In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats

Zhao Li Sun, Andrew S. Klein, Svetlana Radaeva, Feng Hong, Osama El-Assal, Hong Na Pan, Barbara Jaruga, Sandor Batkai, Sumito Hoshino, Zhigang Tian, George Kunos, Anna Mae Diehl, Bin Gao

Research output: Contribution to journalArticle

Abstract

Background & Aims: Orthotopic liver transplantation is currently the only curative therapy for chronic end-stage liver disease and acute liver failure. However, a scarcity of cadaveric donors has led to a critical shortage of organs available for transplant. This is further complicated by the prevalence of steatosis in about 13%-50% of donor livers, which is associated with a high risk of dysfunction and primary nonfunction. Methods: Steatotic Zucker rat livers and livers from alcohol-fed rats were transplanted into lean control rats. Liver injury, activation of survival signals, and hepatic microcirculation were compared in nontreated and interleukin-6 (IL6)-treated steatotic isografts. Results: IL-6 pretreatment of steatotic Zucker rat liver isografts dramatically reduces mortality and liver injury following transplantation. Reperfusion after transplantation induces significant sinusoidal endothelial cell necrapoptosis in steatotic Zucker rat liver isografts, which is prevented by in vitro IL-6 pretreatment. IL-6 treatment activates cell survival signal transducer and activator of transcription factor 3 (STAT3) in hepatocytes and sinusoidal endothelial cells. Laser Doppler imaging and microsphere analyses demonstrate that IL-6 treatment markedly improves hepatic microcirculation, which is impaired in steatotic Zucker rat liver transplants. Finally, in vitro IL-6 treatment of donor livers also markedly reduces mortality associated with fatty liver transplants from alcohol-fed rats. Conclusions: IL-6 induces hepatoprotection of steatotic liver isografts via preventing sinusoidal endothelial cell necrapoptosis and consequent amelioration of hepatic microcirculation, and protecting against hepatocyte death. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation.

Original languageEnglish (US)
Pages (from-to)202-215
Number of pages14
JournalGastroenterology
Volume125
Issue number1
DOIs
StatePublished - Jul 1 2003

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Fatty Liver
Interleukin-6
Transplants
Mortality
Liver
Isografts
Zucker Rats
Therapeutics
Microcirculation
Endothelial Cells
Transplantation
In Vitro Techniques
Hepatocytes
Alcohols
Transcription Factor 3
STAT3 Transcription Factor
End Stage Liver Disease
Acute Liver Failure
Wounds and Injuries
Microspheres

ASJC Scopus subject areas

  • Gastroenterology

Cite this

In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats. / Sun, Zhao Li; Klein, Andrew S.; Radaeva, Svetlana; Hong, Feng; El-Assal, Osama; Pan, Hong Na; Jaruga, Barbara; Batkai, Sandor; Hoshino, Sumito; Tian, Zhigang; Kunos, George; Diehl, Anna Mae; Gao, Bin.

In: Gastroenterology, Vol. 125, No. 1, 01.07.2003, p. 202-215.

Research output: Contribution to journalArticle

Sun, ZL, Klein, AS, Radaeva, S, Hong, F, El-Assal, O, Pan, HN, Jaruga, B, Batkai, S, Hoshino, S, Tian, Z, Kunos, G, Diehl, AM & Gao, B 2003, 'In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats', Gastroenterology, vol. 125, no. 1, pp. 202-215. https://doi.org/10.1016/S0016-5085(03)00696-6
Sun, Zhao Li ; Klein, Andrew S. ; Radaeva, Svetlana ; Hong, Feng ; El-Assal, Osama ; Pan, Hong Na ; Jaruga, Barbara ; Batkai, Sandor ; Hoshino, Sumito ; Tian, Zhigang ; Kunos, George ; Diehl, Anna Mae ; Gao, Bin. / In vitro interleukin-6 treatment prevents mortality associated with fatty liver transplants in rats. In: Gastroenterology. 2003 ; Vol. 125, No. 1. pp. 202-215.
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abstract = "Background & Aims: Orthotopic liver transplantation is currently the only curative therapy for chronic end-stage liver disease and acute liver failure. However, a scarcity of cadaveric donors has led to a critical shortage of organs available for transplant. This is further complicated by the prevalence of steatosis in about 13{\%}-50{\%} of donor livers, which is associated with a high risk of dysfunction and primary nonfunction. Methods: Steatotic Zucker rat livers and livers from alcohol-fed rats were transplanted into lean control rats. Liver injury, activation of survival signals, and hepatic microcirculation were compared in nontreated and interleukin-6 (IL6)-treated steatotic isografts. Results: IL-6 pretreatment of steatotic Zucker rat liver isografts dramatically reduces mortality and liver injury following transplantation. Reperfusion after transplantation induces significant sinusoidal endothelial cell necrapoptosis in steatotic Zucker rat liver isografts, which is prevented by in vitro IL-6 pretreatment. IL-6 treatment activates cell survival signal transducer and activator of transcription factor 3 (STAT3) in hepatocytes and sinusoidal endothelial cells. Laser Doppler imaging and microsphere analyses demonstrate that IL-6 treatment markedly improves hepatic microcirculation, which is impaired in steatotic Zucker rat liver transplants. Finally, in vitro IL-6 treatment of donor livers also markedly reduces mortality associated with fatty liver transplants from alcohol-fed rats. Conclusions: IL-6 induces hepatoprotection of steatotic liver isografts via preventing sinusoidal endothelial cell necrapoptosis and consequent amelioration of hepatic microcirculation, and protecting against hepatocyte death. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation.",
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AU - Sun, Zhao Li

