Back to Search
Start Over
Protection of transplant-induced hepatic ischemia/reperfusion injury with carbon monoxide via MEK/ERK1/2 pathway downregulation.
- Source :
-
American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2008 Jan; Vol. 294 (1), pp. G236-44. Date of Electronic Publication: 2007 Nov 15. - Publication Year :
- 2008
-
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-alpha 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.
- Subjects :
- Administration, Inhalation
Alanine Transaminase blood
Animals
Apoptosis Regulatory Proteins genetics
Apoptosis Regulatory Proteins metabolism
Carboxyhemoglobin metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Down-Regulation
Heme Oxygenase (Decyclizing) genetics
Heme Oxygenase (Decyclizing) metabolism
Interleukin-6 genetics
Interleukin-6 metabolism
Liver enzymology
Liver pathology
MAP Kinase Kinase 1 metabolism
MAP Kinase Kinase 2 metabolism
Male
Necrosis
Neutrophil Infiltration drug effects
Nitric Oxide metabolism
Nitric Oxide Synthase Type II genetics
Nitric Oxide Synthase Type II metabolism
Phosphorylation
Proto-Oncogene Proteins c-myc metabolism
RNA, Messenger metabolism
Rats
Rats, Inbred Lew
Reperfusion Injury enzymology
Reperfusion Injury etiology
Reperfusion Injury pathology
STAT Transcription Factors metabolism
Time Factors
Tumor Necrosis Factor-alpha genetics
Tumor Necrosis Factor-alpha metabolism
Carbon Monoxide administration & dosage
Cold Ischemia adverse effects
Liver drug effects
Liver Transplantation adverse effects
MAP Kinase Kinase Kinases metabolism
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 metabolism
Protective Agents administration & dosage
Reperfusion Injury prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 0193-1857
- Volume :
- 294
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Publication Type :
- Academic Journal
- Accession number :
- 18006605
- Full Text :
- https://doi.org/10.1152/ajpgi.00144.2007