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OBJECTIVES: Volatile anaesthetics can provide significant protection against reperfusion injury in various experimental settings. The aim of this study was to assess the potential of sevoflurane treatment, the most commonly used volatile anaesthetic in modern anaesthesia, in rat lungs donated after circulatory death and reconditioned in an ex vivo lung perfusion (EVLP) system. METHODS: Fifteen rats were sacrificed and divided into 3 groups. In the control and sevoflurane groups, the heart–lung blocks were exposed to 1 h of warm ischaemia and 2 h of cold ischaemia and were mounted on an EVLP circuit for 3 h, in the absence or in the presence of 2% sev- oflurane. In the baseline group, heart–lung blocks were harvested immediately after euthanasia. Physiological data, lung nitro-oxidative stress, lactate dehydrogenase (LDH), expression of cytokines, oedema and histopathological findings were assessed during or post-EVLP. RESULTS: The sevoflurane group showed significantly reduced LDH (8.82 ± 3.58 arbitrary unit vs 3.80 ± 3.02 arbitrary unit, P = 0.03), protein -1 -1 -1 -1 carbonyl (1.17 ± 0.44 nmolmg vs 0.55 ± 0.11 nmolmg , P = 0.006), 3-nitrotyrosine (197.44 ± 18.47 pgmg vs 151.05 ± 23.54 pgmg , -1 -1 P = 0.004), cytokine-induced neutrophil chemoattractant factor 1 (1.17 ± 0.32 ngmg vs 0.66 ± 0.28 ngmg , P = 0.03) and tumour necrosis -1 factor alpha (1.50 ± 0.59 vs 0.59 ± 0.38 ngmg , P = 0.02) when compared with the control group. In addition, sevoflurane lungs gained sig- nificantly less weight (0.72 ± 0.09 g vs 0.72 ± 0.09 g, P = 0.044), had less perivascular oedema (0.58 ± 0.09 vs 0.47 ± 0.07, P = 0.036), and -1 improved static pulmonary compliance (+0.215 mlcmH O , P = 0.003) and peak airways pressure (–1.33 cmH O, P = 0.04) but similar oxy- 2 2 -1 genation capacity (+1.61 mmHg, P = 0.77) and pulmonary vascular resistances (+0.078 mmHgminml , P = 0.15) when compared with the control group. CONCLUSIONS: These findings suggest that the potential of sevoflurane in protecting the lungs donated after cardiac death and recondi- tioned using EVLP could improve the outcome of these lungs following subsequent transplantation. Keywords: Ex vivo lung perfusion • Sevoflurane • Damaged donor lung grafts dysfunction are the duration of WI and the subsequent ischaemia– INTRODUCTION reperfusion/reoxygenation (IR) injury [8]. Theoretically, IR injury The low acceptance rate of donor lungs is a challenge in lung can be prevented or blunted by pharmacological reconditioning during EVLP [9], which would therefore rehabilitate a damaged transplantation [1, 2]. Ways to increase the number of eligible organs have been evaluated and include donation after circulatory lung and make it more suitable for subsequent transplantation. death (DCD) [3] and removing extra fluids from the lungs by using Volatile anaesthetics, such as isoflurane, sevoflurane or desflur- ane, can provide significant protection against reperfusion injury ex vivo lung perfusion (EVLP) to recondition damaged lungs [4, 5]. However, because of an unavoidable period of warm ischaemia in various experimental settings [10]. This led to the concept of (WI), DCD lungs are at increased risk of primary graft dysfunction anaesthetic preconditioning (before the period of ischaemia) and [6]. Primary graft dysfunction is the main cause of short-term mor- post-conditioning (after the period of ischaemia), in the context bidity and mortality and may be associated with chronic allograft of heart transplantation, with non-conclusive results. In lung dysfunction [7]. The leading contributors to primary graft transplantation, the preconditioning of lungs with inhaled The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved. Downloaded from