Sepsis Therapy Research Articles

Acute Kidney Injury During Sepsis and Prognostic Role of Coexistent Chronic Heart Failure

Background: The recently updated definition of sepsis considers pathophysiologic mechanisms to guide initial therapy. Clearly, generalized recommendations for sepsis therapy may be limited by pre-existing multimorbidity in addition to sepsis-related multi-organ failure. In particular, a recommendation regarding fluid rescue therapy may require adequate cardiac function and/or the absence of sepsis-induced cardiomyopathy. In all sepsis patients with compromised cardiac function or sepsis-induced cardiomyopathy, a patient-specific therapy regimen is required to prevent pulmonary edema and early death. Similarly, in sepsis, acute kidney injury with or without pre-existing chronic kidney disease requires attention to be paid to excretory renal function to avoid hypervolemia-mediated acute heart failure. In addition, hyponatremia related to intravascular hypovolemia may be explained by vasopressin stimulation. However, hypothetically, vasopressin hyporesponsiveness may contribute to sepsis-related acute kidney injury. In this review, relevant cardiorenal pathomechanisms will be assessed in the context of sepsis therapy. Conclusions: In conclusion, therapy for sepsis with acute kidney injury has to take cardiac comorbidity, if present, into account. The extent to which vasopressin hyporesponsiveness aggravates sepsis-mediated hypovolemia and renal insufficiency should remain a subject of further study.

Unlocking the Potential of miRNAs in Sepsis Diagnosis and Prognosis: From Pathophysiology to Precision Medicine.

The clinical syndrome appears as a dysregulated host response to infection that results in life-threatening organ dysfunction known as Sepsis. Sepsis is a serious public health concern where for every five deaths in ICU there is one patient who dies with sepsis worldwide. Sepsis is featured as unbalanced inflammation and immunosuppression which is sustained and profound, increasing patient susceptibility to secondary infections and mortality. microRNAs (miRNAs) play a central role in the control of many biological processes, and the deregulation of their expression has been linked to the development of oncological, cardiovascular, neurodegenerative, and metabolic diseases. In this review, we discuss the role of miRNAs in sepsis pathophysiology. Overall, miRNAs are seen as promising biomarkers, and it has been proposed to develop miRNA-based diagnosis and therapies for sepsis. Yet, the picture is not so straightforward because of miRNAs' versatile and dynamic features. More research is needed to clarify the expression and role of miRNAs in sepsis and promote the use of miRNAs for sepsis management. This study provides an extensive, current, and thorough analysis of the involvement of miRNAs in sepsis. Its purpose is to encourage future research in this area, as tiny miRNAs have the potential to be used for rapid diagnosis, prognosis, and treatment of sepsis.

Sialic acid-modified nanomedicines modulate neutrophils for dual therapy of cancer and sepsis: addressing neglected sepsis comorbidities during cancer treatment.

Advanced cancer patients face a high risk of sepsis due to immune suppression and infection susceptibility. To tackle this challenge, we developed an innovative animal model that simulates the clinical scenario of late-stage cancer complicated by sepsis and designed a sialic acid (SA)-modified paclitaxel (PTX) liposome (PTX-SAL). This formulation specifically targets overactivated peripheral blood neutrophils (PBNs) by binding to L-selectin on their surface. It effectively eliminates hyperactive neutrophils and blocks their migration, thus reducing infiltration into tumor and inflammation sites. In sepsis and melanoma mouse models, PTX-SAL demonstrated superior therapeutic efficacy and a favorable safety profile. Notably, in the late-stage tumor model with sepsis, PTX-SAL significantly improved survival rates, with a 72-hour survival rate of 66.7%. In stark contrast, the PTX solution (PTX-S) group exhibited accelerated mortality, with all animals succumbing within 24h, highlighting the detrimental effects of PTX-S's non-selective cytotoxicity on immune cells. These findings underscore the superior long-term safety and therapeutic advantage of nanomedicines like PTX-SAL over conventional drug formulations. In summary, SA-modified nanomedicines offer a dual benefit by targeting and eliminating inflammatory neutrophils, addressing both tumor progression and sepsis, and significantly reducing mortality in preclinical models. This innovative strategy fills a critical gap in the treatment of advanced cancer complicated by sepsis.

