Daily Sepsis Research Analysis
Analyzed 8 papers and selected 3 impactful papers.
Summary
Mechanistic advances highlight innate immune modulation in sepsis: epithelial-derived BDNF directly antagonizes TLR4, and a dodecapeptide derivative (BDP-12) shows anti-inflammatory activity in acute lung injury models. In parallel, neutrophil-mimetic nanoscavengers are engineered to dismantle NETs, neutralize ROS, and tune cGAS-STING signaling in septic AKI, while a pragmatic limited-sampling strategy enables polymyxin B TDM across ICU contexts including RRT and ECMO.
Research Themes
- Innate immune modulation and TLR4 antagonism in sepsis-related lung injury
- Nanomedicine targeting NETs/ROS and cGAS-STING in septic AKI
- Precision dosing and limited sampling strategies for antimicrobials in critical care
Selected Articles
1. Brain-derived neurotrophic factor and the derived dodecapeptide function as Toll-like receptor 4 antagonists in acute lung injury.
Using ALI and sepsis models, the study shows epithelial BDNF is reduced, inversely tracks inflammation, and directly antagonizes macrophage TLR4. A BDNF-derived dodecapeptide (BDP-12) preserves TLR4 antagonism and anti-inflammatory activity without pro-proliferative effects, nominating it as a therapeutic lead.
Impact: Reveals a previously unrecognized receptor target of BDNF in innate immunity and provides a minimal peptide (BDP-12) with in vivo efficacy, offering a translatable anti-inflammatory strategy for sepsis-related lung injury.
Clinical Implications: TLR4 antagonism via BDP-12 could represent a new class of host-directed therapy to mitigate macrophage-driven inflammation in acute lung injury secondary to sepsis, pending pharmacokinetic and safety evaluation.
Key Findings
- BDNF is reduced in pulmonary epithelial cells and inversely correlates with inflammatory responses in ALI and sepsis models.
- Augmenting BDNF alleviates inflammatory lung injury, but this protection is lost in macrophage-deleted mice.
- Proteomics identifies macrophage TLR4 as a direct binding target of BDNF; the BDNF fragment aa104-115 mediates this interaction.
- A synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4 antagonism and anti-inflammatory effects without pro-proliferative side effects.
Methodological Strengths
- Integrated in vivo ALI/sepsis models with in vitro macrophage assays to establish causality.
- Proteomics-based receptor identification and peptide mapping pinpointing the BDNF–TLR4 interaction site.
- Use of macrophage-deleted mice to demonstrate cell-type specificity of BDNF’s protective effects.
Limitations
- Preclinical models without human validation; translational efficacy and safety remain to be established.
- Potential off-target effects and immunogenicity of BDP-12 were not fully characterized.
- Dose–response, pharmacokinetics, and long-term outcomes were not reported.
Future Directions: Advance BDP-12 to pharmacokinetic, toxicology, and large-animal studies; evaluate efficacy in clinically relevant sepsis-induced lung injury models and explore biomarkers for patient stratification.
The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-established acute lung injury (ALI) and sepsis models, we demonstrate that brain-derived neurotrophic factor (BDNF), a key NTF, is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and further proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. In conclusion, our findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlights BDP-12 as a potential therapeutic agent for acute inflammatory diseases.
2. Neutrophil-Mimetic Nanoscavengers Target the Inflammatory Microenvironment to Eliminate NETs/ROS and Immunomodulate cGAS-STING Signaling in Septic AKI.
The authors engineer neutrophil-mimetic nanoscavengers (MD@NM) with a DNase-1-loaded Mn catalytic core to target the inflammatory microenvironment in septic AKI. The platform is designed to dismantle NETs, neutralize ROS, and modulate cGAS-STING signaling, addressing multiple intertwined drivers of renal injury.
Impact: Introduces a biomimetic, multi-pronged nanoplatform that converges NETs degradation, ROS scavenging, and innate immune pathway modulation—an innovative approach for SAKI.
