Lung transplantation is the only definitive therapy for selected patients with end-stage respiratory disease. Although survival after lung transplantation has improved over recent decades, long-term outcomes remain inferior to those of other solid organ transplants, largely because of chronic lung allograft dysfunction and infection-related complications. In this review, we synthesize contemporary practice across the lung transplant continuum, from donor identification and optimization to long-term survivorship. We first examine donor selection, management, and expansion strategies, including extended-criteria and donation-after-circulatory-death donors, ex vivo lung perfusion, uncontrolled DCD, and living-donor lobar transplantation. We then review current allocation frameworks, with emphasis on the U.S. composite allocation score, and highlight key candidate-level factors such as frailty, nutritional status, comorbidities, and the unique considerations for pediatric candidates and those bridged with extracorporeal support. Advances in operative techniques, intraoperative mechanical support, enhanced recovery pathways, and early extubation are discussed in the context of primary graft dysfunction and perioperative morbidity. We outline contemporary maintenance immunosuppressive regimens, infection prophylaxis strategies, and the spectrum of early and late alloimmune events, as well as post-transplant malignancies and their impact on long-term outcomes. Finally, we address functional recovery, health-related quality of life, reproductive health, and preventive care, and explore emerging frontiers including precision immunomonitoring with donor-derived cell-free DNA, cell-based immunotherapies, and lung xenotransplantation. Together, these developments underscore the substantial progress achieved and the opportunities that remain to extend allograft survival, reduce treatment-related toxicity, and improve the lived experience of lung transplant recipients.
The circulating ligands bone morphogenetic protein (BMP)-9 and BMP-10 are emerging as dual regulators of pulmonary and systemic vascular biology. Acting through activin receptor-like kinase 1 (ALK1), BMP receptor type II (BMPRII) and endoglin receptor complexes, they maintain endothelial quiescence and vascular tone under physiological conditions. Yet, the same axis can turn pathogenic when its intensity, timing or cellular context are altered. We propose viewing BMP-9/10 not as a linear protective pathway but as a bimodal system in which both deficiency and hyperactivation disrupt vascular homeostasis, leading to distinct phenotypes such as obstructive pulmonary arterial remodeling in pulmonary arterial hypertension (PAH), intrapulmonary vasodilatation in hepatopulmonary syndrome (HPS), and arteriovenous shunting in hereditary haemorrhagic telangiectasia (HHT). The clinical success of sotatercept, an activin signaling inhibitor with partial BMP-ligand trap properties, underscores the translational potential of therapeutically “retuning” this pathway rather than globally enhancing it. Understanding when BMP-9/10 signaling protects and when it becomes pathogenic will be crucial for designing next-generation interventions that stabilize, instead of destabilize, pulmonary vascular integrity.
INTRODUCTION:In the updated 9th TNM non-small cell lung cancer (NSCLC) staging edition, pleural and pulmonary metastases remain grouped within the M1a category, inferring similar prognostic implications. The aim was to evaluate the prognostic implication on overall survival (OS) of pleural versus contralateral pulmonary metastases in a stage M1a cohort, when treated with immune checkpoint inhibitors (ICI), chemotherapy, or chemo-ICI. METHODS:Retrospective real-world data from the Netherlands Cancer Registry was used, including patients with M1a NSCLC that received systemic treatment between 2010-2022. The primary outcome was 2-year OS. RESULTS:5632 patients were included: 2701 with contralateral lung metastases, 2590 with pleural metastases and 341 with both. Pleural metastases were more common in men (p=<0.001), in patients with worse performance score (p=<0.001) and in patients receiving mono-ICI (p=<0.001).Patients with contralateral lung metastases had a better 2-year OS (for chemo, ICI and chemo-ICI, this was 26.9% (95% CI 24.9-28.9), 49.5% (95% CI 43.4-55.2) and 40.4% (95% CI 36.5-44.2), respectively) than patients with pleural metastases (18.5% (95% CI 16.6-20.4), 41.6% (95% CI 36.6-46.5) and 28.6% (95% CI 24.9-32.4), respectively). Patients with both contralateral lung and pleural metastases had the worst OS (12.1% (95% CI 8.2-16.7), 31.1% (95% CI 18.4-44.7) and 25.0% (95% CI 15.7-35.4), respectively). The difference in OS was irrespective of the type of systemic treatment. CONCLUSION:Patients with pleural metastases have inferior OS compared to those with contralateral lung metastases. These findings indicate prognostic heterogeneity between M1a descriptors.
Background Pulmonary arterial hypertension (PAH) is a severe, progressive disease of the small pulmonary arteries. These guidelines provide updated evidence-based recommendations for the treatment of PAH focusing on the latest scientific evidence on sotatercept, an activin signalling inhibitor targeting a novel pathway for the treatment of PAH, and on the role of right heart catheterisation (RHC) in the management of PAH patients during follow-up. Methods A European Respiratory Society (ERS) Task Force, comprising global experts, methodologists and a patient representative, developed these clinical practice guidelines in accordance with ERS methodology and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. Four PICO (Patients, Intervention, Comparator, Outcomes) questions and one narrative question have been addressed. Recommendations The Task Force recommends add-on treatment with sotatercept in PAH patients who already receive PAH drugs and are at intermediate-low, intermediate-high or high risk of death during follow-up; this recommendation is based on a high certainty of evidence available from randomised controlled trials (RCTs). In PAH patients at low risk of death, the Task Force does not provide a recommendation due to the low certainty of evidence and the limited number of such patients included in RCTs. To monitor safety and efficacy, patients receiving sotatercept should be treated in pulmonary hypertension centres and their management should include regular follow-up and appropriate examinations. To guide treatment strategy, the Task Force suggests performing RHC during follow-up in PAH patients who receive PAH drugs and are at intermediate-low, intermediate-high or high risk of death, when therapeutic consequences are expected. The Task Force does not provide a recommendation for this question in PAH patients at low risk of death, due to the very low certainty of evidence. Conclusion The ERS guidelines on the treatment of PAH provide an updated evidence-based framework for the optimal management of patients with PAH.
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.
