Daily Sepsis Research Analysis
Three impactful sepsis-related studies span translational genomics, neuroimmune mechanisms, and neonatal prevention. Targeting enhancer RNAs to suppress TNFα mitigated inflammation across models including LPS-induced sepsis; spinal astrocyte α2A adrenoceptor activation by dexmedetomidine protected against sepsis-induced cardiomyopathy in mice; and a randomized trial showed oropharyngeal colostrum reduced sepsis in preterm neonates.
Summary
Three impactful sepsis-related studies span translational genomics, neuroimmune mechanisms, and neonatal prevention. Targeting enhancer RNAs to suppress TNFα mitigated inflammation across models including LPS-induced sepsis; spinal astrocyte α2A adrenoceptor activation by dexmedetomidine protected against sepsis-induced cardiomyopathy in mice; and a randomized trial showed oropharyngeal colostrum reduced sepsis in preterm neonates.
Research Themes
- eRNA-directed regulation of TNFα as an anti-inflammatory therapeutic strategy
- Neuroimmune pathways in sepsis-induced cardiomyopathy and α2A-adrenergic modulation
- Low-cost neonatal sepsis prevention via oropharyngeal colostrum
Selected Articles
1. Targeting eRNA-Producing Super-Enhancers Regulates TNFα Expression and Mitigates Chronic Inflammation in Mice and Patient-Derived Immune Cells.
Deleting a TNFα-regulating enhancer (TNF-9) and knocking down its eRNA reduced TNFα output, ameliorating inflammation across rheumatoid arthritis, psoriasis, and LPS-induced sepsis models. Antisense oligonucleotides against mouse and human TNF-9 eRNAs suppressed TNFα, supporting eRNA-targeted therapeutics.
Impact: This study provides a mechanistically novel, targetable layer of gene regulation (eRNA) to modulate TNFα, a central mediator in sepsis and chronic inflammation.
Clinical Implications: While preclinical, eRNA-directed antisense strategies could complement or replace protein-targeted anti-TNF approaches, offering a new class of anti-inflammatory therapies for sepsis and autoimmune diseases.
Key Findings
- Deletion of a TNFα-regulating enhancer (TNF-9) reduced Tnfα levels and improved outcomes in RA, psoriasis, and LPS-induced sepsis models.
- Integrative epigenomic/transcriptomic analyses identified additional LPS-responsive, eRNA-producing enhancers regulating inflammatory responses.
- ASO-mediated knockdown of TNF-9 eRNA decreased TNFα in mouse macrophages and reduced inflammatory symptoms; human homolog eRNA inhibition similarly lowered TNFα.
Methodological Strengths
- Multi-system validation including genetic knockout mice, ASO perturbation, and patient-derived human immune cells
- Integrative epigenomic and transcriptomic mapping to identify functional, LPS-responsive enhancers
Limitations
- Preclinical study without in-human efficacy or safety data
- ASO delivery, biodistribution, and off-target effects remain to be optimized for systemic inflammatory indications
Future Directions: Develop systemic delivery and pharmacokinetic strategies for eRNA-targeting ASOs, evaluate efficacy in clinically relevant sepsis models, and initiate early-phase clinical trials.
Chronic inflammatory diseases are driven by immune cell dysregulation and overproduction of pro-inflammatory molecules, such as tumor necrosis factor alpha (TNFα). Super-enhancers (SEs) and their enhancer RNAs (eRNAs) are critical gene expression regulators and offer therapeutic potential beyond protein-targeting approaches. This work hypothesizes that targeting eRNAs could reduce chronic inflammation by modulating TNFα expression. This work generates TNF-9 knockout (KO) mice by deleting a Tnfα-regulating enhancer region. These mice exhibit significantly reduced Tnfα levels, improved disease outcomes, and diminished immune cell activation in models of rheumatoid arthritis (RA), psoriasis, and lipopolysaccharide (LPS)-induced sepsis. Integrative epigenomic and transcriptomic analysis identify additional LPS-responsive, eRNA-producing enhancers as therapeutic targets. Antisense oligonucleotide (ASO)-mediated knockdown of TNF-9 eRNA in mouse macrophages demonstrate decreased Tnfα expression and alleviated RA symptoms. Furthermore, ASO-mediated inhibition of the eRNA of the human homolog of TNF-9 similarly reduce TNFα levels. These findings support eRNA-targeted interventions as potential treatment for chronic inflammatory diseases.
2. The Effect of Oral Immunotherapy on Preterm Neonates: A Promising Adjuvant Therapy in a Clinical Trial Study.
In a three-arm randomized controlled trial of 96 preterm neonates, oropharyngeal colostrum given for 3 or 10 days reduced sepsis rates, length of hospital stay, and time to full enteral feeding versus usual care. NEC incidence did not differ, and greater daily weight gain was observed particularly with 10-day administration.
Impact: Provides randomized evidence for a simple, low-cost intervention that reduces sepsis in a highly vulnerable population.
Clinical Implications: Oropharyngeal colostrum can be considered as an adjunct early immunotherapy to reduce neonatal sepsis and expedite feeding milestones, potentially decreasing antibiotic exposure and length of stay.
Key Findings
- Both 3-day and 10-day oropharyngeal colostrum significantly reduced sepsis rates compared with control (p < 0.001).