Multifunctional nanoparticles confers both multiple inflammatory mediators scavenging and macrophage polarization for sepsis therapy

Multifunctional nanoparticles confers both multiple inflammatory mediators scavenging and macrophage polarization for sepsis therapy

P-2237. Mortality and Causative Pathogens of Sepsis Differ by Molecular Phenotype in a Secondary Analysis of MARS

Abstract Background Heterogeneity of host response has been a barrier to identifying novel therapies in sepsis. Two molecular phenotypes of critical illness, called the Hyperinflammatory and Hypoinflammatory, have been identified in multiple cohorts of sepsis and ARDS ( >12,000 patients), with divergent biology, clinical course, and responses to therapy1. We evaluated whether these phenotypes were identifiable in MARS-- a large observational cohort of critically ill patients-- and whether the pathogens present in each phenotype differed. Methods MARS recruited critically ill patients from two Dutch ICUs. Only patients meeting sepsis or ARDS diagnostic criteria were included for this analysis. We applied latent class analysis (LCA) to vital signs, clinical laboratory values, and protein biomarkers from Day 1 of ICU admission in 1,485 patients. LCA models with 1-5 classes were fitted. We assigned class membership using the best fitting model and compared characteristics between classes. The present classes’ overlap with prior phenotypes was evaluated by comparison to an extensively validated parsimonious model,2 trained previously to classify molecular phenotypes. Results A two-class model best fit the cohort (VLMR p< .001), and the parsimonious model and multivariate profiles suggested high overlap (AUC=.929) with previously described ‘Hypoinflammatory’ (Class 1; n=895) and ‘Hyperinflammatory’ (Class 2; n=590) phenotypes (Figure 1). Bacteremia was more prevalent in the Hyperinflammatory phenotype (27.2% vs 7.8%; p< .001), with Enterobacteriaceae as the most prevalent species. For primary infection sites, lower respiratory tract was more common in the Hypoinflammatory (56% vs 36%) and abdomen more common in the Hyperinflammatory phenotype (26% vs 9%). Mortality was significantly higher in the Hyperinflammatory phenotype at both 30 days (OR=2.54, CI95%= 2.003—3.235 ) and 90 days (OR=2.41, CI95% = 1.925—3.016; both p< .001). Conclusion In MARS, we identified the previously described Hypo- and Hyperinflammatory phenotypes with divergent host response, pathogen profiles, and outcomes. These findings suggest that host phenotype signatures in part may be driven by sites of infection and pathogen species. Disclosures Lieuwe D.J. Bos, MD-PhD, Astra Zeneca: Advisor/Consultant|CSL Behring: Advisor/Consultant|Impentri: Advisor/Consultant|Novartis: Advisor/Consultant|Scailyte: Advisor/Consultant|Sobi: Advisor/Consultant Pratik Sinha, MBChB/PhD, AstraZeneca: Advisor/Consultant|Prenosis Inc: Board Member Carolyn S. Calfee, MD, Cellenkos: Advisor/Consultant|Gen1e Life Sciences: Advisor/Consultant|Janssen: Advisor/Consultant|NGMBio: Advisor/Consultant|Santhera: Advisor/Consultant|Vasomune: Advisor/Consultant

P-2007. Prognosis of COVID-19 Patients with Preexisting Dementia: Findings from a Comprehensive Multicenter Propensity-Matched Cohort Study in Brazil

