Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation

Takashi Kaizu, Atsushi Ikeda, Atsunori Nakao, Allan Tsung, Hideyoshi Toyokawa, Shinya Ueki, David A. Geller, Noriko Murase

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Carbon monoxide (CO), a product of heme degradation by heme oxygenases (HO), has been shown to provide cytoprotection in various tissue injury models. This study examined the efficacy and molecular mechanisms of exogenously delivered inhaled CO in protecting liver grafts from cold ischemia/reperfusion (I/R) injury associated with liver transplantation. Orthotopic syngenic liver transplantation (OLT) was performed in Lewis rats with 18-h cold preservation in University of Wisconsin solution. Recipients were exposed to air or different concentrations of CO (20-250 ppm) for 1 h before and 24 h after OLT and killed 1-48 h posttransplant. CO inhalation significantly decreased serum alanine transaminase (ALT) levels and suppressed hepatic necrosis and neutrophil accumulation at 24-48 h after OLT in a dose-dependent manner. Reduced hepatic injury with inhaled CO is associated with marked downregulation of early mRNA expression for TNF-α and IL-6. Expression in liver grafts of mRNA and protein of the stress-responding enzyme inducible nitric oxide synthase was significantly reduced by CO, while HO-1 was only marginally suppressed. Cold hepatic I/R injury was associated with prompt MAPK phosphorylation in liver grafts at 1 h after OLT, and CO significantly inhibited phosphorylation of ERK1/2 MAPK and its upstream MEK1/2 and downstream transcriptional factor c-Myc. CO also significantly inhibited I/R injury-induced STAT1 and STAT3 activation. In contrast, CO did not inhibit p38 or JNK MAPK pathways during hepatic I/R injury. Results demonstrate that exogenous CO suppresses early proinflammatory and stress-response gene expression and efficiently ameliorates hepatic I/R injury. The possible mechanism may include the downregulation of MEK/ERK1/2 signaling pathway with CO.

Original languageEnglish
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume294
Issue number1
DOIs
Publication statusPublished - 2007
Externally publishedYes

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MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Carbon Monoxide
Reperfusion Injury
Down-Regulation
Transplants
Liver
Isogeneic Transplantation
Liver Transplantation
Cold Ischemia
Phosphorylation
Heme Oxygenase (Decyclizing)
Messenger RNA
Heme Oxygenase-1
Cytoprotection
Wounds and Injuries
Nitric Oxide Synthase Type II
Heat-Shock Proteins
Alanine Transaminase
Heme

Keywords

  • Extracellular signal-regulated kinase
  • Heme oxygenase-1
  • Hepatic nonparenchymal cells
  • Inducible nitric oxide synthase
  • Proinflammatory cytokines

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. / Kaizu, Takashi; Ikeda, Atsushi; Nakao, Atsunori; Tsung, Allan; Toyokawa, Hideyoshi; Ueki, Shinya; Geller, David A.; Murase, Noriko.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 294, No. 1, 2007.

Research output: Contribution to journalArticle

Kaizu, Takashi ; Ikeda, Atsushi ; Nakao, Atsunori ; Tsung, Allan ; Toyokawa, Hideyoshi ; Ueki, Shinya ; Geller, David A. ; Murase, Noriko. / Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2007 ; Vol. 294, No. 1.
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T1 - Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation

AU - Kaizu, Takashi

AU - Ikeda, Atsushi

AU - Nakao, Atsunori

AU - Tsung, Allan

AU - Toyokawa, Hideyoshi

AU - Ueki, Shinya

AU - Geller, David A.

AU - Murase, Noriko

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AB - Carbon monoxide (CO), a product of heme degradation by heme oxygenases (HO), has been shown to provide cytoprotection in various tissue injury models. This study examined the efficacy and molecular mechanisms of exogenously delivered inhaled CO in protecting liver grafts from cold ischemia/reperfusion (I/R) injury associated with liver transplantation. Orthotopic syngenic liver transplantation (OLT) was performed in Lewis rats with 18-h cold preservation in University of Wisconsin solution. Recipients were exposed to air or different concentrations of CO (20-250 ppm) for 1 h before and 24 h after OLT and killed 1-48 h posttransplant. CO inhalation significantly decreased serum alanine transaminase (ALT) levels and suppressed hepatic necrosis and neutrophil accumulation at 24-48 h after OLT in a dose-dependent manner. Reduced hepatic injury with inhaled CO is associated with marked downregulation of early mRNA expression for TNF-α and IL-6. Expression in liver grafts of mRNA and protein of the stress-responding enzyme inducible nitric oxide synthase was significantly reduced by CO, while HO-1 was only marginally suppressed. Cold hepatic I/R injury was associated with prompt MAPK phosphorylation in liver grafts at 1 h after OLT, and CO significantly inhibited phosphorylation of ERK1/2 MAPK and its upstream MEK1/2 and downstream transcriptional factor c-Myc. CO also significantly inhibited I/R injury-induced STAT1 and STAT3 activation. In contrast, CO did not inhibit p38 or JNK MAPK pathways during hepatic I/R injury. Results demonstrate that exogenous CO suppresses early proinflammatory and stress-response gene expression and efficiently ameliorates hepatic I/R injury. The possible mechanism may include the downregulation of MEK/ERK1/2 signaling pathway with CO.

KW - Extracellular signal-regulated kinase

KW - Heme oxygenase-1

KW - Hepatic nonparenchymal cells

KW - Inducible nitric oxide synthase

KW - Proinflammatory cytokines

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