Therapeutic reconditioning of damaged lungs by transient heat stress during ex vivo lung perfusion

Ojanguren, Amaia; Parapanov, Roumen; Debonneville, Anne; Lugrin, Jérôme; Szabó, Csaba; Hasenauer, Arpad; Rosner, Lorenzo; Gonzalez, Michel; Perentes, Jean-Yannis; Krueger, Thorsten; Liaudet, Lucas

doi:10.1016/j.ajt.2023.05.009

Cited by 3 publications

(8 citation statements)

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“…We used our well-established protocol of warm ischemic donor lung procurement and EVLP ( 15 , 17 – 19 ). Under general anesthesia (5% isoflurane, followed by Ketamine 80 mg/kg and Xylazine 8 mg/kg i.p.…”

Section: Methodsmentioning

confidence: 99%

“…The experimental protocols are detailed in Figure 1 . Lungs were either maintained at a perfusate temperature of 37°C until the end of EVLP (group EVLP 37°C ) or exposed to a transient heat stress (group EVLP HS ), performed by the rapid warming of perfusate temperature at 41.5°C after 1h EVLP, maintained for 30 minutes and followed by rapid cooling at 37°C until the end of EVLP, as described previously ( 15 ). The perfusate temperature was monitored at the entry of the PA with a digital thermometer (TES-1303, Type-K, TES Electrical Electronic Corp.).…”

Section: Methodsmentioning

confidence: 99%

“…In a separate experimental group, EVLP was performed for 1h only (pre-heating, baseline, n=5). At the end of EVLP (1h or 6h), the heart-lung blocks were weighted and the difference between the weight before and after EVLP was computed as an index of lung edema ( 15 , 19 , 20 ). Lungs were then separated, the right lungs were snap-frozen and kept at -80°C for tissue analysis, and the left lungs were fixed in 4% paraformaldehyde and paraffine-embedded for histology and immunofluorescence studies (performed only at the 6h time-point).…”

Section: Methodsmentioning

confidence: 99%

“…The static pulmonary compliance (SPC) was determined during EVLP using the Flexivent FX3 Flexiware® software, as previously described ( 15 , 19 ). The partial pressure of O 2 was measured at the end of EVLP in the effluent perfusate, using CG4+ cartridge (Abbott i-STAT analyzer, East Windsor, KJ).…”

Section: Methodsmentioning

confidence: 99%

“…The EVLP platform is ideally suited to address this hypothesis, as it permits to selectively expose the lungs to a precisely calibrated temperature with well-defined time limits. We recently provided evidence that transient heat exposure during EVLP conferred protection against I/R injury of damaged lung grafts, by attenuating lung inflammation, oxidative stress, epithelial damage and physiological deterioration after LTx ( 15 ). In the present study, we sought to expand further on the effects of ex-vivo therapeutic heat application, by addressing more specifically its effects on the lung endothelium.…”

Section: Introductionmentioning

confidence: 99%

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Transient heat stress protects from severe endothelial damage and dysfunction during prolonged experimental ex-vivo lung perfusion

Parapanov,

Debonneville,

Allouche

et al. 2024

Front. Immunol.

