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.

Lung transplantation improves the outcome and quality of life of patients with end-stage pulmonary disease. However, the procedure is still hampered by the lack of suitable donors, the complexity of the surgery, and the risk of developing chronic lung allograft dysfunction. Over the past decades, translational experiments in animal models have led to a better understanding of physiology and immunopathology following the lung transplant procedure. Small animal models (e.g., rats and mice) are mostly used in experiments regarding immunology and pathobiology and are preferred over large animal models due to the ethical aspects, the cost–benefit balance, and the high throughput possibility. In this comprehensive review, we summarize the reported surgical techniques for lung transplantation in rodent models and the management of perioperative complications. Furthermore, we propose a guide to help identify the appropriate species for a given experiment and discuss recent experimental findings in small animal lung transplant models.

To improve outcomes following lung transplantation, it is essential to understand the immunological mechanisms that result in chronic graft failure. The associated clinical syndrome is termed chronic lung allograft dysfunction (CLAD), which is known to be induced by alloimmune-dependent (i.e., rejection) and alloimmune-independent factors (e.g., infections, reflux and environmental factors). We aimed to explore the alloimmune-related mechanism, i.e., pulmonary rejection. In this study, we use a murine orthotopic left lung transplant model using isografts and allografts (C57BL/6 or BALB/c as donors to C57BL/6 recipients), with daily immunosuppression (10 mg/kg cyclosporin A and 1.6 mg/kg methylprednisolone). Serial sacrifice was performed at days 1, 7 and 35 post-transplantation (n = 6 at each time point for each group). Left transplanted lungs were harvested, a single-cell suspension was made and absolute numbers of immune cells were quantified using multicolor flow cytometry. The rejection process followed the principles of a classic immune response, including innate but mainly adaptive immune cells. At day 7 following transplantation, the numbers of interstitial macrophages, monocytes, dendritic cells, NK cells, NKT cells, CD4+ T cells and CD8+ T and B cells were increased in allografts compared with isografts. Only dendritic cells and CD4+ T cells remained elevated at day 35 in allografts. Our study provides insights into the immunological mechanisms of true pulmonary rejection after murine lung transplantation. These results might be important in further research on diagnostic evaluation and treatment for CLAD.

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).