Abstract Background Despite the increasing knowledge about Covid-19 manifestations, there is still a lack of studies regarding the impact of the pandemic in patients with dementia. This study aims to evaluate clinical characteristics and outcomes of patients with dementia hospitalized due to Covid-19. Methods This retrospective observational study is part of a multicentric cohort that analyzed data from 38 hospitals from 19 Brazilian cities. Patients were included if they were ≥ 60 years old and hospitalized due to laboratory-confirmed Covid-19 between March 2020 and March 2022. Demographics data, clinical characteristics at admission, laboratory findings and outcomes were collected. Patients were matched in a propensity score analysis according to the presence or absence of dementia and stratified by age, sex, number of comorbidities, hospital, and year. A logistic regression model to estimate the propensity score was employed. Results Overall, 1,556 patients were included (median age 82 [interquartile range [IQR] 76-87 years], 58.7% women). A total of 405 had dementia diagnosed in medical records or by statement. Dementia group presented a higher prevalence of dyspnoea, cough, myalgia, headache, anosmia and ageusia compared to those without dementia. At hospital admission, dementia group had a higher prevalence of delirium (38.5% vs. 22.5%; p< 0.001), fever (49.4% vs. 41.7%; p=0.009), sensory impairment (57.3% vs. 25.6%; p< 0.001) and lower frequency of invasive mechanical ventilation support (23% vs. 37.8%; p< 0.0001). Palliative care was more frequent in dementia patients when compared to controls (39.8% vs. 19.7%; p< 0.001). There were no clinically relevant differences in laboratory results. Regarding outcomes, those with dementia had shorter length of stay in hospital (7.0 vs. 9.0 days; p=0.026), lower frequency of sepsis (17.0% vs. 24.0%; p=0.005) and kidney replacement therapy (6.4% vs. 9.8; p=0.002). There was no difference observed in hospital mortality between groups. Conclusion Clinical characteristics of Covid-19 differ between older patients with and without dementia. Dementia alone cannot explain the higher short-term mortality due to Covid-19. Other risk factors such as frailty and acute morbidity should be considered. Disclosures All Authors: No reported disclosures

Advancements in Extracorporeal Therapies for Managing Sepsis: A Comprehensive Review

Sepsis remains a critical condition associated with high morbidity and mortality rates despite advances in medical care. The dysregulated host response to infection leads to systemic inflammation and multi-organ dysfunction, often exacerbated by a cytokine storm involving both proinflammatory and anti-inflammatory mediators. Extracorporeal therapies have emerged as potential adjuncts in sepsis management, aiming to mitigate the inflammatory response and support vital organ function. These therapies include various modalities such as adsorption of inflammatory mediators, removal of endotoxins and cytokine clearance using specialised filters and devices. This review explores the principles, mechanisms and clinical evidence surrounding extracorporeal therapies in sepsis, highlighting their potential benefits and current limitations. Key devices discussed include polymyxin B haemoperfusion, CytoSorb haemoadsorption, high-volume hemofiltration and novel technologies such as the oXiris membrane and Seraph-100 Microbind Affinity Blood Filter. Clinical trials and studies assessing these therapies provide insights into their efficacy in improving haemodynamics, organ function and mortality outcomes in septic patients. Despite promising results in certain trials, variability in patient responses and conflicting evidence necessitate further research to refine treatment protocols and optimise patient selection criteria for extracorporeal therapies in sepsis.

Safety and efficacy of cellular therapy with mesenchymal stromal cells in sepsis, meta-analysis

BackgroundSepsis is a major cause of death in hospitalised patients. Dysregulated immune response is the driving pathophysiologic phenomenon underlying tissue damage and organ failure. Due to immune-modulatory properties of mesenchymal stromal cells (MSCs) several trials experimented their efficacy in sepsis. In-vitro and preclinical studies are quite promising however, clinical trials showed inconsistent results.Methods and resultsWe gathered available evidence in a meta-analysis to figure out if clinical advantage of cellular therapy in sepsis. Eleven trials were included with total of 360 patients, 191 received MSCs and 169 as control. The overall mortality was 0.248 with 95% CI 0.191–0.316. Relative to control, mortality Odds ratio (OR) was 0.54, 95% CI 0.294–1.006 and P = 0.05. Frequent MSCs infusions showed better survival, OR = 0.3, 95% CI 0.1–0.87 and P = 0.03. While survival in the cohort that received infrequent MSCs infusions was comparable with the control, OR = 0.7, 95% CI 0.35–1.41 and P = 0.3. Also, survival benefit was associated with the 1 × 106 cell/kg dose, OR = 0.31, 95% CI 0.14–0.68 and P = 0.004. While the cohort that received higher doses had OR 1.22, 95% CI 0.54–2.75 and P = 0.6. Length of hospitalisation in the MSCs cohort was significantly shorter. The standardized difference in means (d) was − 0.443, 95% CI − 0.743 to − 0.144, P = 0.004. Also, MSCs therapy was associated with significantly shorter ICU stay, d = − 0.349 with 95% CI of − 0.647 to − 0.051 and P = 0.022. Furthermore, MSCs therapy was associated with significant reduction of the proinflammatory cytokines IL-6 and IL-8 but non-significant increase of the anti-inflammatory cytokine IL-10.ConclusionCellular therapy with MSCs is a promising therapeutic modality in sepsis. Positive effects are mainly associated with frequent infusions and the dose of 1 × 106 cell/kg. Larger scale studies are needed to address the pending questions about the optimal indications and cell manipulation conditions.

