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Biomedical subjects

David A Geller

Publications and source records attributed to David A Geller.

At least 19 recordsLinked to original sources
PubMed2006

Glycochenodeoxycholate (GCDC) inhibits cytokine induced iNOS expression in rat hepatocytes.

BACKGROUND: Although the accumulation of hydrophobic bile acid (e.g., glycine conjugated chenodeoxycholic acid, GCDC) is considered to be an important factor contributing to cholestatic liver dysfunction, its pathogenesis is poorly understood. The purpose of this study was to examine the effect of the bile salt GCDC on the regulation of iNOS expression, a key immune modulator during liver inflammation. MATERIALS AND METHODS: GCDC significantly decreased cytokine-stimulated iNOS promoter activity, and both iNOS mRNA and protein expression. GCDC decreased iNOS promoter activity by preventing IkappaB degradation and inhibiting NF-kappaB DNA-binding activity. To explore the role of iNOS in bile salt induced apoptosis, we also examined the effect of NO on caspase-3 activity. RESULTS: GCDC strongly induced caspase-3 activity, and this increase was abrogated by both exogenous NO exposure and endogenous NO synthesis. Furthermore, adenoviral iNOS (AdiNOS) pre-treatment decreased acute cholestatic-induced liver injury in a rat bile duct ligation model. CONCLUSIONS: These findings indicate a novel signaling pathway where potentially toxic bile salts down-regulate hepatic iNOS expression. This blockade of the iNOS mediated antiapoptotic phenotype may have important implications in certain liver disorders.

Adenoviridae↗
PubMed2006

Identification of a classic cytokine-induced enhancer upstream in the human iNOS promoter.

The human inducible NOS (iNOS) promoter transcriptionally regulated by 5' flanking region extending 16 kb upstream that contains cytokine-responsive DNA motifs. In this study, we further identified a classic inducible enhancer located between -5 and -6 kb in the hiNOS upstream promoter. This 1 kb promoter sequence functions as a cytokine-inducible enhancer in an orientation- and position-independent manner in human lung A549 and liver AKN1 cells. This DNA enhancer also confers cytokine inducibility to the heterologous thymidine kinase (TK) promoter. Chromatin immunoprecipitation (ChIP) analysis was applied, and confirmed cytokine-inducible in vivo DNA-protein interactions within this enhancer region. In vivo functional binding of both NF-kappaB (p65/p50) and Stat-1alpha at the -5.8 kb human iNOS promoter site was significantly increased in A549 cells after cytokine stimulation, while only Stat-1alpha bound at the -5.2 kb site. These results identify the -5 to -6 kb promoter region as a classic transcriptional enhancer for the human iNOS gene and provide definitive in vivo evidence of specific NF-kappaB and Stat-1 nuclear protein binding that mediates transcription of the hiNOS gene under cytokine stimulation.

Binding Sites↗
PubMed2006

Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury.

Endogenous ligands released from damaged cells, so-called damage-associated molecular pattern molecules (DAMPs), activate innate signaling pathways including the TLRs. We have shown that hepatic, warm ischemia and reperfusion (I/R) injury, generating local, noninfectious DAMPs, promotes inflammation, which is largely TLR4-dependent. Here, we demonstrate that increasing dendritic cell (DC) numbers enhance inflammation and organ injury after hepatic I/R. High-mobility group box 1 (HMGB1), a NF released by necrotic cells or secreted by stimulated cells, is one of a number of ligands promoting TLR4 reactivity. Augmentation of DC numbers in the liver with GM-CSF hydrodynamic transfection significantly increased liver damage after I/R when compared with controls. TLR4 engagement on hepatic DC was required for the I/R-induced injury, as augmentation of DC numbers in TLR4 mutant (C3H/HeJ) mice did not worsen hepatic damage. It is interesting that TLR4 expression was increased in hepatic DC following HMGB1 stimulation in vitro, suggesting a mechanism for the increased liver injury following I/R. It thus appears that functional TLR4 on DC is required for I/R-induced injury. Furthermore, HMGB1 may direct the inflammatory responses mediated by DC, at least in part, by enhancing TLR4 expression and reactivity to it and other DAMPs.

Animals↗
PubMed2006

Liver I/R injury is improved by the arginase inhibitor, N(omega)-hydroxy-nor-L-arginine (nor-NOHA).