- Hospital stay and time to full enteral intake were significantly shorter in colostrum groups versus control (p < 0.001).
- No significant difference in NEC incidence among groups (p = 0.314); daily weight gain improved, especially in the 10-day group (p = 0.028).
Methodological Strengths
- Prospective randomized controlled design with three parallel arms
- Clinically meaningful endpoints including sepsis, feeding milestones, and length of stay
Limitations
- Single-center, relatively small sample size without blinding
- Not powered to detect differences in NEC or long-term outcomes
Future Directions: Multicenter, adequately powered RCTs with standardized protocols to assess optimal dosing/duration, long-term neurodevelopment, and antibiotic stewardship outcomes.
INTRODUCTION: Breastfeeding is currently recommended as the optimal and initial feeding option for all newborns, as it protects against illness and reduces neonatal mortality. Furthermore, premature infants exhibit reduced swallowing ability and an increased risk of developing necrotizing enterocolitis (NEC), which may hinder suckling and delay the initiation of enteral feeding. Our aim was to investigate the effects of oropharyngeal colostrum delivery in preterm neonates <34 weeks of gestation on hospital outcomes, specifically differences in hospital stay between neonates who received colostrum for 3 days and those who did not. METHODS: This prospective, interventional, randomized controlled trial enrolled ninety-six preterm neonates, who were allocated into three groups: group A, neonates who received oropharyngeal colostrum for 3 days along with routine care; group B, neonates who received oropharyngeal colostrum for 10 days along with routine care; and group C, neonates who received routine care only. The Kruskal-Wallis test was used to compare medians among the three groups. Associations between categorical variables were analyzed using the chi-squared test and Monte Carlo test. RESULTS: The two groups that received colostrum showed significantly reduced median hospital stays, time to reach full enteral intake, and sepsis rates compared to the control group (p < 0.001). A significant difference in daily weight gain was observed between groups, particularly between the control group and neonates who received colostrum for 10 days (p = 0.028). Regarding the incidence of NEC, no significant difference was found among the groups (p = 0.314). CONCLUSION: Oropharyngeal colostrum may be considered a potential oral immunotherapy.
3. Activation of Spinal Astrocyte α2A Adrenoceptors Protects Against Sepsis-Induced Heart Injury Through Inhibition of GABAergic Neuronal Necroptosis.
In a CLP mouse model, sepsis induced necroptosis in spinal GABAergic neurons and reduced cardiac function. Necrostatin-1 preserved neurons and reversed cardiac dysfunction, while dexmedetomidine activation of α2A adrenoceptors in spinal astrocytes suppressed inflammatory signaling and protected the heart.
Impact: Reveals a neuroimmune mechanism for sepsis-induced cardiomyopathy and identifies α2A-adrenergic signaling as a modifiable target using a clinically available drug.
Clinical Implications: Supports investigation of dexmedetomidine’s cardio-protective effects and α2A-AR–targeted strategies in sepsis, with careful evaluation of dosing, timing, and neurological safety.
Key Findings
- Sepsis (CLP) reduced cardiac function and induced necroptosis marker co-expression (RIPK1, RIPK3, MLKL) in spinal GABAergic neurons.
- Necrostatin-1 preserved neurons and reversed sepsis-associated cardiac dysfunction.
- Dexmedetomidine (α2A-AR agonist) inhibited astrocyte inflammatory mediators (C3, IL-6, TNF-α), reduced neuronal damage, and protected cardiac function.
Methodological Strengths
- In vivo CLP model with multimodal assessments (echocardiography, histology, molecular markers)
- Targeted intrathecal pharmacology and RNAi to dissect spinal neuroimmune pathways
Limitations
- Preclinical mouse study; translatability of intrathecal interventions to human sepsis is uncertain
- Potential confounding by systemic sedative effects of dexmedetomidine needs careful control
Future Directions: Clinical studies to evaluate dexmedetomidine’s cardiac outcomes in sepsis and mechanistic biomarkers; exploration of selective α2A-AR modulators.
The peripheral immune system contributes to the development of sepsis-induced cardiomyopathy. However, the underlying mechanisms linking central immune cells and neurons to sepsis-induced cardiomyopathy remain to be clarified. Here, acute sepsis is induced by cecal ligation puncture (CLP), and pharmacological and RNAi interventions are administered to the thoracic spinal cord via intrathecal injection. Echocardiography and histology confirm reduced cardiac function following CLP. Sepsis-induced spinal cord changes involved neuronal activation and loss with decreased gamma-aminobutyric acid (GABA) levels. Necroptosis effector genes are markedly upregulated with increased RIPK1, RIPK3, and MLKL co-expression evident in spinal GABAergic neurons, while administration of the necroptosis inhibitor Necrostatin-1 substantially preserves neurons and reverses sepsis-associated cardiac functional changes. Sepsis triggers increased C3, IL-6 and TNF-α in spinal astrocytes, while administration of the α2A-adrenergic receptor (α2-AR) agonist dexmedetomidine blocked inflammatory factor production, neuronal damage, and cardiac dysfunction. These findings suggest that sepsis-induced cardiomyopathy arises from a neuroimmune interplay involving spinal astrocyte activation, GABAergic neuronal necroptosis, and cardiac damage driven by sympathetic hyperstimulation.