Albumin-based delivery systems: Recent advances, challenges, and opportunities.

Albumin and albumin-based biomaterials have been explored for various applications, including therapeutic delivery, as therapeutic agents, as components of tissue adhesives, and in tissue engineering applications. It has been approved as an albumin nanoparticle containing paclitaxel (Abraxane®), as an albumin-binding peptide (Victoza®), and as a glutaraldehyde-crosslinked tissue adhesive (BioGlue®). Albumin is also approved as a supportive therapy for various conditions, including hypoalbuminemia, sepsis, and acute respiratory distress syndrome (ARDS). However, no other new albumin-based systems in a hydrogel format have been used in the clinic. A review of publicly available clinical trials indicates that no new albumin drug delivery formats are currently in the clinical development pipeline. Although albumin has shown promise as a carrier of therapeutics for various diseases, including diabetes, cancers, and infectious diseases, its potential for treating blood-borne diseases such as HIV and leukemia has not been translated. This review offers a perspective on the use of albumin-based drug delivery systems for a broader range of disease applications, considering the protein properties and a review of the currently approved albumin-based technologies. This review supports ongoing efforts to advance biomedical research and clinical interventions through albumin-based delivery systems.

Granulocyte and Monocyte Adsorption Therapy in Patients With Sepsis: A Feasibility Study.

The pathogenesis of sepsis is thought to be linked to a dysregulated immune response, particularly that involving neutrophils. We have developed a granulocyte adsorption column as a "decoy organ," which relocates the massive inflammation in organs in the body to a blood purification column. This study was conducted to assess the safety and experimental effectiveness of granulocyte monocyte adsorption apheresis-direct hemoperfusion (G1-DHP) in the treatment of patients with sepsis, using a prospective, multicenter design. The study included patients diagnosed with sepsis and with an APACHE II score ranging from 17 to 34. A total of five G1-DHP were performed within 3 days of patient enrollment. The primary endpoint was the change in sequential organ failure assessment (SOFA) score from enrollment to 7 days, and the safety endpoints were adverse events and mortality at 28 days. G1-DHP was performed on 82 patients. The median (interquartile range) SOFA score decreased from 10 (8-11) to 4 (3-7) after 7 days (n = 70; p < 0.01). Granulocytes, mainly neutrophils, were adsorbed, and the neutrophil-to-lymphocyte ratio significantly improved (p < 0.01). Notable improvements were observed in the SOFA scores for circulation and renal function. The acute physiology and chronic health evaluation II score of the 77 patients evaluated for mortality was 27, and the 28-day mortality rate was 7.8%. This study confirmed that G1-DHP can be safely used as an adjunct to standard sepsis treatment regimens. Although further investigations are required, G1-DHP is a promising supplemental therapy for sepsis. jRCT1080225183 (Japan Registry of Clinical Trials identifier).

Design and Synthesis of Hederagenin Derivatives for the Treatment of Sepsis by Targeting TAK1 and Regulating the TAK1-NF-κB/MAPK Signaling.