https://academic.oup.com/icvts/article-abstract/26/6/977/4823621 by Ed 'DeepDyve' Gillespie user on 20 June 2018 EXPERIMENTAL 978 X. Wang et al. / Interactive CardioVascular and Thoracic Surgery sevoflurane has been associated with reduced IR injury in ex vivo models of isolated rat lungs [11] and in vivo autotransplanted pig lungs [12]. In contrast, post-conditioning with sevoflurane has only been evaluated in a rat lung transplantation model after cold ischaemia [13]. The aim of this study was to test the hypothesis that sevoflur- ane treatment during EVLP can attenuate IR injury of rat lungs damaged by WI. MATERIALS AND METHODS Animals Fifteen male adult (9–11 weeks) Sprague–Dawley rats weighing 300–350 g (Charles River Laboratory, L’Arbresle, France) were div- ided into 3 groups: baseline (the BASELINE group, n = 3) group, the control group (CONT group, n = 6) and the sevoflurane group (SEVO group, n = 6). In the BASELINE group, rats were euthanized without any intervention. The CONT and SEVO groups under- went the complete surgical procedure and EVLP procedure. All Figure 1: Ex vivo lung perfusion system. Blue line indicates affluent Steen solu- tion and red line indicates effluent Steen solution. PO Tr.: oxygen electrodes the animal experiments were performed in accordance with the 2 transducers; PT: pressure transducers. Animal Welfare Act and the National Institute of Health ‘Guidelines for the Care and Use of Laboratory Animals’ and were temperature at 10 C by an external heater–cooler unit (Sarns approved by our local ethics committee (Service de la TCMII, 3M, Saint Paul, MN, USA). During EVLP, the perfusate was Consommation et des Affaires Ve ´te ´ rinaire Cantonal de l’Etat de Vaud, Epalinges, Switzerland, Authorization No. 2637). deoxygenated using a gas mixture containing 6% O ,10% CO and 2 2 -1 84% N delivered at a flow of a 1 lmin over a gas-exchange membrane (Hemofilter D150, Medica S.P.A., Italy) connected to Surgical preparation and lung harvesting the affluent arm of the heart–lung block. The PO in the affluent and effluent arms of the circuit was measured using O electrodes Animals were anaesthetized with intraperitoneal sodium pento- (Hugo Sachs Elektronik, Hugstetten, Germany). barbital (50 mg/kg) placed on a heating pad to maintain core -1 EVLP was initiated at a flow rate of 2 mlmin at 10 C and was temperature of 37 C. The trachea was cannulated, and mechani- -1 stepwise increased to the target flow defined as 7.5 mlmin , cor- cal ventilation was initiated using a rodent respirator (Model 683, responding to 7.5% of theoretical cardiac output [14] and Harvard Apparatus, Holliston, MA, USA), with a respiratory rate -1 -1 rewarmed to 37 C (Alpha immersion thermostat 6, Laud- of 75 breathsmin , a tidal volume of 7 mlkg and an FiO of Brinkmann, Delran, NJ, USA) over 40 min. The left atrial pressure 0.21. After median thoracotomy, 600-IU heparin was adminis- was set at 4 cm H O by adjusting the height of an outflow vessel. tered into the right ventricle, and the pulmonary artery (PA) and The pH of the perfusate was maintained in the range of 7.35– left atrium were cannulated using metal catheters (Hugo Sachs 7.45 using THAM solution (Tham-Ko ¨ hler 3M, ko ¨ hler Pharma Elektronik, Hugstetten, Germany). The animals were then sacri- GmbH, Alsbach-Ha ¨hnlein, Germany). At 35 C, mechanical venti- ficed by exsanguination through a left ventricular puncture. In -1 lation was initiated using a tidal volume of 3 mlkg , a respiratory the CONT and SEVO groups, to mimic the DCD explantation -1 rate of 7 min and a FiO of 0.21 (flexiVent FX3 ventilator, procedure, the lungs were maintained in situ for 1 h at room 2 SCIREQ Inc., Montre ´ al, Canada). After 40 min of EVLP, the perfu- temperature (WI time), in a deflated