The role of ex vivo lung perfusion in lung transplantation

Tatham, Kate; O’Dea, Kieran P.; Wakabayashi, Kenji; Marczin, Nándor; Takata, Masao

doi:10.1177/1751143714554062

Cited by 3 publications

(2 citation statements)

References 54 publications

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“…The model facilitates characterizing biological mechanisms that may preserve the lung for transplantation as well as response to clinically relevant pathological conditions, such as exposure to endotoxin or bacteria [1][2][3]. The experimental preparation has improved the available pool of lungs appropriate for transplantation [4][5][6][7][8][9] and understanding mechanisms that contribute to primary graft dysfunction in lung transplant recipients [10]. It also offers insight into lung physiology in injury [11,12] and as such, allows for the testing of new therapeutics (mesenchymal stem cells, microvesicles) [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

The endogenous capacity to produce proinflammatory mediators by the ex vivo human perfused lung

Leligdowicz

Ross

Nesseler

et al. 2020

ICMx

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Background The ex vivo human perfused lung model has enabled optimizing donor lungs for transplantation and delineating mechanisms of lung injury. Perfusate and airspace biomarkers are a proxy of the lung response to experimental conditions. However, there is a lack of studies evaluating biomarker kinetics during perfusion and after exposure to stimuli. In this study, we analyzed the ex vivo-perfused lung response to three key perturbations: exposure to the perfusion circuit, exogenous fresh whole blood, and bacteria. Results Ninety-nine lungs rejected for transplantation underwent ex vivo perfusion. One hour after reaching experimental conditions, fresh whole blood was added to the perfusate (n = 55). Two hours after reaching target temperature, Streptococcus pneumoniae was added to the perfusate (n = 42) or to the airspaces (n = 17). Perfusate and airspace samples were collected at baseline (once lungs were equilibrated for 1 h, but before blood or bacteria were added) and 4 h later. Interleukin (IL)-6, IL-8, angiopoietin (Ang)-2, and soluble tumor necrosis factor receptor (sTNFR)-1 were quantified. Baseline perfusate and airspace biomarker levels varied significantly, and this was not related to pre-procurement PaO2:FiO2 ratio, cold ischemia time, and baseline alveolar fluid clearance (AFC). After 4 h of ex vivo perfusion, the lung demonstrated a sustained production of proinflammatory mediators. The change in biomarker levels was not influenced by baseline donor lung characteristics (cold ischemia time, baseline AFC) nor was it associated with measures of experimental epithelial (final AFC) or endothelial (percent weight gain) injury. In the presence of exogenous blood, the rise in biomarkers was attenuated. Lungs exposed to intravenous (IV) bacteria relative to control lungs demonstrated a significantly higher rise in perfusate IL-6. Conclusions The ex vivo-perfused lung has a marked endogenous capacity to produce inflammatory mediators over the course of short-term perfusion that is not significantly influenced by donor lung characteristics or the presence of exogenous blood, and only minimally affected by the introduction of systemic bacteremia. The lack of association between biomarker change and donor lung cold ischemia time, final alveolar fluid clearance, and experimental percent weight gain suggests that the maintained ability of the human lung to produce biomarkers is not merely a marker of lung epithelial or endothelial injury, but may support the function of the lung as an immune cell reservoir.

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Section: Introductionmentioning

confidence: 99%

The endogenous capacity to produce proinflammatory mediators by the ex vivo human perfused lung

Leligdowicz

Ross

Nesseler

et al. 2020

ICMx

View full text Add to dashboard Cite

show abstract

“…The model facilitates characterizing biological mechanisms that may preserve the lung for transplantation as well as response to clinically relevant pathological conditions, such as exposure to endotoxin or bacteria [1][2][3]. The experimental preparation has improved procurement of lungs for transplantation [4][5][6][7][8][9] and understanding mechanisms that contribute to primary graft dysfunction in lung transplant recipients [10]. It also offers insight into lung physiology in injury [11,12] and as such, allows for the testing of new therapeutics (mesenchymal stem cells, microvesicles) [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Interaction of Endogenous Proinflammatory Mediators on the Function of the Ex Vivo Perfused Human lung

Leligdowicz

Ross

Nesseler³

et al. 2020

Preprint

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Background The ex vivo human perfused lung model has enabled optimizing donor lungs for transplantation and delineating mechanisms of lung injury. Perfusate and airspace biomarkers are a proxy of the lung response to experimental conditions. However, there is a lack of studies evaluating biomarker kinetics during perfusion and after exposure to stimuli. In this study we analyzed the ex vivo perfused lung response to three key perturbations: exposure to the perfusion circuit, exogenous fresh whole blood, and bacteria. Results 99 lungs rejected for transplantation underwent ex vivo perfusion. One hour after reaching experimental conditions, fresh whole blood was added to the perfusate (n=55). Two hours after reaching target temperature, Streptococcus pneumoniae was added to the perfusate (n=42) or to the airspaces (n=17). Perfusate and airspace samples were collected at baseline (once lungs were equilibrated for 1 hour, but before blood or bacteria were added) and 4 hours later. Interleukin (IL)-6, IL-8, Angiopoietin (Ang)-2, and soluble tumor necrosis factor receptor (sTNFR)-1 were quantified. Baseline perfusate and airspace biomarker levels varied significantly, and this was not related to pre-procurement PaO2:FiO2 ratio, cold ischemia time, and baseline alveolar fluid clearance (AFC). After 4 hours of ex vivo perfusion, the lung demonstrated a sustained production of proinflammatory mediators. The change in biomarker levels was not influenced by baseline donor lung characteristics (cold ischemia time, baseline AFC) nor was it associated with measures of experimental epithelial (final AFC) or endothelial (percent weight gain) injury. In the presence of exogenous blood, the rise in biomarkers was attenuated. Lungs exposed to intravenous (IV) bacteria relative to control lungs demonstrated a significantly higher rise in perfusate IL-6. Conclusions The ex vivo perfused lung has a marked endogenous capacity to generate inflammatory responses over the course of short-term perfusion. The lack of association between biomarker change and donor lung cold ischemia time as well as final alveolar fluid clearance and experimental percent weight gain suggests that the maintained ability to produce biomarkers is not merely a marker of lung epithelial or endothelial injury but may support the lung’s role as an immune cell reservoir.

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