Daily Respiratory Research Analysis
A phase 3 randomized trial showed that the oral DPP-1 inhibitor brensocatib significantly reduced exacerbations in bronchiectasis, marking a potential new anti-neutrophilic strategy. Preclinical work identified neuregulin-1 as a host-protective factor against lethal respiratory viral infection by stabilizing epithelial integrity and limiting necroptosis. A prospective study linked elevated H3K18 lactylation in BALF with early diagnosis and prognosis of sepsis-related ARDS, highlighting epigeneti
Summary
A phase 3 randomized trial showed that the oral DPP-1 inhibitor brensocatib significantly reduced exacerbations in bronchiectasis, marking a potential new anti-neutrophilic strategy. Preclinical work identified neuregulin-1 as a host-protective factor against lethal respiratory viral infection by stabilizing epithelial integrity and limiting necroptosis. A prospective study linked elevated H3K18 lactylation in BALF with early diagnosis and prognosis of sepsis-related ARDS, highlighting epigenetic lactylation as a clinically relevant biomarker.
Research Themes
- Anti-neutrophilic therapy to prevent bronchiectasis exacerbations
- Host-directed protection against respiratory viral injury via epithelial stabilization
- Epigenetic lactylation as a biomarker for sepsis-related ARDS
Selected Articles
1. Phase 3 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis.
In a 52-week, double-blind phase 3 trial (n=1,721), once-daily brensocatib (10 or 25 mg) significantly reduced the annualized rate of pulmonary exacerbations versus placebo and delayed time to first exacerbation. Nearly half of brensocatib-treated patients remained exacerbation-free at week 52 compared with 40.3% on placebo.
Impact: This trial provides the first phase 3 evidence that targeting DPP-1 to suppress neutrophil serine proteases reduces exacerbations in bronchiectasis, offering a mechanistically novel, oral therapy.
Clinical Implications: Brensocatib may become an option to prevent exacerbations in bronchiectasis, particularly for patients with neutrophil-dominant inflammation; integration into guidelines will depend on long-term safety and functional outcomes.
Key Findings
- Annualized exacerbation rate reduced to 1.02–1.04 on brensocatib vs 1.29 on placebo (rate ratio 0.79 and 0.81; adjusted P=0.004 and 0.005).
- Time to first exacerbation was prolonged (HR 0.81 and 0.83; adjusted P=0.02 and 0.04).
- 48.5% of brensocatib patients remained exacerbation-free at week 52 vs 40.3% with placebo.
Methodological Strengths
- Large, multicenter, double-blind randomized design with 1,721 participants over 52 weeks.
- Prespecified hierarchical endpoints with adjudicated exacerbations and time-to-event analyses.
Limitations
- Abstract truncation limits detail on lung function outcomes and safety signals.
- Adolescent subgroup small; long-term safety and effects on FEV1 and quality of life require further reporting.
Future Directions: Assess long-term safety, durability of efficacy, impact on lung function and microbiology, and identify biomarkers of response to anti–neutrophil protease therapy.
