RESUMO
BACKGROUND: Compromised microvasculature resulting from disrupted bronchial arterial circulation appears to trigger chronic lung allograft dysfunction. Maintaining the microvasculature throughout the transplant process could improve the long-term health of transplanted lungs. We recently developed a bronchial-arterial-circulation-sparing (BACS) lung preservation approach and tested whether this approach would decrease microvascular damage and improve allograft function. METHODS: The lungs of Lewis rats were procured using either the BACS approach, where the bronchial and pulmonary arteries were synchronously perfused; a conventional approach, where only the pulmonary artery was perfused; or a conventional approach with a prostaglandin flush. After 4 hours of cold ischemia, physiologic function and vascular tone of the grafts were evaluated during ex vivo lung perfusion (EVLP), and microvasculature damage was assessed using 2-photon microscopy analysis. Lung function was compared after transplant among the groups. RESULTS: After 4 hours of cold ischemia, the BACS group exhibited significantly higher adenosine triphosphate levels and lower expression of phosphorylated myosin light chain, which is essential for vascular smooth muscle contraction. On EVLP, the BACS and prostaglandin groups showed lower pulmonary vascular resistance and less arterial stiffness. BACS attenuated microvasculature damage in the lung grafts when compared with conventional preservation. After transplantation, the lungs preserved with the BACS approach exhibited significantly better graft function and lower expression of phosphorylated myosin light chain. CONCLUSIONS: Our data suggest that BACS lung preservation protects the dual circulation inherent to the lungs, facilitating robust microvasculature in lung grafts after transplantation, leading to better posttransplant outcomes.
Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Pulmão/efeitos adversos , Perfusão/métodos , Aloenxertos/irrigação sanguínea , Aloenxertos/patologia , Animais , Brônquios/irrigação sanguínea , Brônquios/patologia , Artérias Brônquicas/patologia , Artérias Brônquicas/transplante , Modelos Animais de Doenças , Circulação Extracorpórea/instrumentação , Circulação Extracorpórea/métodos , Rejeição de Enxerto/patologia , Humanos , Transplante de Pulmão/métodos , Masculino , Microvasos/patologia , Preservação de Órgãos , Soluções para Preservação de Órgãos , Perfusão/instrumentação , Pneumonectomia/métodos , Artéria Pulmonar/patologia , Artéria Pulmonar/transplante , Ratos , Ratos Endogâmicos Lew , Obtenção de Tecidos e Órgãos/métodos , Isquemia Quente/efeitos adversosRESUMO
Chronic allograft dysfunction (CLAD) remains a major complication, causing the poor survival after lung transplantation (Tx). Although strenuous efforts have been made at preventing CLAD, surgical approaches for lung Tx have not been updated over the last 2 decades. The bronchial artery (BA), which supplies oxygenated blood to the airways and constitutes a functional microvasculature, has occasionally been revascularized during transplants, but this technique did not gain popularity and is not standard in current lung Tx protocols, despite the fact that a small number of studies have shown beneficial effects of BA revascularization on limiting CLAD. Also, recent basic and clinical evidence has demonstrated the relationship between microvasculature damage and CLAD. Thus, the protection of the bronchial circulation and microvasculature in lung grafts may be a key factor to overcome CLAD. This review revisits the history of BA revascularization, discusses the role of the bronchial circulation in lung Tx, and advocates for novel bronchial-arterial-circulation sparing approaches as a future direction for overcoming CLAD. Although there are some already published review articles summarizing the surgical techniques and their possible contribution to outcomes in lung Tx, to the best of our knowledge, this review is the first to elaborate on bronchial circulation that will contribute to prevent CLAD from both scientific and clinical perspectives: from bedside to bench to bedside, and beyond.
Assuntos
Brônquios/irrigação sanguínea , Artérias Brônquicas/fisiologia , Pneumopatias/cirurgia , Transplante de Pulmão , Pulmão/irrigação sanguínea , Animais , Bronquiolite Obliterante/etiologia , Progressão da Doença , Rejeição de Enxerto/etiologia , Humanos , Microcirculação , Modelos Animais , Oximetria , Circulação Pulmonar , Transplante Homólogo/efeitos adversosRESUMO
BACKGROUND: The role of the circulating leukocytes in lungs and their relationship with circulating proinflammatory cytokines during ischemia-reperfusion injury is not well understood. Using ex vivo lung perfusion (EVLP) to investigate the pathophysiology of isolated lungs, we aimed to identify a therapeutic target to optimize lung preservation leading to successful lung transplantation. METHODS: Rat heart-lung blocks were placed on EVLP for 4 hours with or without a leukocyte-depleting filter (LF). After EVLP, lung grafts were transplanted, and posttransplant outcomes were compared. RESULTS: Lung function was significantly better in lung grafts on EVLP with a LF than in lungs on EVLP without a LF. The interleukin (IL)-6 levels in the lung grafts and EVLP perfusate were also significantly lower after EVLP with a LF. Interestingly, IL-6 levels in the perfusate did not increase after the lungs were removed from the EVLP circuit, indicating that the cells trapped by the LF were not secreting IL-6. The trapped cells were analyzed with flow cytometry to detect apoptosis and pyroptosis; 26% were pyroptotic (Caspase-1-positive). After transplantation, there was better graft function and less inflammatory response if a LF was used or a caspase-1 inhibitor was administered during EVLP. CONCLUSIONS: Our data demonstrated that circulating leukocytes derived from donor lungs, and not circulating proinflammatory cytokines substantially impaired the quality of lung grafts through caspase-1-induced pyroptotic cell death during EVLP. Removing these cells with a LF and/or inhibiting pyroptosis of the cells can be a new therapeutic approach leading to long-term success after lung transplantation.
Assuntos
Leucócitos/citologia , Transplante de Pulmão/métodos , Pulmão/patologia , Pulmão/fisiologia , Preservação de Órgãos/métodos , Piroptose , Animais , Ponte Cardiopulmonar , Caspase 1/metabolismo , Citocinas/metabolismo , Humanos , Inflamação , Interleucina-6/metabolismo , Leucócitos/metabolismo , Masculino , Microcirculação , Perfusão , Ratos , Ratos Endogâmicos Lew , Testes de Função Respiratória , Resultado do TratamentoRESUMO
Ex vivo lung perfusion (EVLP) promises to be a comprehensive platform for assessment, reconditioning, and preservation of donor lungs and has been dramatically changing the face of clinical lung transplantation. Besides its increasing role in lung transplantation, EVLP has also been recognized as a useful tool for translational research involving the lungs. Based on recent remarkable evidence and experience using EVLP in lung transplantation, there is growing interest in, and expectations for, the use of EVLP beyond the field of lung transplantation. By combining EVLP with advances in regenerative medicine, stem cell biology, and oncology, the evolving technology of EVLP has tremendous potential to advance pulmonary medicine and science. In this review, we revisit recent advances in EVLP technology and research and discuss the future translation of EVLP applications into life-changing medicine.