Liver ischemia-reperfusion (I/R) injury is associated with profound arginine depletion due to arginase release from injured hepatocytes. The purpose of this study was to determine whether arginase inhibition with N(omega)-hydroxy-nor-l-arginine (nor-NOHA) would increase circulating arginine levels and decrease hepatic damage during liver I/R injury. The effects of nor-NOHA were initially tested in normal animals to determine in vivo toxicity. In the second series of experiments, orthotopic syngeneic liver transplantation (OLT) was performed after 18 h of cold ischemia time in Lewis rats. Animals were given nor-NOHA (100 mg/kg) or saline before and after graft reperfusion. In normal animals treated with nor-NOHA, there were no histopathological changes to organs, liver enzymes, serum creatinine, or body weight. In the OLT model, animals treated with saline exhibited markedly elevated serum transaminases and circulating arginase protein levels. Nor-NOHA administration blunted the increase in serum arginase activity by 80% and preserved serum arginine levels at 3 h after OLT. Nor-NOHA treatment reduced post-OLT serum liver enzyme release by 50%. Liver histology (degree of necrosis) in nor-NOHA-treated animals was markedly improved compared with the saline-treated group. Furthermore, use of the arginase inhibitor nor-NOHA did not influence polyamine synthesis owing to the decrease in ornithine levels. Arginase blockade represents a potentially novel strategy to combat hepatic I/R injury associated with liver transplantation.

Alanine Transaminase↗
PubMed2006

Hydrodynamic plasmid DNA gene therapy model in liver transplantation.

BACKGROUND: There is great interest in the field of transplantation to genetically modify grafts to decrease preservation injury or allograft rejection. Although adenoviral gene transfer has been effective in experimental liver transplantation, viral toxicity and safety concerns limit potential use in clinical trials. Therefore, the purpose of this study was to develop a model of nonviral gene transfer in the liver transplant setting, allowing for efficient transgene expression. MATERIALS AND METHODS: Orthotopic syngeneic rat liver transplantation was performed with 3 h cold ischemia using University of Wisconsin (UW) preservation. A hydrodynamic gene transfer technique was developed where plasmid DNA was delivered to the liver graft by ex vivo rapid infusion of DNA in UW via the IVC with other vessels clamped. Expression plasmids for the marker genes luciferase and secreted human alpha1-antitrypsin (alpha1-AT) were used. Hepatic injury was assessed by graft histology and liver transaminases. Transgene expression was determined by hepatic luciferase relative light units activity (RLU) and serum alpha1-AT protein levels. Variables examined included the effect of (a) volume injected on the intravenous pressure in the liver graft; (b) injury to the liver, as measured by hepatic enzymes and histopathology; (c) variable expression between lobes; (d) volume of UW that the plasmid is administered in; (e) amount of DNA plasmid; (f) type of the promoter used; (g) clamp time; as well as (h) the time course of the marker gene expression. RESULTS: Control rats underwent standard orthotopic syngeneic rat liver transplantation and had no detectable hepatic luciferase activity or serum human alpha1-AT. The optimal DNA plasmid dose was found to be 400 mug/liver graft, as there was no increase in the luciferase expression by increasing the dose. Furthermore, cytomegalovirus promoter yielded greater expression than Rous sarcoma virus. A high injection pressure gradient allowed for more efficient transgene expression, but produced greater liver injury shown by elevated transaminases and centrilobular necrosis. Lowering injection volume from 75 to 50% of graft weight decreased liver injury by 4.5-fold. Although higher UW injection volumes were associated with increased expression, volumes of only 50% led to luciferase expression up to 10,000,000 RLU/mg; this expression was homogeneous between the different liver lobes. Human alpha1-AT was detected in recipient blood as early as 6 h, peaked at 24 h, and remained high for 5 days. CONCLUSIONS: We have developed a nonviral gene transfer technique where hydrostatic pressure across the cold-preserved liver vascular bed allows for efficient plasmid DNA delivery. This simple strategy should prove useful to genetically modify liver grafts in the transplantation setting.

Analysis of Variance↗
PubMed2006

Regulation of human nitric oxide synthase 2 expression by Wnt beta-catenin signaling.

Nitric oxide (NO.), an important mediator of inflammation, and beta-catenin, a component of the Wnt-adenomatous polyposis coli signaling pathway, contribute to the development of cancer. We have identified two T-cell factor 4 (Tcf-4)-binding elements (TBE1 and TBE2) in the promoter of human inducible NO synthase 2 (NOS2). We tested the hypothesis that beta-catenin regulates human NOS2 gene. Mutation in either of the two TBE sites decreased the basal and cytokine-induced NOS2 promoter activity in different cell lines. The promoter activity was significantly reduced when both TBE1 and TBE2 sites were mutated (P < 0.01). Nuclear extract from HCT116, HepG2, or DLD1 cells bound to NOS2 TBE1 or TBE2 oligonucleotides in electrophoretic mobility shift assays and the specific protein-DNA complexes were supershifted with anti-beta-catenin or anti-Tcf-4 antibody. Overexpression of beta-catenin and Tcf-4 significantly increased both basal and cytokine-induced NOS2 promoter activity (P < 0.01), and the induction was dependent on intact TBE sites. Overexpression of beta-catenin or Tcf-4 increased NOS2 mRNA and protein expression in HCT116 cells. Lithium chloride (LiCl), an inhibitor of glycogen synthase kinase-3beta, increased cytosolic and nuclear beta-catenin level, NOS2 expression, and NO. production in primary human and rat hepatocytes and cancer cell lines. Treatment with Wnt-3A-conditioned medium increased beta-catenin and NOS2 expression in fetal human hepatocytes. When administered in vivo, LiCl increased hepatic beta-catenin level in a dose-dependent manner with simultaneous increase in NOS2 expression. These data are consistent with the hypothesis that beta-catenin up-regulates NOS2 and suggest a novel mechanism by which the Wnt/beta-catenin signaling pathway may contribute to cancer by increasing NO. production.

