Targeting Circulating Leukocytes and Pyroptosis During Ex Vivo Lung Perfusion Improves Lung Preservation

Noda, Kentaro; Tane, Shinya; Haam, Seokjin; D’Cunha, Jonathan; Hayanga, Awori J.; Luketich, James D.; Shigemura, Norihisa

doi:10.1097/tp.0000000000001798

Cited by 45 publications

(37 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies have demonstrated the accumulation of inflammatory cytokines during MP, attributed to release by tissue resident leukocytes. (7,8) Moreover, graft cells injured during the ischemia/reperfusion (I-R) process release various damage-associated molecular patterns (DAMPs) into the perfusate. (9) DAMPs are a heterogeneous collection of molecules released by injured and dying cells that bind to distinct pattern-recognition receptors on tissue resident leukocytes and graft cells, initiating proinflammatory responses.…”

Section: Original Article | 611mentioning

confidence: 99%

See 1 more Smart Citation

Damage‐Associated Molecular Patterns Induce Inflammatory Injury During Machine Preservation of the Liver: Potential Targets to Enhance a Promising Technology

et al. 2019

View full text Add to dashboard Cite

Machine preservation (MP) has emerged as a promising technology in liver transplantation, but the cellular processes occurring during MP have not been characterized. Recent studies have noted the presence of inflammatory molecules generated during MP. We hypothesized that there is a metabolism‐dependent accumulation of damage‐associated molecular patterns (DAMPs) and inflammatory cytokines during MP and that these molecules provoke inflammation in the graft. To stratify groups by metabolic rate, MP was performed on rat livers from standard donors at 3 different temperatures: room temperature (RT), subnormothermic (30°C), and normothermic (37°C). Static cold storage at 4°C was included as a reference group. Following a 4‐hour preservation period, graft reperfusion was performed ex vivo at 37°C (n = 6 for all groups). Levels of DAMPs and inflammatory cytokines were measured, and their biological activity was assessed by determining toll‐like receptor (TLR) stimulation, inflammatory gene expression, and activation of cell death pathways. There was a time‐dependent increase in levels of DAMPs during MP with high‐mobility group box 1 and extracellular DNA levels increasing for all groups ( P < 0.05, 30 versus 240 minutes). Tumor necrosis factor α levels in the perfusate also increased during MP for all groups ( P < 0.05, 30 minutes versus 240 minutes). Levels of inflammatory molecules correlated with increased activation of TLRs (TLR3, P = 0.02, normothermic machine preservation [MP37] versus machine preservation at room temperature [MPRT]; TLR9, P = 0.02, MP37 versus MPRT). Priming of the NLRP3 inflammasome and activation of cell death pathways were reduced in grafts preserved by MP at room temperature. In conclusion, inflammatory molecules produced during MP have a biological impact on the graft. Therapies to attenuate DAMP‐mediated inflammation during MP may further enhance this promising technology.

show abstract

Section: Original Article | 611mentioning

confidence: 99%

“…Recent studies have demonstrated the accumulation of inflammatory cytokines during MP, attributed to release by tissue resident leukocytes . Moreover, graft cells injured during the ischemia/reperfusion (I‐R) process release various damage‐associated molecular patterns (DAMPs) into the perfusate .…”

mentioning

confidence: 99%

Damage‐Associated Molecular Patterns Induce Inflammatory Injury During Machine Preservation of the Liver: Potential Targets to Enhance a Promising Technology

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In addition, recipient T cell infiltration of the donor lung was significantly diminished in the study group (158). In another study by Noda et al, the role of circulating leukocytes in lungs and their relationship with circulating pro-inflammatory cytokines on ischemia-reperfusion injury was investigated in a rat lung transplant model (159). Lung function was significantly better in lung grafts on EVLP with a leucocyte filter in the circuit compared to a control group without.…”

Section: Lungmentioning

confidence: 88%

Machine perfusion of thoracic organs

Raemdonck¹,

Rega²,

Rex³

et al. 2018

J. Thorac. Dis.

View full text Add to dashboard Cite

This article summarizes recent knowledge and clinical advances in machine perfusion (MP) of thoracic organs. MP of thoracic organs has gained much attention during the last decade. Clinical studies are investigating the role of MP to preserve, resuscitate, and assess heart and lungs prior to transplantation. Currently, MP of the cardiac allograft is essential in all type DCD heart transplantation while MP of the pulmonary allograft is mandatory in uncontrolled DCD lung transplantation. MP of thoracic organs also offers an exciting platform to further investigate downregulation of the innate and adaptive immunity prior to reperfusion of the allograft in recipients. MP provides a promising technology that allows pre-transplant preservation, resuscitation, assessment, repair, and conditioning of cardiac and pulmonary allografts outside the body in a near physiologic state prior to planned transplantation. Results of ongoing clinical trials are awaited to estimate the true clinical value of this new technology in advancing the field of heart and lung transplantation by increasing the total number and the quality of available organs and by further improving recipient early and long-term outcome.

show abstract

“…It is well established that PMNs recruited within the lung allograft represent crucial cellular effectors of PGD . PMNs within the transplanted lungs may arise from two distinct sources, the first one being the donor lung itself, which possesses an important reservoir of marginated neutrophils, forming highly toxic NETs (neutrophil extracellular traps) and being immediately recruitable upon transplantation, and the second one being the circulating PMNs from the recipient . The latter pool of PMNs infiltrate the graft upon interaction between leukocyte‐derived integrins with selectins and adhesion molecules expressed by the endothelium in the donor lung .…”

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

Targeting Circulating Leukocytes and Pyroptosis During Ex Vivo Lung Perfusion Improves Lung Preservation

Cited by 45 publications

References 51 publications

Damage‐Associated Molecular Patterns Induce Inflammatory Injury During Machine Preservation of the Liver: Potential Targets to Enhance a Promising Technology

Damage‐Associated Molecular Patterns Induce Inflammatory Injury During Machine Preservation of the Liver: Potential Targets to Enhance a Promising Technology

Machine perfusion of thoracic organs

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

Contact Info

Product

Resources

About