Elevated lactate levels in lung tissue are a distinct hallmark of acute lung injury (ALI), but the biological functions of glycolytic reprogramming and lactate-derived protein modification in damaged alveolar epithelial cells remain poorly elucidated. In the present study, we validated markedly increased lactate abundance in peripheral samples and lung tissues of multiple ARDS patients and multiple ALI mouse models. Administration of glycolysis inhibitor 2-DG to deplete endogenous lactate effectively mitigated lung injury and alveolar epithelial barrier dysfunction, whereas exogenous lactate supplementation significantly worsened these pathological manifestations. Genetic silencing of pulmonary LDHA via intratracheal injection of AAV9-shLdha successfully reproduced the protective phenotypes conferred by 2-DG treatment. Mechanistically, accumulated lactate facilitated Tip60-dependent lactylation modification of YY1 at lysine 183. Biochemical assays confirmed that YY1 K183 lactylation inhibited the expression of PGC-1α at transcriptional level, further causing mitochondrial homeostasis disorder and destruction of alveolar epithelial barrier. In vivo rescue experiments using lactylation-deficient YY1-K183R mutant verified the essential pathogenic role of this site-specific lactylation in LPS-triggered ALI progression. Additionally, we established two feasible translational therapeutic strategies, including K183-targeted cell-penetrating peptide and glycyrrhizin screened from compound libraries. Both candidates efficiently suppressed YY1 K183 lactylation, restored PGC-1α expression and mitochondrial function, and relieved pulmonary edema, inflammatory infiltration and cell apoptosis. In summary, lactate-driven YY1 K183 lactylation disrupts PGC-1α-mediated mitochondrial quality control and epithelial barrier stability. Intervening this lactate-YY1 lactylation axis provides a reliable and promising therapeutic direction for clinical treatment of ALI and ARDS.
BACKGROUND:Pediatric pulmonary arterial hypertension (PAH) carries high mortality with 81% 5-year transplant-free survival. The global Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension-2 (TOPP-2; NCT02610660) registry was created to assess the treatments and outcomes of newly diagnosed pediatric PAH patients. This study evaluates real-world treatment strategies and their relationship with outcomes. METHODS:Within TOPP-2, 445 subjects with newly diagnosed, catheterization-confirmed WSPH Group 1 pediatric PAH were enrolled. Treatment regimens were classified as none, calcium channel blocker monotherapy, PAH-targeted Monotherapy (Mono), Dual, Triple (enteral/inhaled only), or triple including parenteral prostanoid (TripleX). Baseline treatment strategy was defined as medications received three months following diagnosis. Primary clinical endpoint was death or lung transplantation. RESULTS:Dual therapy was the most common baseline treatment regimen (40.2%), followed by Monotherapy (29.0%). Phosphodiesterase type 5 inhibitors were the most common class of PAH-targeted therapy (72.4%) followed by endothelin receptor antagonists (59.3%). Adjusting for disease severity at diagnosis, baseline Dual patients had lesser hazard of death/transplant than Mono patients escalating to Dual by year one (HR=0.30, 95% CI=0.16-0.56, p<0.001). Baseline TripleX patients had lesser hazard of death/transplant than those started on enteral/inhaled therapy only and escalated to parenteral by year one (HR=0.28, 95% CI=0.15-0.50, p<0.001). DISCUSSION:A wide range of pediatric PAH initial medication strategies were observed in the TOPP-2 registry. Therapy regimen escalation within the first year, to Dual for lower-risk patients or to TripleX for higher-risk patients, was associated with worse outcomes compared to those treated more aggressively upfront, supporting upfront over sequential combination therapies.
BACKGROUND:Neutrophilic inflammation is a common feature of chronic obstructive pulmonary disease (COPD). Mitiperstat, an inhibitor of myeloperoxidase expressed in neutrophils, may have potential as a COPD treatment. METHODS:This phase 2a, randomised, placebo-controlled, double-blind, parallel-arm, event-driven trial evaluated the efficacy and safety of mitiperstat 5 mg daily up to 24 weeks (NCT05492877). Adults (40-80 years) with moderate-to-severe COPD, at high risk of exacerbation, and receiving dual or triple inhaled therapy were included. The primary endpoint was time to first composite endpoint for exacerbations in COPD (COPDCompEx) event. Secondary endpoints included time to first moderate-to-severe COPD exacerbation, post-bronchodilator forced expiratory volume in 1 s (post-BD FEV1) change at Week 12, respiratory symptoms, disease impact and safety. RESULTS:Overall, 381 participants (mean age, 66.0 years; 39.6% female) were randomised to mitiperstat (n=189) or placebo (n=192). In total, 125 (66.1%) mitiperstat-treated versus 125 (65.1%) placebo-treated participants experienced COPDCompEx events over 24 weeks. There was no improvement in time to first COPDCompEx event (hazard ratio [HR] 1.07 [90% confidence interval (CI) 0.87, 1.32]; p=0.599) or time to first moderate-to-severe COPD exacerbation (HR 1.23 [90% CI 0.88, 1.73]) with mitiperstat versus placebo. Improvements in post-BD FEV1, respiratory symptoms or disease impact were not seen with mitiperstat. A similar proportion of participants in both groups reported adverse events; seven mitiperstat-treated participants and two placebo-treated participants had pneumonia during the study. CONCLUSION:These results indicate that the risks outweigh the benefits of mitiperstat as a treatment for COPD.