status, followed by the instil- sate reached 37 C, and the tidal volume was increased to lation of the cold Perfadex (XvivoPerfusion, Go ¨ teborg, Sweden), -1 6mlkg . A recruitment manoeuvre (inspiratory pressure of through the PA cannula, and ventilation at a rate of 15 breath- -1 15 cm H O during 20 s) was performed 60 min after the onset of smin and a V of 7 ml/kg, at FiO of 0.21. The heart–lung blocks 2 t 2 EVLP and repeated every 30 min. were then harvested and stored at 4 C during 2 h (cold ischaemic After 180 min of EVLP, the heart–lung block was withdrawn time), in an inflated status with an FiO of 0.5. from the circuit and weighed. Two millilitres of sterile PBS, pH 7.4, was then instilled into the trachea to perform a bronchoal- Ex vivo lung perfusion veolar lavage (BAL). The left lung was flash frozen and stored at -80 C, whereas the right lung was fixed in 4% paraformaldehyde After cold preservation, the heart–lung blocks were weighed, for further histological analysis. This protocol is based on the mounted in an isolated rat EVLP system (Harvard IL-2 System, strategy described for clinical EVLP by Cypel et al. [4] and Hugo Sachs Elektronik, Hugstetten, Germany) and primed with V R adapted to our rat model of EVLP [15]. Steen solution (Xvivo Perfusion, Go ¨ teborg, Sweden) (Fig. 1). In this system, a pump drives the perfusate from a reservoir through a gas exchanger and a heat exchanger before entering the PA. The Experimental groups pulmonary effluent from the left atrium drains back to the reser- voir. During 30 min prior to the EVLP procedure, the circuit was In the CONT group, Steen solution alone was used throughout run in closed loop at a flow of 10 ml/min to stabilize the perfusate the EVLP procedure. In the SEVO group, a flow adaptable Downloaded from https://academic.oup.com/icvts/article-abstract/26/6/977/4823621 by Ed 'DeepDyve' Gillespie user on 20 June 2018 X. Wang et al. / Interactive CardioVascular and Thoracic Surgery 979 sevoflurane vaporizer (Vapor2000 Sevoflurane, Dra ¨gerwerk AG, Protein concentration and lactate dehydrogenase (LDH) Lu ¨ beck, Germany) was connected in line with the gas-exchange levels in bronchoalveolar lavage. Total protein concentration membrane on the affluent arm of the perfusion circuit (Fig. 1). in BAL was determined using the BCA assay and expressed in -1 Based on previous studies [11, 12], a concentration of 2% sevo- mgml BAL fluid. LDH in BAL was measured using the PLUS flurane was added into the gas mixture. To ensure a stable and Cytotoxicity Detection Kit (Roche Molecular Biochemicals, relevant sevoflurane concentration in the Steen solution, the cir- Basel, Switzerland) and was expressed in arbitrary units (AUs). cuit was primed with sevoflurane during the closed loop run. Sevoflurane was administered during the first 30 min of EVLP and Histological evaluation. The right lungs were fixed with OCT stopped when mechanical ventilation was initiated. and 4% paraformaldehyde, embedded in paraffin, sliced longitu- In the BASELINE group, the heart–lung blocks were harvested dinally in 5-mm slices and stained with haematoxylin and eosin. immediately after euthanasia and were not subjected to EVLP. All slides were digitalized using Hamamatsu NanoZoomer HT BAL and lung processing were done exactly as described earlier. Digital slide scanner (Hamatsu Photonics, K.K., Japan) and visual- This group was used to determine the normal values for the dif- ized by uploading to an image analysis programme (Slidepath, ferent biochemical measurements and normal lung histology in Leica Biosystems) for morphometric determination. Pulmonary the absence of any intervention. perivascular oedema was quantified by the ratio of perivascular oedema thickness to the inner diameter of the