Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia-reperfusion injury and enhance reconditioning of donor lungs after circulatory death

Stone, Matthew L.; Zhao, Yunge; Smith, Joshua R.; Weiss, Mark L.; Krön, Irving L.; Laubach, Victor E.; Sharma, Ashish K.

doi:10.1186/s12931-017-0704-9

Cited by 105 publications

(81 citation statements)

References 58 publications

(66 reference statements)

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“…We found that EVLP reduced the amount of infiltrating PMNs after LTx in comparison to lung grafts not exposed to EVLP, despite an increase in the expression of various adhesion molecules (including P and E-selectin, as well as VCAM-1). This suggests that EVLP primarily reduced the pool of PMNs from the donor lung, in line with data from previous investigators, 47 which could reflect the mechanical removal of marginated PMNs during EVLP. 48 It seems intriguing at first glance that, despite an increased expression of inflammatory mediators, EVLP-treated lungs displayed such reduction of inflammatory cell infiltration and improved histological status after LTx.…”

Section: Discussionsupporting

confidence: 90%

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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Section: Discussionsupporting

confidence: 90%

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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“…EVs were obtained from supernatants of MSCs cultured overnight in RPMI deprived of fetal bovine serum and supplemented with 0.5% bovine serum albumin (MilliporeSigma), as we have recently described (32). The cell viability was 99% for MSCs, as detected by trypan blue exclusion.…”

Section: Isolation and Characterization Of Evsmentioning

confidence: 99%

Human mesenchymal stromal cell‐derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA‐147

Spinosa

et al. 2018

FASEB j.

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The formation of an abdominal aortic aneurysm (AAA) is characterized by inflammation, macrophage infiltration, and vascular remodeling. In this study, we tested the hypothesis that mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) immunomodulate aortic inflammation, to mitigate AAA formation via modulation of microRNA-147. An elastase-treatment model of AAA was used in male C57BL/6 wild-type (WT) mice. Administration of EVs in elastase-treated WT mice caused a significant attenuation of aortic diameter and mitigated proinflammatory cytokines, inflammatory cell infiltration, an increase in smooth muscle cell α-actin expression, and a decrease in elastic fiber disruption, compared with untreated mice. A 10-fold up-regulation of microRNA (miR)-147, a key mediator of macrophage inflammatory responses, was observed in murine aortic tissue in elastase-treated mice compared with controls on d 14. EVs derived from MSCs transfected with miR-147 mimic, but not with miR-147 inhibitor, attenuated aortic diameter, inflammation, and leukocyte infiltration in elastase-treated mice. In vitro studies of human aortic tissue explants and murine-derived CD11b macrophages induced proinflammatory cytokines after elastase treatment, and the expression was attenuated by cocultures with EVs transfected with miR-147 mimic, but not with miR-147 inhibitor. Thus, our findings define a critical role of MSC-derived EVs in attenuation of aortic inflammation and macrophage activation via miR-147 during AAA formation.-Spinosa, M., Lu, G., Su, G., Bontha, S. V., Gehrau, R., Salmon, M. D., Smith, J. R., Weiss, M. L., Mas, V. R., Upchurch, G. R., Sharma, A. K. Human mesenchymal stromal cell-derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA-147.

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“…The mechanisms of IRI are well documented and several interventions have tried to limit the extent of overall graft damage during the recovery phase . These include, but are not limited to, sphingosine‐1‐phosphate, alpha‐1‐anti‐trpysin, noble gases, and mesenchymal stem cells . However, assuming the graft has not suffered an irremediable insult, the organ ultimately reaches a stable plateau in lung function.…”

Section: Discussionmentioning

confidence: 99%

Total parenteral nutrition in ex vivo lung perfusion: Addressing metabolism improves both inflammation and oxygenation

Buchko

Stewart

Hatami

et al. 2019

American Journal of Transplantation

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Ex vivo lung perfusion (EVLP) protocols generally limit metabolic supplementation to insulin and glucose. We sought to determine whether the addition of total parenteral nutrition (TPN) would improve lung function in EVLP. Ten porcine lungs were perfused using EVLP for 24 hours and supplemented with insulin and glucose. In the treatment group (n = 5), the perfusate was also supplemented with a continuous infusion of TPN containing lipids, amino acids, essential vitamins, and cofactors. Physiologic parameters and perfusate electrolytes were continuously evaluated. Perfusate lactate, lipid and branch chain amino acid (BCAA) concentrations were also analyzed to elucidate how substrates were being utilized over time. Lungs in the TPN group exhibited significantly better oxygenation. Perfusate sodium was more stable in the TPN group. In the control group, free fatty acids (FFA) were quickly depleted, reaching negligible levels early in the perfusion. Alternatively, BCAA in the control group rose continually over the perfusion demonstrating a shift toward proteolysis for energy substrate. In the TPN group, both FFA and BCAA concentrations remained stable at in vivo levels after initial stabilization. TNF‐α concentrations were lower in the TPN group. The addition of TPN in EVLP allows for better electrolyte composition, decreased inflammation, and improved graft performance.

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Mesenchymal stromal cell-derived extracellular vesicles attenuate lung ischemia-reperfusion injury and enhance reconditioning of donor lungs after circulatory death

Cited by 105 publications

References 58 publications

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

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

Human mesenchymal stromal cell‐derived extracellular vesicles attenuate aortic aneurysm formation and macrophage activation via microRNA‐147

Total parenteral nutrition in ex vivo lung perfusion: Addressing metabolism improves both inflammation and oxygenation

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