RESUMEN
Currently, lung transplantation outcome remains inferior compared to other solid organ transplantations. A major cause for limited survival after lung transplantation is chronic lung allograft dysfunction. Numerous animal models have been developed to investigate chronic lung allograft dysfunction to discover adequate treatments. The murine orthotopic lung transplant model has been further optimized over the last years. However, different degrees of genetic mismatch between donor and recipient mice have been used, applying a single, minor, moderate, and major genetic mismatch. This review aims to reassess the existing murine mismatch models and provide a comprehensive overview, with a specific focus on their eventual histopathological presentation. This will be crucial to leverage this model and tailor it according to specific research needs.
RESUMEN
Antifibrotic therapy with nintedanib is the clinical mainstay in the treatment of progressive fibrosing interstitial lung disease (ILD). High-dimensional medical image analysis, known as radiomics, provides quantitative insights into organ-scale pathophysiology, generating digital disease fingerprints. Here, we performed an integrative analysis of radiomic and proteomic profiles (radioproteomics) to assess whether changes in radiomic signatures can stratify the degree of antifibrotic response to nintedanib in (experimental) fibrosing ILD. Unsupervised clustering of delta radiomic profiles revealed 2 distinct imaging phenotypes in mice treated with nintedanib, contrary to conventional densitometry readouts, which showed a more uniform response. Integrative analysis of delta radiomics and proteomics demonstrated that these phenotypes reflected different treatment response states, as further evidenced on transcriptional and cellular levels. Importantly, radioproteomics signatures paralleled disease- and drug-related biological pathway activity with high specificity, including extracellular matrix (ECM) remodeling, cell cycle activity, wound healing, and metabolic activity. Evaluation of the preclinical molecular response-defining features, particularly those linked to ECM remodeling, in a cohort of nintedanib-treated fibrosing patients with ILD, accurately stratified patients based on their extent of lung function decline. In conclusion, delta radiomics has great potential to serve as a noninvasive and readily accessible surrogate of molecular response phenotypes in fibrosing ILD. This could pave the way for personalized treatment strategies and improved patient outcomes.
Asunto(s)
Indoles , Proteómica , Fibrosis Pulmonar , Animales , Indoles/uso terapéutico , Indoles/farmacología , Ratones , Humanos , Proteómica/métodos , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/diagnóstico por imagen , Fibrosis Pulmonar/patología , Antifibróticos/farmacología , Antifibróticos/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Masculino , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/metabolismo , Pulmón/efectos de los fármacos , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/metabolismo , Matriz Extracelular/metabolismoRESUMEN
In European countries, nearly 10% of all hospital admissions are related to respiratory diseases, mainly chronic life-threatening diseases such as COPD, pulmonary hypertension, IPF or lung cancer. The contribution of blood vessels and angiogenesis to lung regeneration, remodeling and disease progression has been increasingly appreciated. The vascular supply of the lung shows the peculiarity of dual perfusion of the pulmonary circulation (vasa publica), which maintains a functional blood-gas barrier, and the bronchial circulation (vasa privata), which reveals a profiled capacity for angiogenesis (namely intussusceptive and sprouting angiogenesis) and alveolar-vascular remodeling by the recruitment of endothelial precursor cells. The aim of this review is to outline the importance of vascular remodeling and angiogenesis in a variety of non-neoplastic and neoplastic acute and chronic respiratory diseases such as lung infection, COPD, lung fibrosis, pulmonary hypertension and lung cancer.
Asunto(s)
Neovascularización Patológica , Animales , Humanos , Pulmón/irrigación sanguínea , Pulmón/patología , Neovascularización Patológica/patología , Enfermedades Respiratorias/fisiopatología , Enfermedades Respiratorias/patología , Remodelación VascularRESUMEN
PURPOSE OF REVIEW: Chronic lung allograft dysfunction (CLAD) remains a life-threatening complication following lung transplantation. Different CLAD phenotypes have recently been defined, based on the combination of pulmonary function testing and chest computed tomography (CT) scanning and spurred renewed interests in differential diagnosis, risk factors and management of CLAD. RECENT FINDINGS: Given their crucial importance in the differential diagnosis, we will discuss the latest development in assessing the pulmonary function and chest CT scan, but also their limitations in proper CLAD phenotyping, especially with regards to patients with baseline allograft dysfunction. Since no definitive treatment exists, it remains important to timely identify clinical risk factors, but also to assess the presence of specific patterns or biomarkers in tissue or in broncho alveolar lavage in relation to CLAD (phenotypes). We will provide a comprehensive overview of the latest advances in risk factors and biomarker research in CLAD. Lastly, we will also review novel preventive and curative treatment strategies for CLAD. SUMMARY: Although this knowledge has significantly advanced the field of lung transplantation, more research is warranted because CLAD remains a life-threatening complication for all lung transplant recipients.
Asunto(s)
Trasplante de Pulmón , Pruebas de Función Respiratoria , Tomografía Computarizada por Rayos X , Humanos , Trasplante de Pulmón/efectos adversos , Factores de Riesgo , Rechazo de Injerto/diagnóstico , Aloinjertos , Biomarcadores/metabolismo , Biomarcadores/análisis , Enfermedad Crónica , Disfunción Primaria del Injerto/diagnóstico , Disfunción Primaria del Injerto/terapia , Disfunción Primaria del Injerto/etiología , Disfunción Primaria del Injerto/fisiopatología , Diagnóstico Diferencial , Pulmón/fisiopatología , Pulmón/diagnóstico por imagenRESUMEN
Chronic obstructive pulmonary disease (COPD), a devastating and irreversible lung disease, causes structural and functional defects in the bronchial epithelium, the (ir)reversibility of which remains unexplored in vitro. This study aimed to investigate the persistence of COPD-related epithelial defects in long-term airway epithelial cultures derived from non-smokers, smokers, and COPD patients. Barrier function, polarity, cell commitment, epithelial-to-mesenchymal transition, and inflammation were evaluated and compared with native epithelium characteristics. The role of inflammation was explored using cytokines. We show that barrier dysfunction, compromised polarity, and lineage abnormalities observed in smokers and COPD persisted for up to 10 wk. Goblet cell hyperplasia was associated with recent cigarette smoke exposure. Conversely, increased IL-8/CXCL-8 release and abnormal epithelial-to-mesenchymal transition diminished over time. These ex vivo observations matched surgical samples' abnormalities. Cytokine treatment induced COPD-like changes in control cultures and reactivated epithelial-to-mesenchymal transition in COPD cells. In conclusion, these findings suggest that the airway epithelium of smokers and COPD patients retains a multidimensional memory of its original state and previous cigarette smoke-induced injuries, maintaining these abnormalities for extended periods.