vessel. Twenty symmetrically cross-sectioned vessels per slide were independ- Measurements ently evaluated by 2 investigators who were blinded for the experimental groups. Physiological variables. PA and left atrium pressures were continuously recorded using pressure transducers (Hugo Sachs Elektronik, Hugstetten, Germany). Pulmonary vascular resistances Statistical analysis (PVRs) were calculated according to the standard formula: PVR = (mean pulmonary artery pressure-left atrial pressure)/flow. All the data are presented as mean ± standard deviation. Data Peak airway pressure (PAWP) was continuously recorded. Static analysis was performed by the Stata 14.2 (StataCorp LLC, TX, pulmonary compliance (SPC) was determined after 60 min and USA). The Kolmogorov–Smirnov test was performed for testing normality of the distribution. For repeated physiological meas- repeated every 30 min, by computing the change in lung volume elicited by an automated stepwise increase of inspiratory pres- urements during EVLP, data were analysed using multilevel mixed-effects linear regression to assess for the effects of time sure up to 15 cmH O. Oxygenation capacity (DppO ) was calcu- 2 2 and treatment group. In case of significant time–group interac- lated as the difference between effluent and affluent PO . Finally, tion, further pairwise comparisons were done to assess differen- the difference in lung weight before and after EVLP was used as a ces between treatment groups at selected time points using the measure of lung oedema. Sidak’s test. In the absence of significant time–group interaction, we evaluated differences between groups by computing the Inflammatory cytokines in lung tissue. The lung tissue was overall effects collapsed over time, expressed as the difference in grounded in liquid nitrogen using a mortar and a pestle, then means (95% confidence interval) and using marginal testing with homogenized in lysis buffer (TrisHCl 10 mM, NP40 0.5%, NaCl Delta-method adjustment. The unpaired t-test was used to com- 0.15 M, Na VO 1 mM, NaF 10 mM, PMSF 1 mM, ethylene- 3 4 pare the lung weight gain between the CONT and SEVO groups. diaminetetraacetic acid 1 mM, aprotinin 10 lg/ml, leupeptin For all the other comparisons, 1-way analysis of variance 10 lg/ml and pepstatin 1 lg/ml), sonicated and incubated for (ANOVA) followed by the Tukey’s correction was used. A P-value 20 min on ice. After centrifugation, cytokines were measured in <0.05 was considered statistically significant. the supernatant. Protein concentration was measured with the Sample size was chosen on the basis of previous studies [15, 16]. BCA assay (Thermo Scientific Pierce, Rockford, IL, USA) and -1 expressed in mgml BAL fluid. The concentrations of tumour necrosis factor alpha (TNF-a), interleukin-6 (IL-6) and cytokine- RESULTS induced neutrophil chemoattractant factor 1 (CINC-1) were measured using specifically designed ELISA kits (R&D System, Physiological data during ex vivo lung perfusion Minneapolis, MN, USA) and were normalized to the concentra- -1 Physiological data obtained during EVLP in the CONT and SEVO tion of proteins (ngmg protein). groups are presented in Fig. 2. Throughout EVLP, SPC increased and was higher in the SEVO Protein carbonyls. Protein carbonyls were quantified as an group when compared with the CONT group (Fig. 2A). At 90 min, index of oxidative modifications in lung tissue proteins using an -1 SPC was 0.70 ± 0.21 mlcmH O in the SEVO group vs 0.41 ± ELISA-based assay (OxiSelect Protein Carbonyl ELISA Kit; Cell -1 0.08 mlcmH O in the CONT group (P = 0.015); at 120 min, -1 Biolabs Inc., San Diego, CA, USA) and expressed in nanomolmg -1 0.70 ± 0.19 mlcmH O in the SEVO group vs 0.44 ± 0.09 ml protein. -1 cmH O in the CONT group (P = 0.001); at 150 min, 00.69 ± 0.2 ml -1 -1 cmH O in the SEVO group vs 0.45 ± 0.09 mlcmH O in the CONT 2 2 Nitro-oxidative stress. 