BACKGROUND: In bronchiectasis, neutrophilic inflammation is associated with an increased risk of exacerbations and disease progression. Brensocatib, an oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), targets neutrophil serine proteases, key mediators of neutrophilic inflammation. METHODS: In a phase 3, double-blind trial, we randomly assigned patients with bronchiectasis (in a 1:1:1 ratio for adults and a 2:2:1 ratio for adolescents) to receive brensocatib (10 mg or 25 mg once per day) or placebo. The primary end point was the annualized rate of adjudicated pulmonary exacerbations over a 52-week period. The secondary end points, listed in hierarchical testing order, were the time to the first exacerbation during the 52-week period; the percentage of patients remaining exacerbation-free at week 52; the change in forced expiratory volume in 1 second (FEV RESULTS: A total of 1721 patients (1680 adults and 41 adolescents) underwent randomization and received brensocatib or placebo. The annualized rate of pulmonary exacerbations was 1.02 in the 10-mg brensocatib group, 1.04 in the 25-mg brensocatib group, and 1.29 in the placebo group (rate ratio, brensocatib vs. placebo, 0.79 [95% confidence interval {CI}, 0.68 to 0.92; adjusted P = 0.004] with the 10-mg dose and 0.81 [95% CI, 0.69 to 0.94; adjusted P = 0.005] with the 25-mg dose). The hazard ratio for the time to the first exacerbation was 0.81 (95% CI, 0.70 to 0.95; adjusted P = 0.02) with the 10-mg dose and 0.83 (95% CI, 0.70 to 0.97; adjusted P = 0.04) with the 25-mg dose. In each brensocatib group, 48.5% of patients remained exacerbation-free at week 52, as compared with 40.3% in the placebo group (rate ratio, 1.20 [95% CI, 1.06 to 1.37; adjusted P = 0.02] with the 10-mg dose and 1.18 [95% CI, 1.04 to 1.34; adjusted P = 0.04] with the 25-mg dose). At week 52, FEV CONCLUSIONS: Among patients with bronchiectasis, once-daily treatment with brensocatib (10 mg or 25 mg) led to a lower annualized rate of pulmonary exacerbations than placebo, and the decline in FEV
2. Neuregulin-1 prevents death from a normally lethal respiratory viral infection.
NRG1 levels rise in atopic lungs and exogenous NRG1 administration protected naïve mice from lethal SeV and influenza infection. Protection correlated with reduced alveolar leak and inhibition of epithelial necroptosis (reduced MLKL phosphorylation), with parallel effects in human bronchial epithelial cells infected with RSV.
Impact: Reveals a host-derived factor that limits lethal viral lung injury by preserving epithelial integrity and suppressing necroptosis, suggesting a host-directed therapeutic avenue.
Clinical Implications: While preclinical, these data support exploring NRG1 or pathways that enhance epithelial resilience and inhibit necroptosis as adjunctive therapies for severe viral pneumonia.
Key Findings
- NRG1 administration rescued naïve mice from death with Sendai virus and mouse-adapted influenza A virus.
- Protection associated with reduced alveolar epithelial permeability and decreased MLKL phosphorylation (necroptosis inhibition).
- In human bronchial epithelial cells infected with RSV, NRG1 reduced transepithelial leak and expression of RIPK3/MLKL.
Methodological Strengths
- Multiple in vivo viral models (SeV, influenza) and in vitro human airway epithelial validation.
- Mechanistic readouts including epithelial permeability and necroptosis markers (MLKL phosphorylation, RIPK3/MLKL gene expression).
Limitations
- Preclinical murine models; human dosing, timing, and safety remain unknown.
- Potential variability across viral strains and host contexts requires broader validation.
Future Directions: Define optimal dosing/regimens, assess safety, and test NRG1-pathway agonists in larger translational models prior to early phase clinical trials in severe viral pneumonia.
Respiratory infections with RNA viruses such as respiratory syncytial virus (RSV) and influenza lead to significant morbidity and mortality. Using a natural rodent pathogen, Sendai virus (SeV), which is similar to RSV, mice made atopic with house dust mite survived a normally lethal SeV infection. One protein that we found markedly elevated in the lungs and bronchoalveolar lavage fluid of atopic mice was neuregulin-1 (NRG1). Administration of NRG1 protected naïve (non-atopic) mice from death with both SeV and mouse adapted influenza A virus (IAV). Survival was associated with reduced alveolar epithelium permeability and reduced phosphorylation of mixed lineage kinase domain-like (MLKL) protein indicating inhibition of necroptosis. In vitro, treatment of mouse lung epithelial cells with NRG1 inhibited SeV induced necroptosis, and NRG1 administration to differentiated human bronchial epithelial cells infected with RSV reduced transepithelial fluid leak and expression of necroptosis associated genes RIPK3 and MLKL, while regulating genes associated with homeostatic maintenance, suggesting stabilized epithelial integrity. In conclusion, our data demonstrate a unique function of NRG1 in respiratory viral infections by reducing alveolar leak, inhibiting epithelial necroptosis, and promoting homeostatic regulation of airway epithelium, all of which associate with markedly reduced mortality to the respiratory viral insult.