Sepsis is a systemic inflammatory response caused by infection and is a leading cause of death worldwide. We designed and synthesized a series of hederagenin analogues with anti-inflammatory activity. The most effective compound, 14, reduced the release of TNF-α and IL-6 in RAW264.7 cells induced by lipopolysaccharide by affecting NF-κB/MAPK signaling. It demonstrated significant protection against sepsis in vivo and ameliorated histopathological changes in the liver, lungs, and kidneys. It exhibited good safety in subacute toxicity assays. Western blotting results indicated that it reduced the generation of p-p65, p-IκB, p-p38, p-JNK, and p-ERK. Immunofluorescence assay results suggested that the compound inhibited nuclear translocation of p65 and c-Fos. It was found to target TAK1 with a novel molecular backbone, distinct from the few TAK1 inhibitors previously reported. This work provides a new lead structure for the study of TAK1 inhibitors and a potential target for TAK1 in sepsis therapy.

Carbapenem Usage in the Initial Antibiotic Therapy of Sepsis in Japanese Intensive Care Units

Carbapenem Usage in the Initial Antibiotic Therapy of Sepsis in Japanese Intensive Care Units

Author Response: Insights into Immunomodulatory Therapy for Sepsis.

How to cite this article: Ghosh I, Sangha SS, Pandey G, Srivastava A. Author Response: Insights into Immunomodulatory Therapy for Sepsis. Indian J Crit Care Med 2025;29(1):91.

EFFECTS OF MELATONIN AS ADJUVANT THERAPY IN TREATMENT OF NEONATAL SEPSIS

Background: Neonatal sepsis is a critical concern, causing significant morbidity and mortality, especially in preterm and low-birth-weight infants. Traditional treatments, including antibiotics and supportive care, often fall short in reducing high mortality rates, emphasizing the need for effective adjunct therapies. Melatonin, known for its antioxidant and anti-inflammatory properties, may offer therapeutic benefits by modulating immune responses and mitigating oxidative stress in neonatal conditions. Objective: This study evaluates the effectiveness of melatonin as an adjunct therapy in neonatal sepsis, focusing on improvements in clinical and laboratory outcomes. Methods: In this randomized controlled trial conducted at the Department of Neonatology at Children Hospital, PIMS, Islamabad from September 1, 2023, to February 28, 2024, 60 neonates diagnosed with sepsis were divided into two groups. The experimental group (Group A) received 20 mg of enteral melatonin in addition to standard care, while the control group (Group B) received standard care alone. Key metrics such as sepsis scores, C-reactive protein (CRP) levels, and complete blood counts were assessed at baseline and 48 hours post-treatment. Results: Significant improvements were observed in the melatonin group, with sepsis scores decreasing from an average of 12.2 ± 3.1 to 6.1 ± 1.8, CRP levels reducing from 12.5 mg/ml to 6.5 mg/ml, and total leukocyte counts dropping from 12,500 cells/µL to 9,800 cells/µL. The control group showed lesser improvements across these parameters. Conclusion: Melatonin shows potential as an adjunct treatment in neonatal sepsis, effectively reducing inflammation and enhancing clinical outcomes. Further research is needed to substantiate these findings and integrate melatonin into broader clinical practices.

The Role of Scavenger Receptor BI in Sepsis.

Sepsis is a life-threatening condition resulting from a dysregulated host response to infection. Currently, there is no effective therapy for sepsis due to an incomplete understanding of its pathogenesis. Scavenger receptor BI (SR-BI) is a high-density lipoprotein (HDL) receptor that plays a key role in HDL metabolism by modulating the selective uptake of cholesteryl ester from HDL. Recent studies, including those from our laboratory, indicate that SR-BI protects against sepsis through multiple mechanisms: (1) preventing nitric oxide-induced cytotoxicity; (2) promoting hepatic lipopolysaccharide (LPS) clearance and regulating cholesterol metabolism in the liver; (3) inhibiting LPS-induced inflammatory signaling in macrophages; and (4) mediating the uptake of cholesterol from HDL for inducible glucocorticoid (iGC) synthesis in the adrenal gland, which controls systemic inflammatory response. In this article, we review the roles of SR-BI in sepsis.

Clinical and Analytical Performance Evaluation of an Automated Procalcitonin Assay.