3-Nitrotyrosine was determined in group (P < 0.001) and at 180 min, 0.69 ± 0.22 in the SEVO group vs lung’s tissue as a marker of peroxynitrite generation using an 0.45 ± 0.09 in the CONT group (P < 0.001). The sevoflurane treatment -1 ELISA kit (Rat 3-Nitrotyrosine ELISA kit; Amsbio, Abingdon, UK) overall effect collapsed over time was +0.215 mlcmH O (95% con- and expressed in pg/mg tissue. fidence interval 0.040–0.389; P =0.003). Downloaded from https://academic.oup.com/icvts/article-abstract/26/6/977/4823621 by Ed 'DeepDyve' Gillespie user on 20 June 2018 EXPERIMENTAL 980 X. Wang et al. / Interactive CardioVascular and Thoracic Surgery Figure 2: Pulmonary physiological variables during EVLP. (A) SPC, (B) PAWP, (C) PVR and (D) DppO . Data are presented as mean ± standard deviation. *P-value <0.05 between SEVO and CONT at the same time points. P-value <0.05 overall effects collapsed over time. CONT: control group; DppO : oxygenation capacity; EVLP: ex vivo lung perfusion; PAWP: peak airway pressure; PVR: pulmonary vascular resistances; SEVO: sevoflurane group; SPC: static pulmonary compliance. -1 At all time points, PAWP was lower in the SEVO group than that BASELINE and SEVO groups (47.99 ± 23.75 pgmg , P < 0.0001 -1 in the CONT group (Fig. 2B). At 90 min, PAWP was 6.53 ± 1.04 and 151.05 ± 23.54 pgmg , P = 0.004, respectively). Also, the dif- cmH O in the SEVO group vs 7.83 ± 0.75 cmH Oin CONT group ference in 3-nitrotyrosine between BASELINE and SEVO groups 2 2 (P = 0.014); at 120 min, 6.50 ± 1.11 cmH O in the SEVO group vs was highly significant (P < 0.0001). 7.48 ± 0.82 cmH O in the CONT group (P = 0.001); at 150 min, BAL LDH content (Fig. 3C) in the CONT group was 6.48 ± 1.3 cmH O in the SEVO group vs 7.27 ± 0.48 cmH Oin the 8.82 ± 3.58 AU and significantly higher than that in the BASELINE 2 2 CONT group (P < 0.001) and at 180 min, 6.75 ± 1.43 in the SEVO group (0.33 ± 0.13 AU, P = 0.005) and the SEVO group group vs 7.18 ± 0.71 cmH O in the CONT group (P < 0.001). The (3.80 ± 3.02 AU, P = 0.035). LDH in the SEVO group was compara- sevoflurane treatment overall effect collapsed over time was –1.33 ble with that in the BASELINE group (P = 0.2733). cmH O (95% confidence interval -2.47 to -0.18; P = 0.04). Finally, no significant changes regarding PVR (Fig. 2C) and Expression of cytokines during ex vivo lung perfusion. We DppO (Fig. 2D) were observed. measured TNF-a (Fig. 4A), IL-6 (Fig. 4B) and CINC-1 (Fig. 4C) as markers of inflammation in the pulmonary parenchyma. In the BASELINE group, the levels were very low (TNF-a 0.07 ± Biochemical data -1 -1 0.02 ngmg ; IL-6 0.04 ± 0.02 ngmg and CINC-1 0.08 ± -1 Lung nitro-oxidative stress and LDH release in bronchoal- 0.03 ngmg ). In the CONT group, all the cytokines were increased veolar lavage during ex vivo lung perfusion. The protein with respect to the BASELINE group (TNF-a 1.50 ± 0.59, P =0.003; IL-6 2.63 ± 1.06, P = 0.002 and CINC-1 1.17 ± 0.32, P = 0.0003). carbonyl content of lungs (Fig. 3A) in the CONT group -1 -1 In the SEVO group, only IL-6 (1.58 ± 029 ngmg ) was (1.17 ± 0.44 nmolmg ) was significantly higher when compared with -1 increased when compared with the BASELINE group (P = 0.002). both theBASELINEand the SEVO groups(0.48±0.18nmolmg , -1 -1 P = 0.02 and 0.55 ± 0.11 nmolmg , P = 0.006,respectively).Nosignif- No difference was observed for TNF-a (0.59 ± 0.38 ngmg ; -1 P= 0.3) and CINC-1 (0.66 ± 0.28 ngmg ; P = 0.066). The increase icant difference between the BASELINE and SEVO groups (P =0.94) in cytokines in the CONT group when compared with the SEVO was observed. The 3-nitrotyrosine content of lungs (Fig. 3B) was higher in the group was statistically significant