The Protective Effects of Carbon Monoxide Against Hepatic Warm Ischemia-Reperfusion Injury in MHC-lnbred Miniature Swine

Background: The development of treatment strategies to protect against ischemia-reperfusion injury (IRI) to livers is important not only for liver surgeries but also in regard to increasing the utilization of livers from marginal donors. In this study, we examined whether inhalational carbon monoxide (CO) therapy reduced IRI after a 45-minute (min) warm ischemia (WI) in a miniature swine model. Materials and methods: Six CLAWN miniature swine underwent a 45-min hepatic WI induced by clamping the portal vein and proper hepatic artery. Three animals were subjected to control conditions while the remaining three were treated with CO inhalation for a total of 345-min, including 120-min after reperfusion to maintain a concentration of CO-Hb under 15% (CO-treated group). IRI of the livers was evaluated by liver function tests, serum pro-inflammatory cytokines and liver biopsies. Results: All controls had statistically significant increased levels of liver enzymes compared to the CO-treated group (p<0.05). In controls, liver biopsies at 2 hours after reperfusion showed marked histological changes including diffuse hemorrhage, congestion, necrosis, vacuolization and neutrophil infiltration with apoptosis. In contrast, the CO-treated group showed less obvious or only minimal histological changes. Furthermore, increases in HMGB1, TNF-α and IL-6 in sera that were induced by IRI in controls were markedly inhibited by the CO-treatment. Conclusion: We demonstrated that low-dose CO inhalation reduces hepatic warm IRI, potentially through downregulation of pro-inflammatory mediators and activation of anti-apoptotic pathways. To our knowledge, this is the first report demonstrating CO-inhalation attenuated hepatic IRI following WI in a large animal model. Takahiro Murokawa, Hisashi Sahara, Mitsuhiro Sekijima, Thomas Pomposelli, Takehiro Iwanaga, Yurika Ichinari, Akira Shimizu & Kazuhiko Yamada The Protective Effects of Carbon Monoxide Against Hepatic Warm Ischemia–Reperfusion Injury in MHC-Inbred Miniature Swine Journal of Gastrointestinal Surgery 24, 974–982 (2020) https://doi.org/10.1007/s11605-019-04283-0