BACKGROUND:Post-infectious bronchiolitis obliterans (PIBO) may occur following childhood infections. Subsequent dysanaptic lung growth, with differential development of the alveolar compartment over the airways, remains elusive. We performed a morphological characterization of the whole airway tree in PIBO compared to bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS:Lungs from matched PIBO (n=5), BOS (n=5), and non-diseased donors (n=5) were evaluated using ex vivo high-resolution computed tomography (CT) scans followed by three-dimensional (3D)-airway segmentation. Matched lung tissue samples (n=4 locations/lung) were scanned with micro-CT (resolution: 5-10 µm) for 3D terminal bronchiole assessment and histology. RESULTS:No significant difference in the number of airways per generation (until generation 11) was observed between groups (p=0.86). Airway diameters in PIBO (generations 6-11) and BOS (generations 7-10) were increased compared to controls (overall p=0.018), without significant differences between PIBO and BOS. More obstructed airways were present in BOS versus PIBO (p=0.016), but airway obstructions were larger in PIBO versus BOS (p=0.032). There were significantly fewer terminal bronchioles in PIBO compared to BOS and controls (PIBO: median 2934 terminal bronchioles/lung (IQR:2247-4115), BOS 8424 terminal bronchioles/lung (IQR:6207-10480), controls 10 903 terminal bronchioles/lung (IQR:7583-12 820), p=0.0009), but terminal bronchiole diameters were not significantly different (p=0.37). Obstruction of pre-terminal bronchioles was segmental (i.e., focal with normal distal terminal bronchiole) in BOS, but partly non-focal (non-reopening bronchiole) in PIBO. CONCLUSIONS:PIBO lungs display an almost threefold decrease in terminal bronchioles compared to BOS, with morphological differences in the type and location of airway obstructions, providing structural evidence supporting dysanaptic lung growth.
Chronic Obstructive Pulmonary Disease (COPD) is a progressive and heterogeneous condition characterized by varying combinations of emphysema, small airway disease, chronic bronchitis, and exacerbations. Although multiple symptomatic therapies exist, no disease-modifying treatments are available. This gap highlights the need for improved preclinical models with greater translational relevance. Large human cohorts and single-cell/multi-mics studies have informed the development of current COPD models. We provide a state-of-the-art review of the major experimental platforms-in vivo (small and large animals, genetic and injury models, environmental exposures), ex vivo (precision-cut lung slices, organoids, co-cultures, lung-on-chip systems), and in silico (aerosol dispersion and computational tools). While each approach has yielded important mechanistic insights, none fully captures the complexity of COPD progression, comorbidities, gene-environment interactions, or heterogeneous clinical endotypes. Future progress will depend on the development of more integrated, human-relevant modeling systems, alongside advanced exposure platforms and AI-driven multi-omics integration to identify biologically meaningful endotypes and speed the creation of phenotype-specific therapies. We propose a phenotype-driven, cross-platform framework in which hypotheses emerging from human clinical and omics data, are validated in in vitro and ex vivo systems, evaluated in phenotype-specific in vivo models, and ultimately confirmed through clinical studies.
BACKGROUND:Positive airway pressure (PAP) has shown inconsistent effects on cardiovascular (CV) outcomes in obstructive sleep apnoea (OSA). Physiological biomarkers derived from sleep studies such as sleep apnoea-specific hypoxic burden (SASHB) and event-related heart rate response (ΔHR) may help identify OSA patients with modifiable CV risk. METHODS:3370 PAP-treated moderate-to-severe OSA patients, from the Pays de la Loire sleep-clinic cohort linked to the French health database (SNDS), were stratified by a high-risk status defined by SASHB >40.6%·min·h⁻1 or ΔHR >21.7 bpm, using percentile-based approach for threshold estimation. The primary composite outcome was defined using the first occurrence in SNDS of major adverse CV event (MACE). Cox models assessed the association between PAP adherence (mean PAP use ≥4 h/night) and MACE occurrence. RESULTS:Over a median follow-up of 9 years, 740 patients experienced a MACE. PAP adherence versus non-adherence was associated with a reduced risk of MACE (adjusted hazard ratio [HR] 0.53, 95% CI [0.46-0.62], p<0.001), but the association was greater in patients with (71.7%) versus without (28.3%) high risk status (interaction HR 0.61 [0.43-0.87]; interaction p value =0.006). Similar findings were obtained using a simplified version of SASHB and ΔHR automatically derived from the single oximetry signal. The interaction of high-risk status between PAP adherence and MACE appeared stronger in non-sleepy patients. CONCLUSIONS:In sleep-clinic, the association of PAP adherence with reduced MACE risk was stronger in high risk OSA. These findings support the integration of hypoxic and autonomic biomarkers into clinical decision pathways for CV risk reduction in OSA.