3. PREDICTIVE VALUE OF H3K18 LACTYLATION FOR EARLY DETECTION AND PROGNOSIS OF SEPSIS-RELATED ACUTE RESPIRATORY DISTRESS SYNDROME: A PROSPECTIVE OBSERVATIONAL CLINICAL STUDY.
In a prospective ICU cohort (n=91), BALF H3K18 lactylation was significantly elevated in sepsis-related ARDS versus non-ARDS and independently predicted ARDS development (AUC 0.804). Adding SOFA improved discrimination (AUC 0.830), and rising day-3 H3K18la levels were associated with mortality.
Impact: Introduces a mechanistically grounded epigenetic biomarker that can aid early risk stratification and prognostication in sepsis-related ARDS.
Clinical Implications: BALF H3K18la could complement clinical scores (e.g., SOFA) to identify sepsis patients at risk for ARDS and to monitor trajectory; feasibility and less invasive surrogates need evaluation.
Key Findings
- BALF H3K18la levels were significantly higher in sepsis-related ARDS and correlated with lactate, IL-6, TNF-α, APACHE II, and SOFA (P<0.01).
- H3K18la independently predicted ARDS development (AUC 0.804); combining with SOFA improved AUC to 0.830 (sensitivity 88.9%, specificity 67.3%).
- Day-3 H3K18la levels increased significantly in the mortality group.
Methodological Strengths
- Prospective observational design with standardized early BALF sampling (day 1; day 3 in ventilated patients).
- Multivariable logistic regression and ROC analysis with clinically relevant correlations to severity indices.
Limitations
- Single-center study with modest sample size; external validation is needed.
- BALF collection is invasive; translation to blood-based or noninvasive surrogates is required for scalability.
Future Directions: Validate H3K18la in multicenter cohorts, define thresholds, assess temporal kinetics, and explore less-invasive matrices (e.g., plasma, exhaled biomarkers).
Background: This study aimed to investigate the predictive value of histone H3 lysine 18 lactylation (H3K18la) for the early identification and prognosis of sepsis-related acute respiratory distress syndrome (ARDS). Methods: This prospective observational study included patients with sepsis admitted to the intensive care unit (ICU) between March 2023 and September 2024. The patients were divided into two groups: the sepsis with ARDS group and the sepsis without ARDS group. Clinical data were collected within 24 h of ICU admission. Bronchoalveolar lavage fluid (BALF) samples were obtained on day 1 for all participants, and a second BALF sample was collected on day 3 from patients requiring continued mechanical ventilation. Results: In total, 91 sepsis patients were enrolled in the study: 36 with ARDS and 55 without ARDS. H3K18la levels in BALF were significantly higher in the sepsis-related ARDS group than in the non-ARDS group and the control group ( P < 0.05). Elevated H3K18la levels were positively correlated with inflammatory markers (lactate, IL-6, and TNF-α), Acute Physiology and Chronic Health Evaluation II scores, and Sequential Organ Failure Assessment scores ( P < 0.01). Logistic regression analysis revealed that H3K18la was an independent predictor of ARDS development ( P < 0.05), and ROC curve analysis revealed that H3K18la had high diagnostic accuracy (AUC = 0.804). Combining H3K18la with the Sequential Organ Failure Assessment score further improved diagnostic performance (AUC = 0.830, sensitivity = 88.9%, specificity = 67.3%). Furthermore, H3K18la levels significantly increased on day 3 in the mortality group. Conclusion: H3K18la is a promising biomarker for the early identification and prognostic prediction of sepsis-related ARDS.