Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model

Joohyun Kim; Michael A. Zimmerman; Woo Young Shin; Brent T. Boettcher; Ju Seog Lee; Jong In Park; Muhammed Ali; Meiying Yang; Jyotsna Mishra; Catherine E. Hagen; Joseph E. McGraw; Angela Mathison; Harvey J. Woehlck; Gwen Lomberk; Amadou K.S. Camara; Raul A. Urrutia; David F. Stowe; Johnny C. Hong

doi:10.1097/SLA.0000000000005156

Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model

Joohyun Kim, Michael A. Zimmerman, Woo Young Shin, Brent T. Boettcher, Ju Seog Lee, Jong In Park, Muhammed Ali, Meiying Yang, Jyotsna Mishra, Catherine E. Hagen, Joseph E. McGraw, Angela Mathison, Harvey J. Woehlck, Gwen Lomberk, Amadou K.S. Camara, Raul A. Urrutia, David F. Stowe, Johnny C. Hong

Systems Biology

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Objective: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death model. Summary of Background Data: Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. Methods: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control- Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. Results: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. Conclusion: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Sub- normothermic RHR has potential applicability to clinical liver transplantation.

Original language	English (US)
Pages (from-to)	E366-E375
Journal	Annals of surgery
Volume	277
Issue number	2
DOIs	https://doi.org/10.1097/SLA.0000000000005156
State	Published - Feb 1 2023

Keywords

calcium retention capacity
ischemia-reperfusion injury
ischemic gene signature
mitochondrial function
mitogenactivated protein kinase 1
organ resuscitation
reperfusion gene signature
respiratory control index
RNA-sequencing
transcriptome profiling
β-catenin

ASJC Scopus subject areas

Surgery

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10.1097/SLA.0000000000005156

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Kim, J., Zimmerman, M. A., Shin, W. Y., Boettcher, B. T., Lee, J. S., Park, J. I., Ali, M., Yang, M., Mishra, J., Hagen, C. E., McGraw, J. E., Mathison, A., Woehlck, H. J., Lomberk, G., Camara, A. K. S., Urrutia, R. A., Stowe, D. F., & Hong, J. C. (2023). Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model. Annals of surgery, 277(2), E366-E375. https://doi.org/10.1097/SLA.0000000000005156

Kim, J, Zimmerman, MA, Shin, WY, Boettcher, BT, Lee, JS, Park, JI, Ali, M, Yang, M, Mishra, J, Hagen, CE, McGraw, JE, Mathison, A, Woehlck, HJ, Lomberk, G, Camara, AKS, Urrutia, RA, Stowe, DF & Hong, JC 2023, 'Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model', Annals of surgery, vol. 277, no. 2, pp. E366-E375. https://doi.org/10.1097/SLA.0000000000005156

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title = "Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model",

abstract = "Objective: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death model. Summary of Background Data: Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. Methods: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control- Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. Results: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. Conclusion: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Sub- normothermic RHR has potential applicability to clinical liver transplantation.",

keywords = "calcium retention capacity, ischemia-reperfusion injury, ischemic gene signature, mitochondrial function, mitogenactivated protein kinase 1, organ resuscitation, reperfusion gene signature, respiratory control index, RNA-sequencing, transcriptome profiling, β-catenin",

author = "Joohyun Kim and Zimmerman, {Michael A.} and Shin, {Woo Young} and Boettcher, {Brent T.} and Lee, {Ju Seog} and Park, {Jong In} and Muhammed Ali and Meiying Yang and Jyotsna Mishra and Hagen, {Catherine E.} and McGraw, {Joseph E.} and Angela Mathison and Woehlck, {Harvey J.} and Gwen Lomberk and Camara, {Amadou K.S.} and Urrutia, {Raul A.} and Stowe, {David F.} and Hong, {Johnny C.}",

year = "2023",

month = feb,

day = "1",

doi = "10.1097/SLA.0000000000005156",

language = "English (US)",

volume = "277",

pages = "E366--E375",

journal = "Annals of surgery",

issn = "0003-4932",

publisher = "Lippincott Williams and Wilkins",

number = "2",

}

TY - JOUR

T1 - Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model

AU - Kim, Joohyun

AU - Zimmerman, Michael A.

AU - Shin, Woo Young

AU - Boettcher, Brent T.

AU - Lee, Ju Seog

AU - Park, Jong In

AU - Ali, Muhammed

AU - Yang, Meiying

AU - Mishra, Jyotsna

AU - Hagen, Catherine E.

AU - McGraw, Joseph E.

AU - Mathison, Angela

AU - Woehlck, Harvey J.

AU - Lomberk, Gwen

AU - Camara, Amadou K.S.

AU - Urrutia, Raul A.

AU - Stowe, David F.

AU - Hong, Johnny C.

PY - 2023/2/1

Y1 - 2023/2/1

N2 - Objective: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death model. Summary of Background Data: Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. Methods: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control- Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. Results: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. Conclusion: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Sub- normothermic RHR has potential applicability to clinical liver transplantation.

AB - Objective: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death model. Summary of Background Data: Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. Methods: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control- Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. Results: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. Conclusion: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Sub- normothermic RHR has potential applicability to clinical liver transplantation.

KW - calcium retention capacity

KW - ischemia-reperfusion injury

KW - ischemic gene signature

KW - mitochondrial function

KW - mitogenactivated protein kinase 1

KW - organ resuscitation

KW - reperfusion gene signature

KW - respiratory control index

KW - RNA-sequencing

KW - transcriptome profiling

KW - β-catenin

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M3 - Article

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SN - 0003-4932

VL - 277

SP - E366-E375

JO - Annals of surgery

JF - Annals of surgery

IS - 2

ER -

Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model

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