Clinical Implications: If validated in preclinical efficacy and safety studies, this nanoplatform could enable precision, host-directed therapy for septic AKI by concurrently targeting NETs, oxidative stress, and cGAS-STING signaling.
Key Findings
- Engineered neutrophil-mimetic nanoscavengers (MD@NM) to target the inflammatory microenvironment of septic AKI.
- MD@NM incorporates a DNase-1-loaded Mn catalytic core to dismantle NETs and scavenge ROS.
- The design aims to immunomodulate the cGAS-STING pathway in parallel with NETs/ROS elimination.
Methodological Strengths
- Biomimetic design leveraging neutrophil-like features to enhance disease-site targeting.
- Multi-modal mechanism integrating NETs degradation, ROS scavenging, and innate immune pathway modulation.
Limitations
- Efficacy, biodistribution, and safety data are not detailed in the abstract; translational feasibility remains to be demonstrated.
- Potential immunogenicity and clearance mechanisms of the nanoplatform require thorough evaluation.
Future Directions: Perform comprehensive in vivo efficacy, PK/PD, toxicity, and immunogenicity studies; compare against standard-of-care and evaluate synergy with antibiotics in sepsis models.
Sepsis-associated acute kidney injury (SAKI) remains a life-threatening condition with limited therapeutic options, primarily driven by rampant oxidative stress, inflammatory dysregulation. Importantly, aberrant formation of neutrophil extracellular traps (NETs) and sustained innate immune activation further exacerbate renal injury, highlighting the need for strategies that precisely modulate these intertwined pathological mechanisms. Here, we present neutrophil-mimetic nanoscavengers (MD@NM) that comprise a catalytic core of DNase-1-loaded Mn
3. Validation of limited sampling strategies for polymyxin B therapeutic drug monitoring in critical care.
Using PK models built from sepsis, RRT, and ECMO cohorts and 1000 simulated individuals per group, the authors show that three-point limited sampling can accurately predict polymyxin B exposure (AUC). Bayesian approaches underpin a pragmatic TDM pathway across complex ICU settings.
Impact: Provides a feasible, low-burden TDM solution for polymyxin B across ICU modalities, potentially improving efficacy–toxicity balance where extracorporeal supports alter PK.
Clinical Implications: Three-sample LSS could be adopted to estimate AUC for PMB in patients on RRT or ECMO, streamlining TDM and informing dose adjustments without intensive sampling schedules.
Key Findings
- Developed two-compartment PK models from 27 sepsis patients, 11 on RRT, and 14 on ECMO.
- Simulated 1000 individual PK profiles per group to evaluate limited sampling strategies.
- Three-timepoint LSS enabled precise prediction of polymyxin B AUC using a Bayesian approach.
Methodological Strengths
- Inclusion of heterogeneous ICU populations (sepsis, RRT, ECMO) to enhance generalizability.
- Bayesian limited sampling modeling with extensive simulation (1000 virtual individuals/group).
Limitations
- Small empirical datasets for model building and no external prospective validation reported.
- Abstract truncation limits insight into accuracy metrics and practical sampling times.
- Potential center-specific PK factors may limit transportability.
Future Directions: Prospectively validate LSS in multicenter ICU cohorts, define optimal sampling windows, and link AUC targets to microbiological and toxicity outcomes.
OBJECTIVES: To validate previously developed limited sampling strategies (LSS) for polymyxin B (PMB) therapeutic drug monitoring (TDM) in critically ill patients with sepsis, on renal-replacement therapy (RRT) and on extracorporeal membrane oxygenation (ECMO). PATIENTS AND METHODS: Two-compartmental pharmacokinetic (PK) models were produced in 27 patients with sepsis, 11 patients on RRT, as well as 14 patients on ECMO, and then used to simulate 1000 individual PK curves for each group. Limited sampling strategies (LSS) using 1-3 timepoints points were developed using Bayesian approach. RESULTS: The LSSs based on 3 timepoints allowed precise prediction of PMB AUC CONCLUSIONS: The C