for TNF-a (P = 0.0185) and -1 CONT group (197.44 ± 18.47 pgmg ) when compared with both CINC-1 (P = 0.028) but not for IL-6 (P = 0.11). Downloaded from https://academic.oup.com/icvts/article-abstract/26/6/977/4823621 by Ed 'DeepDyve' Gillespie user on 20 June 2018 X. Wang et al. / Interactive CardioVascular and Thoracic Surgery 981 Figure 3: Lung nitro-oxidative stress and LDH release in bronchoalveolar lav- age. (A) Tissue protein carbonyl content. (B) Tissue 3-nitrotyrosin content. (C) Figure 4: Expression of cytokines after ex vivo lung perfusion. (A) TNF-a,(B) IL- LDH bronchoalveolar lavage content. Data are presented as mean ± standard 6 and (C) CINC-1. Data are presented as mean ± standard deviation. *P-value deviation. *P-value <0.05. BASELINE: baseline group; CONT: control group; <0.05. BASELINE: baseline group; CINC-1: cytokine-induced neutrophil chemo- LDH: lactate dehydrogenase; SEVO: sevoflurane group. attractant factor 1; CONT: control group; IL-6: interleukin-6; SEVO: sevoflurane group; TNF-a: tumour necrosis factor alpha. Pulmonary oedema during ex vivo lung perfusion. The protein content in BAL was measured as a marker of alveolar epi- thelial lesions. As illustrated in Fig. 5G, it was highly pronounced when compared with the BASELINE group (0.58 ± 0.09 vs -1 in both CONT (4.41 ± 0.90 mgml ) and SEVO (3.61 ± 0.30 0.05 ± 0.04; P < _ 0.001) (Fig. 5I). Perivascular oedema was signifi- -1 cantly less important in sevoflurane-treated lungs when com- mgml ) groups when compared with the BASELINE group -1 pared with the control (0.58 ± 0.09 vs 0.47 ± 0.07, P = 0.036). (0.76 ± 0.15 mgml ; P = 0.001 and P = 0.01, respectively). However, weight gain due to pulmonary oedema (Fig. 5H) was significantly lower in the SEVO group (0.52 ± 0.06 g) than that in DISCUSSION the CONT group (0.72 ± 0.09 g; P = 0.044). EVLP, first developed as a tool for the evaluation and preserva- Histopathological findings. Perivascular oedema was present tion of marginal donor lungs, has been studied in recent years as in the CONT and SEVO groups (Fig. 5C–F) but not in the a modality to treat injuries of donor lungs such as oedema, BASELINE group, which showed normal pulmonary macrostruc- inflammation, embolism or atelectasis. It opens a platform for ture (Fig. 5A, B). It was strongly increased in the CONT group the administration of various agents such as anti-inflammatory Downloaded from https://academic.oup.com/icvts/article-abstract/26/6/977/4823621 by Ed 'DeepDyve' Gillespie user on 20 June 2018 EXPERIMENTAL 982 X. Wang et al. / Interactive CardioVascular and Thoracic Surgery Figure 5: Pulmonary oedema after ex vivo lung perfusion and histopathological changes. Histopathological sections (HE staining, magnification 4 in upper and 10 in lower pictures). (A, B) The BASELINE group, (C, D) CONT group and (E, F) SEVO group. Black arrows indicate perivascular oedema, arrowheads indicate vessels and open arrows indicate bronchial structures. (G) Protein content in bronchoalveolar lavage. (H) Weight gain. (I) Quantification of perivascular lung oedema in each group. Data are presented as mean ± standard deviation. *P-value <0.05. BASELINE: baseline; CONT: control; HE: haematoxylin and eosin; SEVO: sevoflurane. drugs [14], antioxidants [17], vasodilators [18], bronchodilators implies that sevoflurane better preserved the functional integrity [19] and fibrinolytics [20]. Our study is the first evaluating sevo- of the alveolocapillary membrane. This is further supported by flurane treatment during EVLP of damaged DCD lungs. the reduction in perivascular oedema. However, we did not Sevoflurane is a volatile anaesthetic widely used for induction notice a significant reduction in the release of proteins in BAL in and maintenance of general