AU - Klein, Andrew S.

AU - Radaeva, Svetlana

AU - Hong, Feng

AU - El-Assal, Osama

AU - Pan, Hong Na

AU - Jaruga, Barbara

AU - Batkai, Sandor

AU - Hoshino, Sumito

AU - Tian, Zhigang

AU - Kunos, George

AU - Diehl, Anna Mae

AU - Gao, Bin

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N2 - Background & Aims: Orthotopic liver transplantation is currently the only curative therapy for chronic end-stage liver disease and acute liver failure. However, a scarcity of cadaveric donors has led to a critical shortage of organs available for transplant. This is further complicated by the prevalence of steatosis in about 13%-50% of donor livers, which is associated with a high risk of dysfunction and primary nonfunction. Methods: Steatotic Zucker rat livers and livers from alcohol-fed rats were transplanted into lean control rats. Liver injury, activation of survival signals, and hepatic microcirculation were compared in nontreated and interleukin-6 (IL6)-treated steatotic isografts. Results: IL-6 pretreatment of steatotic Zucker rat liver isografts dramatically reduces mortality and liver injury following transplantation. Reperfusion after transplantation induces significant sinusoidal endothelial cell necrapoptosis in steatotic Zucker rat liver isografts, which is prevented by in vitro IL-6 pretreatment. IL-6 treatment activates cell survival signal transducer and activator of transcription factor 3 (STAT3) in hepatocytes and sinusoidal endothelial cells. Laser Doppler imaging and microsphere analyses demonstrate that IL-6 treatment markedly improves hepatic microcirculation, which is impaired in steatotic Zucker rat liver transplants. Finally, in vitro IL-6 treatment of donor livers also markedly reduces mortality associated with fatty liver transplants from alcohol-fed rats. Conclusions: IL-6 induces hepatoprotection of steatotic liver isografts via preventing sinusoidal endothelial cell necrapoptosis and consequent amelioration of hepatic microcirculation, and protecting against hepatocyte death. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation.

AB - Background & Aims: Orthotopic liver transplantation is currently the only curative therapy for chronic end-stage liver disease and acute liver failure. However, a scarcity of cadaveric donors has led to a critical shortage of organs available for transplant. This is further complicated by the prevalence of steatosis in about 13%-50% of donor livers, which is associated with a high risk of dysfunction and primary nonfunction. Methods: Steatotic Zucker rat livers and livers from alcohol-fed rats were transplanted into lean control rats. Liver injury, activation of survival signals, and hepatic microcirculation were compared in nontreated and interleukin-6 (IL6)-treated steatotic isografts. Results: IL-6 pretreatment of steatotic Zucker rat liver isografts dramatically reduces mortality and liver injury following transplantation. Reperfusion after transplantation induces significant sinusoidal endothelial cell necrapoptosis in steatotic Zucker rat liver isografts, which is prevented by in vitro IL-6 pretreatment. IL-6 treatment activates cell survival signal transducer and activator of transcription factor 3 (STAT3) in hepatocytes and sinusoidal endothelial cells. Laser Doppler imaging and microsphere analyses demonstrate that IL-6 treatment markedly improves hepatic microcirculation, which is impaired in steatotic Zucker rat liver transplants. Finally, in vitro IL-6 treatment of donor livers also markedly reduces mortality associated with fatty liver transplants from alcohol-fed rats. Conclusions: IL-6 induces hepatoprotection of steatotic liver isografts via preventing sinusoidal endothelial cell necrapoptosis and consequent amelioration of hepatic microcirculation, and protecting against hepatocyte death. IL-6 pretreatment of steatotic livers may render such allografts useable for clinical transplantation.

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