Protein Expression Profiling Predicts Graft Performance in Clinical Ex Vivo Lung Perfusion

Machuca, Tiago; Cypel, Marcelo; Yeung, Jonathan C.; Bonato, Riccardo; Zamel, R.; Chen, Manyin; Azad, S.; Hsin, Michael; Saito, Tomohito; Guan, Z.; Waddell, Thomas K.; Liu, Mingyao; Keshavjee, Shaf

doi:10.1097/sla.0000000000000974

Cited by 86 publications

(69 citation statements)

References 31 publications

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“…Our findings during full clinical EVLP support recent observations made by Machuca and colleagues [30] from Toronto and demonstrate the feasibility of identifying biomarkers that might improve EVLP assessment.…”

Section: Discussionsupporting

confidence: 90%

Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during humanex vivolung perfusion

Andreasson

Karamanou

Gillespie

et al. 2017

Eur J Cardiothorac Surg

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OBJECTIVES: Availability of donor lungs suitable for transplant falls short of current demand and contributes to waiting list mortality. Ex vivo lung perfusion (EVLP) offers the opportunity to objectively assess and recondition organs unsuitable for immediate transplant. Identifying robust biomarkers that can stratify donor lungs during EVLP to use or non-use or for specific interventions could further improve its clinical impact. METHODS: In this pilot study, 16 consecutive donor lungs unsuitable for immediate transplant were assessed by EVLP. Key inflammatory mediators and tissue injury markers were measured in serial perfusate samples collected hourly and in bronchoalveolar lavage fluid (BALF) collected before and after EVLP. Levels were compared between donor lungs that met criteria for transplant and those that did not. RESULTS: Seven of the 16 donor lungs (44%) improved during EVLP and were transplanted with uniformly good outcomes. Tissue and vascular injury markers lactate dehydrogenase, HMGB-1 and Syndecan-1 were significantly lower in perfusate from transplanted lungs. A model combining IL-1β and IL-8 concentrations in perfusate could predict final EVLP outcome after 2 h assessment. In addition, perfusate IL-1β concentrations showed an inverse correlation to recipient oxygenation 24 h post-transplant. CONCLUSIONS: This study confirms the feasibility of using inflammation and tissue injury markers in perfusate and BALF to identify donor lungs most likely to improve for successful transplant during clinical EVLP. These results support examining this issue in a larger study.

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Section: Discussionsupporting

confidence: 90%

Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during humanex vivolung perfusion

Andreasson

Karamanou

Gillespie

et al. 2017

Eur J Cardiothorac Surg

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“…We also confirm that EVLP enhances the expression of cytokines (IL‐6, IL‐10) in damaged lungs, in accordance with previous findings, including our own, and that 3‐AB downregulates cytokines during EVLP, as in our recent study . It must be stressed that the degree of cytokine accumulation during EVLP correlates with poor outcomes after LTx . Our finding of reduced cytokines with 3‐AB implicates therefore a key role of PARP in this process, in line with the reported pro‐inflammatory actions of PARP, notably in the lungs …”

Section: Discussionsupporting

confidence: 93%

Treatment with 3-aminobenzamide during ex vivo lung perfusion of damaged rat lungs reduces graft injury and dysfunction after transplantation

Wang

Parapanov

Debonneville

et al. 2020

American Journal of Transplantation

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Ex vivo lung perfusion (EVLP) with pharmacological reconditioning may increase donor lung utilization for transplantation (LTx). 3‐Aminobenzamide (3‐AB), an inhibitor of poly(ADP‐ribose) polymerase (PARP), reduces ex vivo lung injury in rat lungs damaged by warm ischemia (WI). Here we determined the effects of 3‐AB reconditioning on graft outcome after LTx. Three groups of donor lungs were studied: Control (Ctrl): 1 hour WI + 3 hours cold ischemia (CI) + LTx; EVLP: 1 hour WI + 3 hours EVLP + LTx; EVLP + 3‐AB: 1 hour WI + 3 hours EVLP + 3‐AB (1 mg.mL−1) + LTx. Two hours after LTx, we determined lung graft compliance, edema, histology, neutrophil counts in bronchoalveolar lavage (BAL), mRNA levels of adhesion molecules within the graft, as well as concentrations of interleukin‐6 and 10 (IL‐6, IL‐10) in BAL and plasma. 3‐AB reconditioning during EVLP improved compliance and reduced lung edema, neutrophil infiltration, and the expression of adhesion molecules within the transplanted lungs. 3‐AB also attenuated the IL‐6/IL‐10 ratio in BAL and plasma, supporting an improved balance between pro‐ and anti‐inflammatory mediators. Thus, 3‐AB reconditioning during EVLP of rat lung grafts damaged by WI markedly reduces inflammation, edema, and physiological deterioration after LTx, supporting the use of PARP inhibitors for the rehabilitation of damaged lungs during EVLP.

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“…For example, it has been proposed by the National Heart Lung and Blood Institute and found by other studies that many hearts that would provide substantial survival benefits to patients are going unused, largely owing to a lack of reliable methods to assess their suitability for transplantation 79,92 . By allowing organ function to be observed after procurement, perfusion platforms are enabling the investigation of new biomarkers that predict organ health and transplantability 93–96 .…”

Section: Organ Transplantation Without Preservation Constraintsmentioning

confidence: 99%

The promise of organ and tissue preservation to transform medicine

et al. 2017

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The ability to replace organs and tissues on demand could save or improve millions of lives each year globally and create public health benefits on par with curing cancer. Unmet needs for organ and tissue preservation place enormous logistical limitations on transplantation, regenerative medicine, drug discovery, and a variety of rapidly advancing areas spanning biomedicine. A growing coalition of researchers, clinicians, advocacy organizations, academic institutions, and other stakeholders has assembled to address the unmet need for preservation advances, outlining remaining challenges and identifying areas of underinvestment and untapped opportunities. Meanwhile, recent discoveries provide proofs of principle for breakthroughs in a family of research areas surrounding biopreservation. These developments indicate that a new paradigm, integrating multiple existing preservation approaches and new technologies that have flourished in the past 10 years, could transform preservation research. Capitalizing on these opportunities will require engagement across many research areas and stakeholder groups. A coordinated effort is needed to expedite preservation advances that can transform several areas of medicine and medical science.

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Protein Expression Profiling Predicts Graft Performance in Clinical Ex Vivo Lung Perfusion

Abstract: Perfusate protein expression during EVLP can differentiate lungs with good outcome from lungs PGD3 after transplantation. These perfusate biomarkers can be potentially used for more precise donor lung selection improving the outcomes of transplantation.

Cited by 86 publications

References 31 publications

Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during humanex vivolung perfusion

Profiling inflammation and tissue injury markers in perfusate and bronchoalveolar lavage fluid during humanex vivolung perfusion

Treatment with 3-aminobenzamide during ex vivo lung perfusion of damaged rat lungs reduces graft injury and dysfunction after transplantation

The promise of organ and tissue preservation to transform medicine

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