/mL; Crohn's disease, IL-6 = 5 pg/mL), yet respond dramatically to cytokine inhibitors. CONCLUSION: The misleading term "cytokine storm" implies increased blood levels of cytokines are responsible for a grave clinical condition. Not all inflammatory conditions resulting in worsened disease states are correlated with significantly elevated cytokine levels, despite an association with the term "cytokine storm". "Cytokine storm" should be removed from the medical lexicon since it does not reflect the mediators driving the disease nor does it predict which diseases will respond to cytokine inhibitors.

Proteomics reveals disturbances in the immune response and energy metabolism of monocytes from patients with septic shock.

Sepsis results from a dyshomeostatic response to infection, which may lead to hyper or hypoimmune states. Monocytes are central regulators of the inflammatory response, but our understanding of their role in the genesis and resolution of sepsis is still limited. Here, we report a comprehensive exploration of monocyte molecular responses in a cohort of patients with septic shock via proteomic profiling. The acute stage of septic shock was associated with an impaired inflammatory phenotype, indicated by the down-regulation of MHC class II molecules and proinflammatory cytokine pathways. Simultaneously, there was an up-regulation of glycolysis enzymes and a decrease in proteins related to the citric acid cycle and oxidative phosphorylation. On the other hand, the restoration of immunocompetence was the hallmark of recovering patients, in which an upregulation of interferon signaling pathways was a notable feature. Our results provide insights into the immunopathology of sepsis and propose that, pending future studies, immunometabolism pathway components could serve as therapeutic targets in septic patients.

Leukocyte kinetics during the early stage acts as a prognostic marker in patients with septic shock in intensive care unit.

ABSTRACT: The leukocytes play an important role in immune function during sepsis. We performed a retrospective study to investigate if leukocytes kinetics was associated with survival in critically ill patients with septic shock in intensive care unit (ICU).Patients with septic shock from January 1, 2014 to June 30, 2018 in our ICU were included. We extracted the demographic, clinical and laboratory data, comorbidities from our clinical database. The number of white blood cell, neutrophil and lymphocyte on day 1 and day 3 after diagnosis were collected and neutrophil to lymphocyte ratios (NLR) were calculated. Our primary outcome was 28-day mortality. Univariate and multivariate logistic regression models and cox proportional risk model were used to analyze the association between the leukocytes kinetics during first 3 days after ICU admission and the day-28 mortality.A total of 1245 septic shock patients with a 28-day mortality of 35.02% were included into analysis. There were no significant difference of lymphocyte number (0.83 ±â€Š0.02 vs 0.80 ±â€Š0.04, P = .552) between survival and non-survivals on day 1. However, the lymphocyte counts was significantly lower (0.95 ±â€Š0.03 vs 0.85 ±â€Š0.04, P = .024) on the third day. Both multivariate logistic and Cox regression analysis showed that lymphocyte counts on day 3 were associated with day-28 mortality. Moreover, Kaplan-Meier survival analysis revealed that increasing in lymphocyte counts and decreasing WBC, neutrophils and NLR during the first 3 days after diagnosis were associated with longer survival.Leukocytes kinetics during the first 3 days is a valuable prognostic marker in patients with septic shock in the ICU.

Tanshinones inhibit NLRP3 inflammasome activation by alleviating mitochondrial damage to protect against septic and gouty inflammation.

Tanshinones, the active ingredients derived from the roots of Salvia miltiorrhiza, have been widely used as traditional medicinal herbs for treating human diseases. Although tanshinones showed anti-inflammatory effects in many studies, large knowledge gaps remain regarding their underlying mechanisms. Here, we identified 15 tanshinones that suppressed the activation of NLRP3 inflammasome and studied their structure-activity relationships. Three tanshinones (tanshinone IIA, isocryptotanshinone, and dihydrotanshinone I) reduced mitochondrial reactive-oxygen species production in lipopolysaccharide (LPS)/nigericin-stimulated macrophages and correlated with altered mitochondrial membrane potentials, mitochondria complexes activities, and adenosine triphosphate and protonated-nicotinamide adenine dinucleotide production. The tanshinones may confer mitochondrial protection by promoting autophagy and the AMP-activated protein kinase pathway. Importantly, our findings demonstrate that dihydrotanshinone I improved the survival of mice with LPS shock and ameliorated inflammatory responses in septic and gouty animals. Our results suggest a potential pharmacological mechanism whereby tanshinones can effectively treat inflammatory diseases, such as septic and gouty inflammation.

3-Hydroxykynurenine Regulates Lipopolysaccharide-Stimulated IL-6 Production and Protects against Endotoxic Shock in Mice.

Despite advances in our understanding of endotoxic shock, novel therapeutic interventions that can reduce the burden of sepsis remain elusive. Current treatment options are limited, and it is only through refinements in the ways that we deliver supportive care that mortality has fallen over the years. In this study, the role of kynurenine 3-monooxygenase (KMO) in immune regulation was examined in LPS-induced endotoxemia using KMO-/- and KMO+/+ mice treated with the KMO inhibitor Ro61-8048. We showed that LPS-induced or cecal ligation and puncture-induced mortality and hepatic IL-6 production increased in the absence of KMO, possibly involving increased activating transcription factor 4 (ATF4) signaling in hepatic macrophages. Moreover, treatment of septic mice with 3-hydroxykynurenine reduced mortality rates and inflammatory responses regardless of the presence or absence of KMO. According to our results, the administration of 3-hydroxykynurenine as part of the treatment approach for sepsis or as an adjuvant therapy might reduce the overproduction of IL-6, which is responsible for severe endotoxemia, and ultimately improve the survival rates of patients with sepsis.

Polymerized albumin restores impaired hemodynamics in endotoxemia and polymicrobial sepsis.

Fluid resuscitation following severe inflammation-induced hypoperfusion is critical for the restoration of hemodynamics and the prevention of multiorgan dysfunction syndrome during septic shock. Fluid resuscitation with commercially available crystalloid and colloid solutions only provides transient benefits, followed by fluid extravasation and tissue edema through the inflamed endothelium. The increased molecular weight (M.W.) of polymerized human serum albumin (PolyHSA) can limit fluid extravasation, leading to restoration of hemodynamics. In this prospective study, we evaluated how fluid resuscitation with PolyHSA impacts the hemodynamic and immune response in a lipopolysaccharide (LPS) induced endotoxemia mouse model. Additionally, we evaluated fluid resuscitation with PolyHSA in a model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Resuscitation with PolyHSA attenuated the immune response and improved the maintenance of systemic hemodynamics and restoration of microcirculatory hemodynamics. This decrease in inflammatory immune response and maintenance of vascular wall shear stress likely contributes to the maintenance of vascular integrity following fluid resuscitation with PolyHSA. The sustained restoration of perfusion, decrease in pro-inflammatory immune response, and improved vascular integrity that results from the high M.W. of PolyHSA indicates that a PolyHSA based solution is a potential resuscitation fluid for endotoxic and septic shock.