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[D-Ala2, D-Leu5] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion.
J Surg Res 2019; 241:323-335JS

Abstract

BACKGROUND

Meeting the metabolic demands of donor livers using normothermic ex vivo liver perfusion (NEVLP) preservation technology is challenging. The delta opioid agonist [D-Ala2, D-Leu5] enkephalin (DADLE) has been reported to decrease the metabolic demand in models of ischemia and cold preservation. We evaluated the therapeutic potential of DADLE by investigating its ability to protect against oxidative stress and hepatic injury during normothermic perfusion.

MATERIALS AND METHODS

Primary rat hepatocytes were used in an in vitro model of oxidative stress to determine the minimum dose of DADLE needed to induce protection and the mechanisms associated with protection. NEVLP was then used to induce injury in rat livers and determine the effectiveness of DADLE in preventing liver injury.

RESULTS

In hepatocytes, DADLE was protective against oxidative stress and led to a decrease in phosphorylation of JNK and p38. Naltrindole, a δ-opioid receptor antagonist, blocked this effect. DADLE also activated the PI3K/Akt signaling pathway, and PI3K/Akt inhibition decreased the protective effects of DADLE treatment. In addition, DADLE treatment during NEVLP resulted in lower perfusate alanine aminotransferase and tissue malondialdehyde and better tissue adenosine triphosphate and glutathione. Furthermore, perfusion with DADLE compared with perfusate alone preserved tissue architecture.

CONCLUSIONS

DADLE confers protection against oxidative stress in hepatocytes and during NEVLP. These data suggest that the mechanism of protection involved the prevention of mitochondrial dysfunction by opioid receptor signaling and subsequent increased expression of prosurvival/antiapoptotic signaling pathways. Altogether, data suggest that opioid receptor agonism may serve as therapeutic target for improved liver protection during NEVLP.

Authors+Show Affiliations

The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; The Ohio State University, Wexner Medical Center Comprehensive Transplant Center, Columbus, Ohio.The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.The Ohio State University, Wexner Medical Center Comprehensive Transplant Center, Columbus, Ohio.Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio.The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; The Ohio State University, Wexner Medical Center Comprehensive Transplant Center, Columbus, Ohio.The COPPER Laboratory, The Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio; The Ohio State University, Wexner Medical Center Comprehensive Transplant Center, Columbus, Ohio. Electronic address: Sylvester.Black@osumc.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31071481

Citation

Beal, Eliza W., et al. "[D-Ala2, D-Leu5] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion." The Journal of Surgical Research, vol. 241, 2019, pp. 323-335.
Beal EW, Kim JL, Reader BF, et al. [D-Ala2, D-Leu5] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion. J Surg Res. 2019;241:323-335.
Beal, E. W., Kim, J. L., Reader, B. F., Akateh, C., Maynard, K., Washburn, W. K., ... Black, S. M. (2019). [D-Ala2, D-Leu5] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion. The Journal of Surgical Research, 241, pp. 323-335. doi:10.1016/j.jss.2019.04.010.
Beal EW, et al. [D-Ala2, D-Leu5] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion. J Surg Res. 2019;241:323-335. PubMed PMID: 31071481.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - [D-Ala2, D-Leu5] Enkephalin Improves Liver Preservation During Normothermic Ex Vivo Perfusion. AU - Beal,Eliza W, AU - Kim,Jung-Lye, AU - Reader,Brenda F, AU - Akateh,Clifford, AU - Maynard,Katelyn, AU - Washburn,W Kenneth, AU - Zweier,Jay L, AU - Whitson,Bryan A, AU - Black,Sylvester M, Y1 - 2019/05/06/ PY - 2018/08/04/received PY - 2019/02/18/revised PY - 2019/04/04/accepted PY - 2019/5/10/pubmed PY - 2019/5/10/medline PY - 2019/5/10/entrez KW - D-Ala2,D-Leu5 enkephalin (DADLE) KW - Liver KW - Naltrindole KW - Normothermic ex-vivo liver perfusion KW - Transplantation SP - 323 EP - 335 JF - The Journal of surgical research JO - J. Surg. Res. VL - 241 N2 - BACKGROUND: Meeting the metabolic demands of donor livers using normothermic ex vivo liver perfusion (NEVLP) preservation technology is challenging. The delta opioid agonist [D-Ala2, D-Leu5] enkephalin (DADLE) has been reported to decrease the metabolic demand in models of ischemia and cold preservation. We evaluated the therapeutic potential of DADLE by investigating its ability to protect against oxidative stress and hepatic injury during normothermic perfusion. MATERIALS AND METHODS: Primary rat hepatocytes were used in an in vitro model of oxidative stress to determine the minimum dose of DADLE needed to induce protection and the mechanisms associated with protection. NEVLP was then used to induce injury in rat livers and determine the effectiveness of DADLE in preventing liver injury. RESULTS: In hepatocytes, DADLE was protective against oxidative stress and led to a decrease in phosphorylation of JNK and p38. Naltrindole, a δ-opioid receptor antagonist, blocked this effect. DADLE also activated the PI3K/Akt signaling pathway, and PI3K/Akt inhibition decreased the protective effects of DADLE treatment. In addition, DADLE treatment during NEVLP resulted in lower perfusate alanine aminotransferase and tissue malondialdehyde and better tissue adenosine triphosphate and glutathione. Furthermore, perfusion with DADLE compared with perfusate alone preserved tissue architecture. CONCLUSIONS: DADLE confers protection against oxidative stress in hepatocytes and during NEVLP. These data suggest that the mechanism of protection involved the prevention of mitochondrial dysfunction by opioid receptor signaling and subsequent increased expression of prosurvival/antiapoptotic signaling pathways. Altogether, data suggest that opioid receptor agonism may serve as therapeutic target for improved liver protection during NEVLP. SN - 1095-8673 UR - https://www.unboundmedicine.com/medline/citation/31071481/[D-Ala2,_D-Leu5]_Enkephalin_Improves_Liver_Preservation_During_Normothermic_Ex_Vivo_Perfusion L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-4804(19)30197-0 DB - PRIME DP - Unbound Medicine ER -