Abstract Introduction Treatment initiation or intensification to prevent exacerbation of chronic obstructive pulmonary disease (COPD) is based on the identification of patients with high exacerbation risk. The commonly used high-risk category of at least 2 moderate or 1 severe exacerbation within the prior 12 months has limited supporting evidence. We aimed to test the discriminative accuracy and assess the clinical utility of various COPD exacerbation categories for predicting future exacerbations. Methods In the COPDGene and NOVELTY cohorts, for each 1-year and 2-year recall periods, we estimated 6 distinct categories of exacerbation frequencies: ≥1 moderate (M1), ≥2 moderate (M2), ≥1 severe (S1), ≥1 moderate and ≥1 severe (M1andS1), ≥1 moderate or ≥ 1 severe (M1orS1), and ≥2 moderate or ≥ 1 severe (M2orS1), each ascertained in 3 ways: within 1 year, in each of 2 consecutive years (suffix E), and over a rolling combined 2-year period (suffix R). We used the area under the receiver operating characteristic curve (AUC) and decision curve analysis to evaluate the discriminative accuracy and clinical utility of these 18 categories for predicting the occurrence of M2orS1 (current standard) in the subsequent year. Results In COPDGene (n = 3,035), for the prediction of future M2orS1, baseline M1orS1R had the highest AUC (0.69, 95%CI 0.67-0.71) vs. baseline M2orS1 (0.66, 95%CI 0.64-0.67; Δ = 0.03;p<0.001). In NOVELTY (n = 3,080), M1orS1R category had the highest AUC (0.87, 95%CI 0.85-0.88) vs. M2orS1 (0.75, 95%CI 0.72-0.77, Δ = 0.12;p<0.001). Decision curve analysis demonstrated that the two-year rolling patterns provided the highest clinical utility across a clinically relevant treatment threshold range of 5% to 30% (Figure). M1orS1R also had the highest AUC for predicting any exacerbation (M1orS1) in both COPDGene (AUC = 0.68, 95%CI 0.66-0.70) and in NOVELTY (AUC = 0.86, 95%CI 0.85-0.88). Conclusions At least 1 moderate or 1 severe exacerbation over the previous 2 years has the highest discrimination and confers the highest clinical utility for predicting high COPD exacerbation risk. Overall, the combination of higher performance of various exacerbation history patterns in terms of their statistical (AUC) and clinical utility (net benefit) indicates that using a two-year recall and a lower threshold for high-risk classification (any moderate/severe events) is superior to the current standard of care. This abstract is funded by: This work was supported by NHLBI R01 HL151421 (SPB and AN), U01 HL089897 and U01 HL089856, by NIH contract 75N92023D00011, and by a Team Grant from the Canadian Institutes of Health Research (PHT 178432). COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion. The NOVELTY study was funded by AstraZeneca.
BACKGROUND:Respiratory infections are the primary trigger of acute exacerbations in COPD, yet preventive strategies remain limited. This study aims to evaluate the efficacy and safety of MV130, a sublingual mucosal vaccine, in preventing COPD exacerbations alongside maintenance therapy. METHODS:A phase 3, multicentre, double-blind, placebo-controlled, randomised clinical trial included 198 subjects across seven hospitals in Spain, with 1:1 allocation to MV130 or placebo. Eligible patients had ≥3 moderate COPD exacerbations or≥2 with at least one requiring hospitalisation in the previous year. Patients received MV130 (300 FTU) or placebo daily for 12 months. The primary outcome, assessed in both intention-to-treat (ITT) and per-protocol (PP) populations, was the number of exacerbations over 18 months (12 months of treatment +6 months follow-up). Secondary exploratory endpoints related to healthcare resource utilisation and medication use were also evaluated in the ITT population. Safety was also assessed in the ITT population. (ClinicalTrials.gov: NCT01842360; EudraCT: 2012-003253-28). RESULTS:Between May 2013 and January 2018, 198 eligible participants (154 men, 44 women; 97 MV130, 101 placebo) were enrolled. Baseline COPD medication use was well balanced between the treatment groups. Median number of acute exacerbations in the ITT set was 3.0 [interquartile range, IQR, 1.0-5.0] for placebo versus 2.0 [IQR, 1.0-3.0] for MV130 (p=0.001). MV130 reduced exacerbation rate from 2.68 to 1.87 events per patient-year (95% CI 0.44-1.18; p<0.001). There were 229 adverse events (AEs) reported in 103 participants (52%), 113 (48.5%) in the placebo group and 116 (55.7%) in the MV130 group. Two AEs, urticaria (placebo) and pruritus (MV130), were non-serious and assessed as possibly related to the study medication. CONCLUSION:MV130 reduces moderate and severe COPD exacerbations, suggesting its potential role as an adjunct preventive therapy.
