Primary graft dysfunction (PGD) is the clinical syndrome of acute lung injury after lung transplantation (LTx). However, PGD is an umbrella term that encompasses the ongoing pathophysiological and -biological mechanisms occurring in the lung grafts. Therefore, we aim to provide a focused review on the clinical, physiological, radiological, histological and cellular level of PGD. PGD is graded based on hypoxemia and chest X-ray (CXR) infiltrates. High-grade PGD is associated with inferior outcome after LTx. Lung edema is the main characteristic of PGD and alters pulmonary compliance, gas exchange and circulation. A conventional CXR provides a rough estimate of lung edema, while a chest computed tomography (CT) results in a more in-depth analysis. Macroscopically, interstitial and alveolar edema can be distinguished below the visceral lung surface. On the histological level, PGD correlates to a pattern of diffuse alveolar damage (DAD). At the cellular level, ischemia-reperfusion injury (IRI) is the main trigger for the disruption of the endothelial-epithelial alveolar barrier and inflammatory cascade. The multilevel approach integrating all PGD-related aspects results in a better understanding of acute lung failure after LTx, providing novel insights for future therapies.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare form of pulmonary hypertension characterized by the presence of organized thrombi that obstruct pulmonary arteries, ultimately leading to right heart failure and death. Among others, impaired angiogenesis and inflammatory thrombosis have been shown to contribute to the progression of CTEPH. In this review, we summarize the 2-faced nature of angiogenesis in both thrombus formation and resolution in the context of CTEPH and highlight the dual role of angiogenesis and neovascularization in resolving venous thrombi. Furthermore, we discuss relevant in vitro and in vivo models that support the benefits or drawbacks of angiogenesis in CTEPH progression. We discuss the key pathways involved in modulating angiogenesis, particularly the underexplored role of TGFβ (transforming growth factor-beta) signaling in driving fibrosis as an integral element of CTEPH pathogenesis. We finally explore innovative treatment strategies that target angiogenic pathways. These strategies have the potential to pioneer preventive, inventive, or alternative therapeutic options for patients with CTEPH who may not qualify for surgical interventions. Moreover, they could be used synergistically with established treatments such as pulmonary endarterectomy or balloon pulmonary angioplasty. In summary, this review emphasizes the crucial role of angiogenesis in the development of in fibrothrombotic tissue, a major pathological characteristic of CTEPH.

Small airways (<2 mm diameter) are major sites of airflow obstruction in chronic obstructive pulmonary disease (COPD). This study aimed to quantify the impact of small airway disease, characterized by narrowing, occlusion, and obliteration, on airflow parameters in smokers and end-stage patients with COPDs. We performed computational fluid dynamics (CFD) simulations of inspiratory airflow in three lung groups: control non-used donor lungs (no smoking/emphysema history), non-used donor lungs with a smoking history and emphysema, and explanted end-stage COPD lungs. Each group included four lungs, with two tissue cylinders. Micro-CT-scanned small airways were segmented into 3D models for CFD simulations to quantify pressure, resistance, and shear stress. CFD results were benchmarked against simplified linear and Weibel models. CFD simulations showed higher pressures in COPD vs. controls (p = 0.0091) and smokers (p = 0.015), along with increased resistance (p = 0.0057 vs. controls; p = 0.0083 vs. smokers) and up to a tenfold rise in shear stress (p = 0.010 vs. controls). Narrowing and occlusion were shown to independently increase pressure, resistance, and shear stress, which were validated through segmentation corrections. Pressures and resistance assessed with simplified models were up to seven-fold higher for smokers and even 72 higher for COPD compared with CFD values. These findings show that increased airflow parameters can explain the association between small airway disease and airflow limitation in COPD, underscoring small airway vulnerability. Additionally, they highlight the limitations of theoretical models in accurately capturing small airway disease. Supported by the KU Leuven (C16/19/005).