Procalcitonin (PCT) measurement is useful for guiding antibiotic therapy and risk assessment in lower respiratory infections and/or sepsis. This study evaluated clinical and analytical performance of the Vitros® Immunodiagnostic Products B·R·A·H·M·S PCT assay (Vitros PCT). Precision, limits of blank (LoB), detection (LoD), and quantitation (LoQ) were determined for Vitros PCT, along with method comparison and clinical concordance with the B·R·A·H·M·S PCT™-sensitive KRYPTOR™ assay (KRYPTOR PCT). All-cause 28-day mortality was evaluated according to the change in PCT values (ΔPCT) from day 0 through day 4 in samples from 598 intensive care unit patients with sepsis. Comparison of Vitros PCT and KRYPTOR PCT results yielded a Deming regression slope of 1.057, intercept of -0.010, and correlation coefficient (r) of 0.994. Precision analysis demonstrated within-laboratory coefficients of variation for Vitros PCT ranging from 3.1% to 6.4%. The LoD and observed LoQ were determined as 0.007 and 0.013 ng/mL, respectively. Overall agreement between assay methods was 98.5%, 98.0%, 97.4%, and 97.8%, at PCT clinical decision cutoffs of 0.100, 0.250, 0.500, and 2.00 ng/mL, respectively, with Cohen's Kappa coefficients (κ) > 0.91. ΔPCT values ≤80% vs >80% were associated with increased 28-day-all-cause mortality (P = 0.006). Vitros PCT compares well with KRYPTOR PCT, showing excellent agreement at relevant clinical decision cutoffs that have been used for antibiotic decision-making and assessment of risk for sepsis progression. ΔPCT values determined with Vitros PCT were useful for evaluation of 28-day mortality risk in patients with severe sepsis.

Mediating Role of Platelet Count Increase in Unfractionated Heparin Treatment for Sepsis Patients: A Retrospective Cohort Analysis.

Aims/Background The role of heparin in sepsis therapy has been widely debated. The controversy surrounding heparin's use as an anticoagulant in sepsis may stem from differences in sepsis definitions, study designs, timing and dosage of drug administration, treatment duration, complications, and patient severity. In this study, we aimed to determine the optimal timing and dosage of heparin in patients with sepsis, identify specific subgroups that could benefit from heparin therapy, and explore laboratory markers to assess its efficacy. Methods This retrospective cohort study was conducted using the Medical Information Mart for Intensive Care-IV dataset. Data from patients with sepsis were extracted based on the Sepsis 3.0 criteria. Patients were categorized according to heparin use. The effectiveness of early and appropriate heparin administration was assessed, and a subgroup analysis was performed to identify patients most likely to benefit from heparin therapy. Additionally, factors mediating the improvement in sepsis prognosis following heparin treatment were analyzed. Results We recruited 4149 participants who met the inclusion criteria, with an overall 28-day mortality rate of 19.5%. There were 2192 individuals in the heparin group and 1957 in the non-heparin group. After propensity score matching, heparin therapy demonstrated a significantly greater effect on reducing both 28-day and 90-day mortality compared to the non-heparin treatment (18.1% vs. 10.7%, p < 0.001; 18.8% vs. 12.6%, p < 0.001). However, the heparin group had a higher incidence of major bleeding (10.9% vs. 6.3%, p = 0.001), increased use of mechanical ventilation (54.3% vs. 45.1%, p < 0.001), and a longer intensive care unit stay (3.6 vs. 2.5 days, p < 0.001) compared to the non-heparin group. Early administration of high-dose heparin improved 28-day survival. Early and adequate heparin administration was more effective than late and insufficient dosing (p < 0.01), except in patients with sepsis who had low white blood cell counts, alkalosis, or reduced platelet counts. The increase in platelet count had a significant mediating effect on the entire cohort (p < 0.001 for the causal mediation effect), with a mediation proportion of 14%. Conclusion Early and adequate heparin administration can significantly improve the prognosis of sepsis. An increase in platelet count may serve as a potential indicator of the effectiveness of heparin therapy in sepsis.

Heparin in sepsis: current clinical findings and possible mechanisms.

