Daily Ards Research Analysis
Analyzed 5 papers and selected 3 impactful papers.
Summary
Analyzed 5 papers and selected 3 impactful articles.
Selected Articles
1. Nimbolide ameliorates ARDS and ulcerative colitis by disrupting NLRP3 inflammasome activation.
This preclinical study identifies Nimbolide as a selective NLRP3 inflammasome inhibitor that suppresses both NF-κB–dependent priming and inflammasome assembly by binding Lys565 in NLRP3. Nimbolide reduced Caspase-1 activation, IL-1β release, and pyroptosis in macrophages and improved pathology in LPS-induced ARDS and DSS-colitis mouse models, with efficacy dependent on NLRP3.
Impact: Provides a mechanistically detailed, dual-action small molecule inhibitor of NLRP3 with an identified binding residue and in vivo efficacy in ARDS models—advances translational potential for inflammasome-targeted therapies.
Clinical Implications: Preclinical evidence supports Nimbolide as a candidate for development into an NLRP3-targeted therapy for ARDS and other NLRP3-driven inflammatory disorders; however, human safety, pharmacokinetics, and efficacy must be established before clinical application.
Key Findings
- Nimbolide dose-dependently inhibits NLRP3 inflammasome activation, blocking Caspase-1 cleavage, IL-1β release, and pyroptosis in macrophages.
- Nimbolide selectively targets NLRP3 (no significant inhibition of non-NLRP3 inflammasomes) and directly interacts with Lys565 in the NLRP3 NACHT domain.
- Nimbolide administration reduces inflammation and pathological damage in LPS-induced ARDS and DSS-induced ulcerative colitis models; effects are NLRP3-dependent (validated in Nlrp3-knockout mice).
Methodological Strengths
- Comprehensive mechanistic pipeline: screening → cellular assays → molecular target identification → in vivo disease models
- Use of genetic validation (Nlrp3-knockout mice) to demonstrate target-dependent efficacy
Limitations
- Preclinical study limited to murine models and macrophage/ cell assays; human cell and clinical data are lacking
- Pharmacokinetics, toxicity, dosing, and formulation for human use were not addressed
Future Directions: Optimize nimbolide analogs for potency/PK, perform GLP toxicity studies, test in human primary cells and ex vivo lung tissue, and advance to early-phase clinical trials for ARDS or other NLRP3-driven diseases.
Excessive activation of the NLRP3 inflammasome drives the pathogenesis of diverse inflammatory diseases. However, the clinical application of NLRP3 inflammasome inhibitors remains a significant challenge. Here, we screen a natural product library of 126 compounds and identify Nimbolide (NIM), a triterpenoid from Azadirachta indica, as a potent suppressor of IL-1β secretion. Cellular studies reveal that NIM dose-dependently suppresses NLRP3 inflammasome activation, thereby the blocking Caspase-1 cleavage, IL-1β release, and pyroptosis in macrophages. Importantly, NIM exhibits high selectivity for NLRP3 inflammasome, showing no significant inhibition of non-NLRP3 inflammasomes. Mechanistically, NIM exerts dual effects by suppressing both NF-κB-dependent priming and NLRP3 inflammasome assembly. Molecular investigations reveal that NIM directly targets the Lys565 within the NLRP3 NACHT domain, thereby hindering inflammasome assembly. Using male C57BL/6 and Nlrp3-knockout mice, we demonstrate that NIM administration effectively alleviates inflammation and pathological damage in models of LPS-induced acute respiratory distress syndrome (ARDS) and DSS-induced ulcerative colitis.
2. Remimazolam alleviates acute lung injury via translocator protein mediated inhibition of the NF-κB pathway.
Remimazolam reduced neutrophil infiltration and pro-inflammatory cytokine production, and preserved endothelial/epithelial junction integrity in LPS-induced ALI models. Mechanistic studies (network pharmacology, RNA-seq, cell assays) indicate REM inhibits IκB-α phosphorylation and NF-κB activation via the translocator protein (TSPO); TSPO ligands or NF-κB agonists reverse REM's protective effects.
Impact: Demonstrates a repurposing opportunity for an approved ultra-short-acting sedative with a defined TSPO→NF-κB mechanism that preserves barrier function in ALI models—translationally attractive given existing clinical safety data for remimazolam.
Clinical Implications: Provides rationale to evaluate remimazolam in early-phase clinical studies for ALI/ARDS (dose, timing relative to lung injury), particularly investigating anti-inflammatory effects separate from sedative properties; careful safety and PK/PD studies in critically ill patients are needed.
Key Findings
- REM attenuated neutrophil infiltration and preserved inter-endothelial/epithelial junction integrity in LPS-induced ALI mice.
- Network pharmacology and RNA-seq implicated NF-κB pathway and cellular junction regulation as REM targets; REM inhibited IκB-α phosphorylation in vitro and in vivo.
- TSPO involvement: TSPO ligand reversed REM-mediated inhibition of IκB-α phosphorylation and inflammatory responses; NF-κB agonist abrogated REM's protective effects, supporting a TSPO→NF-κB mechanism.
