Metabolomic studies reveal an organ-protective hibernation state in donor lungs preserved at 10 °C.

OBJECTIVE: Previous reports showed enhanced graft function in both healthy and injured porcine lungs after preservation at 10 °C. The objective of the study is to elucidate the mechanism of lung protection by 10 °C and identify potential therapeutic targets to improve organ preservation. METHODS: Metabolomics data were analyzed from healthy and injured porcine lungs that underwent extended hypothermic preservation on ice and at 10 °C. Tissue sampled before and after preservation were subjected to untargeted metabolic profiling. Principal component analysis was performed to test for the separability of the paired samples. Significantly changed metabolites between the 2 time points were identified and analyzed to determine the underlying metabolic pathways. The levels of respiratory activity of lung tissue at hypothermic temperatures were confirmed using high resolution respirometry. RESULTS: In both healthy and injured lungs (n = 5 per intervention), principal component analysis suggested minimal change in metabolites after ice preservation but significant change of metabolites after 10 °C preservation, which was associated with significantly improved lung function as assessed by ex vivo lung perfusion and lung transplantation. For healthy lungs, lipid energy pathway was found primarily active at 10 °C. For injured lungs, additional carbohydrate energy pathway and anti-ferroptosis pathways aiding organ repair were identified. These metabolic features are also key features involved in mammal hibernation. CONCLUSIONS: Untargeted metabolomics revealed a dynamic metabolic gradient for lungs stored at 10 °C. Elucidating the underlying mechanisms behind this pathway regulation may lead to strategies that will allow organs "hibernate" for days, potentially making organ banking a reality.

Protective effects of 10°C preservation on donor lungs with lipopolysaccharide-induced acute lung injury.

OBJECTIVES: Hypothermic lung preservation at 10°C has recently shown to enhance quality of healthy donor lungs during ischemia. This study aims to show generalizability of the 10°C lung preservation using an endotoxin-induced lung injury with specific focus on the benefits of post-transplant lung function and mitochondrial preservation. METHODS: Lipopolysaccharide (3 mg/kg) was injected intratracheally in rats to induce lung injury. Injured lungs were flushed with preservation solution and allocated to 3 groups (n = 6 each): minimum cold storage, 6-hour storage on ice (Ice), and 6-hour storage at 10°C (10C). Left lungs were transplanted and reperfused for 2 hours. After storage, lung tissue was used to evaluate the effects of hypothermic storage on the mitochondrial function: mitochondrial membrane potential was assessed by JC-1 staining; mitochondrial oxygen consumption was assessed using high resolution respirometry. RESULTS: Two hours after reperfusion, the PO2/FiO2 ratio from the graft was significantly higher in the 10C group than in the Ice group (P = 0.015), while the wet-to-dry weight ratio was significantly lower (P = 0.041). Levels of interleukin-8 in lung tissues were significantly lower in the 10C group than in the Ice group (P = 0.004). Mechanistically, we noted higher mitochondrial membrane potential and elevated state III respiration in the 10C group than in the Ice group (P = 0.015 and P = 0.002, respectively), implying higher metabolic activities may be maintained during 10°C preservation. CONCLUSIONS: Favorable metabolism during 10°C preservation prevented ischemia-induced mitochondrial damages in injured lungs, leading to better post-transplant outcomes.

The combination of post-mortem sevoflurane ventilation and in situ topical cooling provides improved 6h lung preservation in an uncontrolled DCD porcine model.

BACKGROUND: Recent clinical series on donation after uncontrolled cardiovascular death (uDCD) reported successful transplantation of lungs preserved by pulmonary inflation up to 3h post-mortem. This study aims to investigate the additive effects of in situ lowering of intrathoracic temperature and sevoflurane preconditioning on lung grafts in a porcine uDCD model. METHODS: After uDCD induction, donor pigs were allocated to one of the following groups: Control - static lung inflation only (SLI); TC - SLI + continuous intrapleural topical cooling (TC); or TC+Sevo - SLI + TC + sevoflurane. Lungs were retrieved 6h post-asystole and evaluated via ex vivo lung perfusion (EVLP) for 6h. A left single lung transplant was performed using lungs from the best performing group, followed by 4h of graft evaluation. RESULTS: Animals that received topical cooling achieved intrathoracic temperature < 15°C within 1 hour after chest filling of coolant. Only lungs from donors that received TC and TC+Sevo completed the planned post-preservation 6h EVLP assessment. Despite similar early performance of the two groups on EVLP, the TC+Sevo group was superior - associated with overall lower airway pressures, higher pulmonary compliances, less edema development, and less release of inflammatory cytokines. Transplantation was performed using lungs from the TC+Sevo group, and excellent graft function was observed post-reperfusion. CONCLUSION: Preservation of uDCD lungs with a combination of static lung inflation, topical cooling and sevoflurane treatment maintains good pulmonary function up to 6h post-mortem with excellent early post-lung transplant function. These interventions may significantly expand the clinical utilization of uDCD donor lungs.

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states.

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials.

Neurogenic Thoracic Outlet Syndrome Caused by Vascular Compression of the Brachial Plexus: A Report of Two Cases.

Thoracic outlet syndrome (TOS) is caused by compression of the brachial plexus and/or subclavian vessels as they pass through the cervicothoracobrachial region, exiting the chest. There are three main types of TOS: neurogenic TOS, arterial TOS, and venous TOS. Neurogenic TOS accounts for approximately 95% of all cases, and it is usually caused by physical trauma (posttraumatic etiology), chronic repetitive motion (functional etiology), or bone or muscle anomalies (congenital etiology). We present two cases in which neurogenic TOS was elicited by vascular compression of the inferior portion of the brachial plexus.