Sepsis is a clinical syndrome resulting from the interaction between coagulation, inflammation, immunity and other systems. Coagulation activation is an initial factor for sepsis to develop into multiple organ dysfunction. Therefore, anticoagulant therapy may be beneficial for sepsis patients. Heparin possesses a variety of biological activities, so it has a broad prospect in sepsis. Previous studies suggested that patients with sepsis-induced disseminated intravascular coagulation and high disease severity might be suitable for anticoagulant therapy. With the development of artificial intelligence (AI), recent studies have shown that patients with severe coagulation activation represent the targeted patients for anticoagulant therapy in sepsis. However, it remains necessary to accurately define the relevant biomarkers indicative of this phenotype and validate their clinical utility by large randomized controlled trials (RCTs). Analyses of data from early small RCTs, subgroup analyses of large RCTs and meta-analyses have collectively suggested that anticoagulant therapy, particularly the use of heparin, may be an effective approach for managing sepsis patients. Concurrently, debate persists regarding the optimal selection of anticoagulants, proper timing, usage and dosage of administration that should be employed to assess treatment efficacy. The primary mechanisms of heparin are acting on heparan sulfate, histones, high mobility group box 1 and heparin-binding protein, which interfere with the regulation of inflammation, vascular permeability, coagulation, endothelial function and other biological activities. However, the underlying pathophysiological processes mediating the potential therapeutic effects of heparin in the context of sepsis remain incompletely understood and warrant additional rigorous investigation to establish the mechanism more conclusively.

FUNCTIONAL IMMUNOPHENOTYPING FOR PRECISION THERAPIES IN SEPSIS.

Sepsis remains a significant cause of morbidity and mortality worldwide. Although many more patients are surviving the acute event, a substantial number enters a state of persistent inflammation and immunosuppression, rendering them more vulnerable to infections. Modulating the host immune response has been a focus of sepsis research for the past 50 years, yet novel therapies have been few and far between. Although many septic patients have similar clinical phenotypes, pathways affected by the septic event differ not only between individuals but also within an individual over the course of illness. These differences ultimately impact overall immune function and response to treatment. Defining the immune state, or endotype, of an individual is critical to understanding which patients will respond to a particular therapy. In this review, we highlight current approaches to define the immune endotype and propose that these technologies may be used to "prescreen" individuals to determine which therapies are most likely to be beneficial.

Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis

Sepsis is a heterogeneous and imprecise disorder characterized by aberrant response to infection which has been accredited for detrimental impact on immune homeostasis. Recently, macrophage metabolism has been recognized as attractive targets to develop novel immunomodulatory therapy for sepsis research. However, the fine-tuning regulators dictating macrophage functions and the specific mechanisms underlying macrophage metabolic reprogramming remain largely obscure. Sphingosine-1-phosphate (S1P), a metabolic mediator of sphingolipid catabolism, predominantly formed through sphingosine kinase 1 (SphK1) catalyzing, mediates inflammation in sepsis by binding to S1P receptor 3 (S1PR3) expressed in macrophages. Here we demonstrate that SphK1/S1PR3 axis was upregulated in lipopolysaccharide (LPS)-induced macrophages and septic mice lungs, cascading the activation of proglycolytic signaling such as HIF-1α, HK2 and PFKFB3. Targeted inhibition of Sphk1 by PF-543 effectively abrogated upregulated SphK1/S1PR3 axis in vitro and in vivo. In addition, PF-543 significantly suppressed sepsis-related inflammation and multi-organ injury in vivo. Furthermore, PF-543 not only blunted key glycolytic enzymes HIF-1α, HK2, and PFKFB3 in LPS-treated macrophages but also inhibited HK2 and PFKFB3 in septic mice. Silencing or inhibiting SphK1 tempered pro-inflammatory M1 macrophages while boosted anti-inflammatory M2 macrophages. Intriguingly, S1PR3 knockdown proficiently dampened glycolysis-associated markers, retrieved LPS-modulated M1/M2 polarization and attenuated NF-κB p65 activation. In conclusion, our study provides the first evidence that PF-543 orchestrates proportional imbalance of macrophage polarization and the Warburg effect in a SphK1/S1PR3 dependent manner during sepsis, mitigating both hyperinflammation and multi-organ failure, adding a novel puzzle piece to pharmacologically exploitable therapy for sepsis.