Sevoflurane preconditioning protects from post-transplant injury in mouse lung transplantation

• Published in: The Journal of surgical research
• Main Authors: Yamada, Yoshito, MD PhD, Laube, Isabelle, Msc, Jang, Jae-Hwi, PhD, Bonvini, John, MD, Inci, Ilhan, MD, Weder, Walter, MD, Beck Schimmer, Beatrice, MD, Jungraithmayr, Wolfgang, MD PhD
• Format: Journal Article
• Language: English
• Published: 2017
• Subjects: Surgery; hematoxylin and eosin; Tx; IHC; ischemia reperfusion; syngeneic; Syn; PGD; Sevo; I/R; Allo; AR; acute rejection; allogeneic; RT-PCR; adenosine triphosphate; transplantation; reverse transcription polymerase chain reaction; AMPK; sevoflurane; immunohistochemistry; ATP; HE; 5' adenosine monophosphate-activated protein kinase; primary graft dysfunction
• ISSN: 0022-4804
• DOI: 10.1016/j.jss.2017.03.021

Abstract Background Although sevoflurane (Sevo) had been shown to ameliorate post-transplant injury in various organs, data available are inconsistent, particularly in the context of lung transplantation (Tx). We here investigated if preconditioning by Sevo can protect from post-transplant injury regarding both, primary graft dysfunction (PGD) and acute rejection (AR) after experimental lung Tx, thereby focusing on two important clinical outcome parameters. Materials and Methods Three experimental approaches were employed: (I) BALB/c mice were preconditioned for 2 hours with Sevo or a fentanyl cocktail (Control) (n=10), (II) syngeneic mouse lung Tx (C57BL/6) with a Sevo-preconditioned graft followed by 18 hours storage to mimic PGD (Syn-Tx, n=12) vs. controls (fentanyl cocktail), and (III) allogeneic Tx (BALB/c, donor; C57BL/6, recipient) to mimic AR (Allo-Tx, n=12) vs. controls (fentanyl cocktail). Syn-Tx grafts were harvested on day 1, Allo-Tx grafts on day 3 and analyzed for histology, immunohistochemistry, blood gas analysis, and inflammatory cytokines (ELISA or RT-PCR). Results Evaluating the preconditioning effect of Sevo only showed significantly better oxygenation (p=0.03) and a tendency towards lower levels of lung tissue mRNA for TNF-α. In Syn-Tx receipients, the Sevo group had histologically a tendency towards an attenuation of PGD and showed significantly lower levels of IL-6 (p=0.01) in plasma, but higher levels of IL-10 (p<0.01) in lungs. Allo-Tx grafts in Sevo Tx recipients showed attenuated AR with histologically significantly lower rejection scores (p=0.03), fewer classical macrophages (F4/80+; p<0.01), but more anti-inflammatory activated macrophages (M2, CD206+; p<0.01). Functionally, the Sevo group had a tendency towards improved oxygenation. Conclusions We demonstrated that Sevo preconditioning has protective effects on lung transplants in both, PGD and AR. The observed amelioration may be attributed to suppressed inflammatory cytokines during PGD and the induction alternatively activated macrophages during AR. These promising data could set the base for employing Sevo preconditioning in donor lungs for a human trial.