Sevoflurane preconditioning attenuates lung injury after mouse lung transplantation

Background: Although sevoflurane has been shown to ameliorate ischemic reperfusion injury in various organs, data available seem inconsistent particularly for the lung. We therefore evaluated if preconditioning by sevoflurane could potentially protects from primary graft dysfunction (PGD) and acute rejection (AR) after lung transplantation (Tx).

Methods: Three experimental approaches were employed; [1] C57BL/6 mice were preconditioned for 2 hours with sevoflurane (Sevo) or fentanyl (Control) and analyzed (n = 10), [2] syngeneic mouse lung Tx (C57BL/6) with a preconditioned graft followed by 18 hours of cold storage was performed to mimic PGD (Syn-Tx, n = 12), and [3] allogeneic Tx (BALB/c as donors and C57BL/6 as recipients) with a preconditioned graft was done to mimic AR (Allo-Tx, n = 12). The Syn-Tx grafts were harvested on day 1 and the Allo-Tx grafts on day 3. Analyses included histology, immunohistochemistry, oxygenation and inflammatory and anti-inflammatory cytokines (ELISA).

Results: Evaluating the preconditioned graft, the Sevo group showed better oxygenation (p = 0.03) and a tendency toward lower level of TNF-α (p = 0.08). In Syn-Tx, the Sevo group was more likely to attenuate PGD in histology, and it had a significantly lower level of IL-6 (p = 0.01), and a higher level of IL-10 (p < 0.01). In Allo-Tx, grafts in the Sevo group showed pronounced attenuation of AR with significantly lower rejection scores in histology (p = 0.03), fewer classical macrophages (F4/80⁺) (p < 0.01), but increased numbers of anti-inflammatory alternative macrophages (CD206⁺) (p < 0.01). Also functionally, the Sevo group had a tendency towards improved oxygenation (p = 0.16).

Conclusion: Sevoflurane preconditioning showed protective effects on lung transplants in both, PGD and AR. The observed amelioration could be attributed to alternatively activated macrophages. These promising results lead to a first clinical trial.