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IntroductionThe pulmonary endothelium is the primary target of lung ischemia-reperfusion injury leading to primary graft dysfunction after lung transplantation. We hypothesized that treating damaged rat lungs by a transient heat stress during ex-vivo lung perfusion (EVLP) to elicit a pulmonary heat shock response could protect the endothelium from severe reperfusion injury.MethodsRat lungs damaged by 1h warm ischemia were reperfused on an EVLP platform for up to 6h at a constant temperature (T°) of 37°C (EVLP37°C group), or following a transient heat stress (HS) at 41.5°C from 1 to 1.5h of EVLP (EVLPHS group). A group of lungs exposed to 1h EVLP only (pre-heating conditions) was added as control (Baseline group). In a first protocol, we measured lung heat sock protein expression (HSP70, HSP27 and Hsc70) at selected time-points (n=5/group at each time). In a second protocol, we determined (n=5/group) lung weight gain (edema), pulmonary compliance, oxygenation capacity, pulmonary artery pressure (PAP) and vascular resistance (PVR), the expression of PECAM-1 (CD31) and phosphorylation status of Src-kinase and VE-cadherin in lung tissue, as well as the release in perfusate of cytokines (TNFα, IL-1β) and endothelial biomarkers (sPECAM, von Willebrand Factor -vWF-, sE-selectin and sICAM-1). Histological and immunofluorescent studies assessed perivascular edema and formation of 3-nitrotyrosine (a marker of peroxinitrite) in CD31 lung endothelium.ResultsHS induced an early (3h) and persisting expression of HSP70 and HSP27, without influencing Hsc70. Lungs from the EVLP37°C group developed massive edema, low compliance and oxygenation, elevated PAP and PVR, substantial release of TNFα, IL-1β, s-PECAM, vWF, E-selectin and s-ICAM, as well as significant Src-kinase activation, VE-cadherin phosphorylation, endothelial 3-NT formation and reduced CD31 expression. In marked contrast, all these alterations were either abrogated or significantly attenuated by HS treatment.ConclusionThe therapeutic application of a transient heat stress during EVLP of damaged rat lungs reduces endothelial permeability, attenuates pulmonary vasoconstriction, prevents src-kinase activation and VE-cadherin phosphorylation, while reducing endothelial peroxinitrite generation and the release of cytokines and endothelial biomarkers. Collectively, these data demonstrate that therapeutic heat stress may represent a promising strategy to protect the lung endothelium from severe reperfusion injury.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transient heat stress protects from severe endothelial damage and dysfunction during prolonged experimental ex-vivo lung perfusion

Parapanov,

Debonneville,

Allouche

et al. 2024

Front. Immunol.

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Racial and Gender Disparities in Transplantation of Hepatitis C+ Hearts and Lungs

Hannan,

Goldberg

2024

The Journal of Heart and Lung Transplantation

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Erythropoietin alleviates lung ischemia-reperfusion injury by activating the FGF23/FGFR4/ERK signaling pathway

Jin,

et al. 2024

PeerJ

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Background The purpose of the present study was to investigate the effect of erythropoietin (EPO) on lung ischemia-reperfusion injury (LIRI). Methods Sprague Dawley rats and BEAS-2B cells were employed to construct an ischemia-reperfusion (I/R)-induced model in vivo and in vitro, respectively. Afterward, I/R rats and tert-butyl hydroperoxide (TBHP)-induced cells were treated with different concentrations of EPO. Furthermore, 40 patients with LIRI and healthy controls were enrolled in the study. Results It was observed that lung tissue damage, cell apoptosis and the expression of BAX and caspase-3 were higher in the LIRI model in vivo and in vitro than in the control group, nevertheless, the Bcl-2, FGF23 and FGFR4 expression level was lower than in the control group. EPO administration significantly reduced lung tissue damage and cell apoptosis while also up-regulating the expression of FGF23 and FGFR4. Rescue experiments indicated that EPO exerted a protective role associated with the FGF23/FGFR4/p-ERK1/2 signal pathway. Notably, the expression of serum EPO, FGF23, FGFR4 and Bcl-2 was decreased in patients with LIRI, while the expression of caspase-3 and BAX was higher. Conclusion EPO could effectively improve LIRI, which might be related to the activation of the FGF23/FGFR4/p-ERK1/2 signaling pathway.

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Therapeutic reconditioning of damaged lungs by transient heat stress during ex vivo lung perfusion

Cited by 3 publications

References 47 publications

Transient heat stress protects from severe endothelial damage and dysfunction during prolonged experimental ex-vivo lung perfusion

Transient heat stress protects from severe endothelial damage and dysfunction during prolonged experimental ex-vivo lung perfusion

Racial and Gender Disparities in Transplantation of Hepatitis C+ Hearts and Lungs

Erythropoietin alleviates lung ischemia-reperfusion injury by activating the FGF23/FGFR4/ERK signaling pathway

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