Rationale: The precise nature of small airway obstructions in chronic obstructive pulmonary disease (COPD) remains poorly understood, especially at early disease stages. Objectives: This study aimed to characterize small airway obstructions and numbers up to the terminal bronchioles (TBs) in smokers with limited emphysema and end-stage COPD. We hypothesized that obstruction subtypes would differ in morphology, nature, and number from early to end-stage COPD. Methods: Whole lungs were inflated and processed from seven control donors (control: declined for extrapulmonary reasons); from eight donors with a history of smoking, of whom three had 5% emphysema (smokers with emphysema); and from eight patients with end-stage COPD. Micro–computed tomography of tissue was used to assess number of TBs, aerated TBs, and number and type of obstructions and was cross-correlated with histopathology. Measurements and Main Results: Obstructions were mainly present in smokers with emphysema and patients with COPD, resulting in less aerated TBs. On the basis of emphysema extent, more nonaerated TBs were present in regions with no emphysema than in regions with mild emphysema; however, destruction was more prominent in mild emphysema. Multiple types of obstructions were identified, comprising occlusions, webs, and collapses. In smokers with emphysema, obstructions primarily comprised webs and occlusions, whereas all obstruction types were present in COPD. On histopathology, obstructions were identified as mucus plugs. Conclusions: Multiple types of obstruction characterized as mucus plugs were identified in smokers with emphysema and patients with end-stage COPD. Their morphology, nature, and number evolved from smokers with emphysema to end-stage COPD. A shift from obstruction-dominant dysfunction to destruction-dominant pathology was found in smokers on the basis of emphysema presence.

Rationale: Cystic fibrosis (CF) is characterized by bronchiectasis on imaging, while functionally evolving toward obstructive impairment. Despite its assumed importance in CF, small airway remodeling and its relation to bronchiectasis remains poorly understood. Objectives: The aim of our study was to explore both large and small airway disease morphometrically, by using detailed imaging techniques, such as ex vivo high-resolution computed tomography (HRCT) and micro–computed tomography (μCT), and histological analysis in advanced CF. Methods: On HRCT (600 μm; CF, n = 21; control, n = 6) and μCT (150 μm; CF, n = 3; control, n = 1) scans of inflated explanted lungs, the ratio of visible airway volume to total lung volume (AV%) was calculated as a marker of bronchiectasis, while airway segmentation was used for generation analysis. Clinical data were retrospectively collected. On μCT (8.5 μm) images of lung cores (±2.8 cm3), extracted randomly from each lobe (three per lobe), distal airway (DA) diameter, number of airway collapses, and number of open terminal bronchioles per milliliter were analyzed. Morphometric analysis was supplemented with histological analysis of DA collapse. Results: AV% on HRCT was heterogeneous among CF lungs (0.7–4.6%), overlapping with controls (0.4–1.2%). However, the pattern of airway loss on μCT was homogeneous among CF lungs and most pronounced from generations 9–16. AV% did not correlate with the number of open terminal bronchioles per milliliter or percentage predicted forced expiratory volume in 1 second, which correlated with each other. Open DAs in CF lungs were narrowed compared with DA in controls. On the other hand, collapsed DAs in CF lungs showed varying degrees of proximal dilation, with DA diameter correlating with AV%. On histology, collapsed CF DAs showed constrictive bronchiolitis. Conclusions: Airway remodeling in end-stage CF is heterogeneous, ranging from minimal bronchiectasis, overlapping with control lungs, to extensive bronchiectasis with small airway dilation. However, the degree of bronchiectasis is unrelated to functional impairment or the amount of small airway loss, underscoring the importance of small airway disease.

Background: Chronic lung allograft dysfunction (CLAD) is the leading cause of late mortality after lung transplantation. Bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) are the main underlying clinical entities. Their molecular and cellular signatures are unclear and, therefore, we aimed to identify molecular programmes associated with morphological disease severity in CLAD. Methods: We performed high-resolution imaging-based gene expression profiling of 128 lung samples from explanted CLAD and donor lungs, using weighted gene co-expression network analysis, cellular and pathway enrichment, and hub gene identification. Findings were validated across four datasets, including a murine transplant model, human BOS lungs, transbronchial biopsies, and bronchoalveolar lavage fluid of lung transplant recipients. Results: Unsupervised clustering revealed two transcriptomic CLAD endotypes aligning with mild-fibrotic (BOS, mild RAS) and advanced-fibrotic disease (moderate/severe RAS). Samples from the same patient often diverged molecularly, underscoring intra-patient heterogeneity and limitations of current phenotypical classification. Five molecular programmes emerged: (1) epithelial stress and innate immunity in early-fibrotic CLAD, (2) progressive adaptive immunity and cytotoxicity in advanced CLAD, (3) transient extracellular matrix remodelling, (4) progressive endothelial loss/dysfunction, and (5) progressive loss of homeostasis, wherein multiple potential druggable targets were detected. Finally, we identified a 26 CLAD hub gene-panel, that showed robust diagnostic performance to discriminate CLAD. Conclusion: CLAD is a spatially heterogeneous, yet molecularly continuous disease process, wherein BOS and RAS represent variable stages of a shared immunopathological continuum. Our findings support the development of lung-specific molecular classifiers to guide diagnostics and reveal novel targets for personalised therapies in transplantation.