Methodological Strengths
- Multi-layered approach: in vivo LPS model, RNA-seq, network pharmacology, and validation in human/murine cell lines
- Mechanistic interrogation using pharmacologic agonists/antagonists to demonstrate TSPO and NF-κB dependence
Limitations
- Preclinical only; sedative effects vs anti-inflammatory effects separation needs clinical investigation.
- Dosing regimens and safety in critically ill patients not evaluated; effects in viral ARDS/sepsis contexts unknown.
Future Directions: Conduct PK/PD and safety studies of remimazolam in critically ill patients, explore non-sedative dosing windows for anti-inflammatory benefit, and design early-phase trials assessing lung injury biomarkers and clinical outcomes.
BACKGROUND: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by inflammatory dysregulation and alveolar-capillary barrier damage, leading to high mortality. Remimazolam (REM), an ultra-short-acting benzodiazepine, shows anti-inflammatory effects preclinically; however, its therapeutic role and mechanism in ALI/ARDS remain unclear. This study aimed to explore the mechanism underlying the effects of REM against ALI/ARDS. METHODS: An ALI model was established by lipopolysaccharide (LPS) challenge in mice to evaluate REM's efficacy. Then, network pharmacology and RNA sequencing were performed to identify the potential mechanism on REM against ALI/ARDS, which were further validated using LPS-stimulated human umbilical vein endothelial cells, murine lung epithelial cells, and ALI murine model. RESULTS: REM significantly attenuated neutrophil infiltration in the lungs of ALI mice. Integrated network pharmacology and RNA sequencing analyses revealed that the targets of REM in ALI/ARDS were significantly enriched in the regulation of inflammatory responses, cellular junctions, and the NF-κB pathway.
3. Preferential boosting of SARS-CoV-2 Omicron lineage-specific immune responses by monovalent XBB.1.5 vaccination.
In healthcare workers, monovalent XBB.1.5 boosting preferentially increased neutralizing and functional antibodies against contemporaneous Omicron subvariants but titers remained lower than against the ancestral strain. Vaccination recalled broadly S-reactive B-cells but generated limited de novo XBB.1.5-specific B-cell clones; T-cell responses were broadly cross-reactive across variants.
Impact: Provides real-world immune-profiling data that inform booster vaccine design and expectations about imprinting (immune history) limiting de novo variant-specific B-cell induction—important for vaccine policy and booster strategy.
Clinical Implications: Suggests monovalent variant boosters can enhance variant-lineage recognition but may not fully redirect immunity away from ancestral spike responses; vaccine policy should consider imprinting effects and possibly alternative approaches (multivalent, adjuvants) to induce broader de novo responses.
Key Findings
- Neutralizing antibodies against contemporaneous Omicron subvariants were preferentially boosted by XBB.1.5 vaccination but remained lower than titers against the ancestral strain.
- Vaccination recalled broadly S-reactive memory B-cells with limited de novo induction of XBB.1.5-specific B-cell clones, indicating imprinting by prior ancestral S exposure.
- T-cell responses were broadly cross-reactive across SARS-CoV-2 variants tested, suggesting preserved cellular immunity despite antigenic shift.
Methodological Strengths
- Comprehensive immune profiling (antibody, B- and T-cell assays) longitudinally up to 6 months post-boost
- Functional antibody assays including neutralization and ADCC-related measures
Limitations
- Sample size not specified in the abstract; generalizability to older or immunocompromised populations unclear.
- Observational immunoprofiling lacks direct clinical efficacy endpoints (infection, severe disease) post-boost.
Future Directions: Larger, diverse cohorts and correlation with clinical endpoints (breakthrough infection, severity); test multivalent vs monovalent boosters and strategies to overcome imprinting (novel antigens, adjuvants).
OBJECTIVES: Ongoing escape from pre-existing antibodies by severe acute respiratory distress syndrome coronavirus-2 (SARS-CoV-2) necessitates yearly coronavirus disease 2019 (COVID-19) vaccine updates. Monovalent variant-specific booster vaccines for at-risk populations aim to re-direct antibody responses towards antigenically distinct variants. However, multiple past exposures to the ancestral SARS-CoV-2 spike (S) protein through vaccination and infection could hinder the de novo induction of variant-specific immune responses. METHODS: Here, we profiled SARS-CoV-2-specific antibody, T- and B-cell immune responses in healthcare workers up to 6 months after monovalent XBB.1.5 vaccination. RESULTS: Neutralizing antibodies targeting Omicron subvariants circulating at the time of vaccination were preferentially boosted by vaccination but remained lower than those neutralizing the ancestral strain. Similar responses were observed for antibodies that mediate functionality through antibody-dependent cellular cytotoxicity, although these responses were more promiscuous. Broadly S-reactive B-cells were recalled by vaccination, with limited de novo induction of XBB.1.5-specific B-cell clones. B-cells targeting the receptor binding domain of circulating Omicron subvariants were favored, and T-cell responses cross-reacted with all SARS-CoV-2 variants that were assessed.