anaesthesia. Sevoflurane has been our model. reported to have protective effects against IR injury in solid We measured an important reduction in oxidative stress in the organs such as the heart, liver and brain. Its use is associated with SEVO group, as indicated by the lack of increase in protein car- a decrease in reactive oxygen species, an inhibition of cell death bonyls. Although we did not explore the underlying mechanisms, they may be comparable with those reported in the heart, cascades and reduced neutrophil/platelet adhesion to the endo- thelial wall. In the lung, immune modulation may also represent including the inhibition of extracellular signal-regulated kinase, an important aspect of sevoflurane effects, as indicated by glycogen synthase kinase-3b [23] and nitric oxide synthase [24]. reduced production of TNF-a and Nitric oxide by sevoflurane Indeed, with respect to the latter, we found sevoflurane to be preconditioning [11, 12]. Such modulation of inflammation is, associated with a significant reduction in 3-nitrotyrosine release however, controversial. In intact porcine lung tissue, sevoflurane during EVLP, a sensitive marker of NO-derived peroxynitrite gen- reduced lung TNF-a and interleukin-1b gene expression [21], yet eration and nitro-oxidative stress [25]. Oxidative stress is a major mechanism of reperfusion injury, and the reduction may explain it increased the levels of various inflammatory mediators (such as leukotrienes and nitrogen oxides) in BAL. the significant attenuation of LDH release, a sensitive marker of In our rodent DCD model, sevoflurane was administered intra- cellular injury. Also, sevoflurane inhibits several cellular pathways vascularly early during EVLP to target the cellular signalling cas- implicated in necrotic cell death, such as the opening of the cades involved in IR. A major consequence of IR injury is the mitochondrial permeability transition pore, which leads to the development of pulmonary oedema. EVLP lungs in the SEVO release of mitochondrial proteases into the cytoplasm. The result- group showed a reduced weight gain and PAWP, and improved ing rupture of the cell membrane promotes the release of SPC. As increased endothelial permeability is one of the principal cytoplasmic proteins within the extracellular milieu, including mechanisms in the development of pulmonary oedema [22], this LDH [26]. Downloaded from https://academic.oup.com/icvts/article-abstract/26/6/977/4823621 by Ed 'DeepDyve' Gillespie user on 20 June 2018 X. Wang et al. / Interactive CardioVascular and Thoracic Surgery 983 It is well established that innate immune activation and expres- limitation of our study is that we did not include a group of nor- sion of inflammatory cytokines upon reperfusion is triggered by mal lungs subjected to EVLP to assess the intrinsic effects of EVLP the release of various ‘danger signals’ by necrotic cells. in the absence of WI. However, we previously reported that in Accordingly, the significant cytoprotective effects of sevoflurane such conditions, no significant lung damage, oedema or physio- noted in this study mitigated the activation of inflammatory cas- logical deterioration occurred [15]. Finally, although our data cades, as shown by decreased expression of inflammatory cyto- indicate that EVLP with sevoflurane significantly improved the kines. These anti-inflammatory effects may be highly relevant in status of lungs explanted after WI, it remains to be established the setting of lung reperfusion and transplantation. TNF-a pro- whether this strategy adequately reconditions the damaged lungs motes the sequestration of neutrophils within the lungs [27], for subsequent transplantation. Future in vivo studies will be nec- which are key actors in the development of lung injury during essary to answer this central clinical issue. reperfusion. CINC-1, a CXC chemokine acting as the rodent homolog of human IL-8 [28], plays a critical role in lung inflam- mation by orchestrating the accumulation of activated neutro- CONCLUSION phils. The significant reduction observed in CINC-1 supports the In conclusion, our study indicates that 2% sevoflurane, adminis- fact that sevoflurane may silence a major mechanism of lung tered intravascularly as a post-conditioning strategy during EVLP, neutrophils recruitment. Of note, neutrophils recruitment could not be investigated in this study due to the acellular fluid used is associated with reduced oxidative stress, attenuated inflamma- for ex vivo perfusion. Finally, sevoflurane also tended to reduce tory response and tissue damage, as well as improved pulmonary the expression of IL-6, another important mediator of inflamma- physiological parameters in DCD rat lungs obtained after a tory injury during ischaemia and reperfusion [29]. period of WI. These findings argue in favour of the concept of No difference in DppO was observed between the 2 experi- pharmacological reconditioning using EVLP as a technique to mental groups. As hypoxemia is related to intrapulmonary shunts rehabilitate damaged lungs for subsequent transplantation and caused by pulmonary oedema, the lack of an effect of sevoflur- support the use of sevoflurane in such indication. ane seems contradictory. It may be explained by the fact that we used an FiO of 0.21 throughout the procedure, where in clinical Funding EVLP protocols, DppO is generally evaluated using an FiO2 of 1.0 [4]. In addition, the use of DppO as a parameter for the eval- This work was supported by the Loterie Romande [to H.B.R. and uation of lung function during acellular EVLP has been chal- T.K.], grants from the Emma Muschamp Foundation from the lenged. Yeung et al. [30] observed that the effect of shunt on PO during EVLP could only be evidenced following the addition of ‘Socie ´te ´ Acade ´ mique Vaudoise’ and from the Mahmoud Darwish red blood cells to the perfusate but not in the presence of an foundation [to L.L.] and by departmental funds from the Services of Thoracic Surgery, Anesthesiology and Adult Intensive Care acellular perfusate, the likely reason being the linear relationship between oxygen content and PO in acellular fluids. Medicine at Lausanne University Hospital Medical Center. PVR was not statistically different between both experimental groups throughout EVLP, a result which agrees with our previous Conflict of interest: None of the authors have any conflicts of work [15]. A likely explanation may be the heparinization of the interest or financial ties to disclose. heart–lung block before harvesting. It has been shown that The experimental model and the method have been partially thrombotic vascular obstruction is a major cause of increased published as a thesis (‘Experimental Ex-Vivo Lung Perfusion for PVR during EVLP [22]. Reconditioning of Lung Grafts’) by Xingyu Wang in 2016 at the University of Lausanne and is available at https://serval.unil.ch/ Limitations resource/serval:BIB_65F2BE7EA248.P001/REF.pdf. There are several limitations in this study. Sevoflurane was only administered during the first 30 min of EVLP, which may have REFERENCES limited its protective effects against IR injury. During this period of time, the perfusate was progressively rewarmed and flow pro- [1] Yeung JC, Cypel M, Waddell TK, van Raemdonck D, Keshavjee S. 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Interactive Cardiovascular and Thoracic Surgery – Oxford University Press
Published: Jun 1, 2018
Keywords: Ex vivo lung perfusion; Sevoflurane; Damaged donor lung grafts
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