Animals↗
PubMed2006

Cutting edge: high-mobility group box 1 preconditioning protects against liver ischemia-reperfusion injury.

High mobility group box 1 (HMGB1) is a NF released extracellularly as a late mediator of lethality in sepsis and as an early mediator of inflammation following injury. Here we demonstrate that in contrast to the proinflammatory role of HMGB1, preconditioning with HMGB1 results in protection following hepatic ischemia/reperfusion (I/R). Pretreatment of mice with HMGB1 significantly decreased liver damage after I/R. The protection observed in mice pretreated with HMGB1 was associated with a higher expression of IL-1R-associated kinase-M, a negative regulator of TLR4 signaling, compared with controls. We thus explored the possibility that HMGB1 preconditioning was mediated through TLR4 activation. HMGB1 preconditioning failed to provide protection in TLR4 mutant (C3H/HeJ) mice, but successfully reduced damage in TLR4 wild-type (C3H/HeOuj) mice. Our studies demonstrate that in contrast to the role of HMGB1 as an early mediator of inflammation and organ damage in hepatic I/R, HMGB1 preconditioning can be protective.

Amino Acid Sequence↗
PubMed2006

The transcription factor interferon regulatory factor-1 mediates liver damage during ischemia-reperfusion injury.

Hepatic ischemia occurs in the settings of trauma, transplantation, and elective liver resections. The initiating events that account for local organ damage are only partially understood. Interferon (IFN) regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of a number of genes involved in both innate and acquired immunity; however, its function in liver injury is unknown. Therefore, the purpose of this study was to investigate the role of IRF-1 in hepatic ischemia-reperfusion (I/R) injury. In C57BL/6 mice undergoing 60 min of hepatic ischemia, IRF-1 protein expression increased as early as 1 h after reperfusion. IRF-1 knockout mice were significantly protected from hepatic I/R-induced damage compared with their wild-type controls. Hepatic I/R injury resulted in marked activation of the MAP kinase c-Jun NH(2)-terminal kinase (JNK) in wild-type mice but not IRF-1 knockout mice. IRF-1 knockout mice also exhibited significantly lower hepatic expression of TNF-alpha, IL-6, ICAM-1, and inducible nitric oxide synthase (iNOS) mRNA. Adenoviral delivery of IRF-1 into C57BL/6 mice resulted in increased liver damage even without an ischemic insult. This injury was associated with increased JNK activation and hepatic iNOS expression. Because IRF-1 contributed to liver injury, we also examined for inflammatory signals that regulated IRF-1 gene expression in cultured hepatocytes. Whereas IFN-gamma and IFN-beta were strong inducers of IRF-1 mRNA (>10-fold) in a time- and dose-dependent manner, TNF-alpha and IL-1beta also induced IRF-1 mRNA to a lesser extent (2- to 3-fold). IL-6 and lipopolysaccharide had no effect on IRF-1 expression. This study demonstrates that IRF-1 exerts a harmful role in hepatic I/R injury by modulating the expression of multiple inflammatory mediators. We further show that IRF-1-mediated injury involves the activation of JNK and that hepatocellular IRF-1 expression itself is regulated by specific cytokines.

Animals↗
PubMed2006

Donor graft adenoviral iNOS gene transfer ameliorates rat liver transplant preservation injury and improves survival.

The exact role of inducible NOS (iNOS) in liver ischemia/reperfusion (I/R) injury is controversial. This study was designed to investigate whether donor liver pretreatment with adenovirus encoding iNOS (AdiNOS) ameliorates I/R injury associated with liver transplantation. Orthotopic syngeneic LEW rat liver transplantation (OLT) was performed after 18 or 24 hours' preservation in cold UW. AdiNOS or control gene vector (AdLacZ) was delivered to the liver by donor intravenous pretreatment 4 days before graft harvesting. Uninfected grafts also served as control. Recipients were sacrificed 1 to 48 hours posttransplantation. An abundant hepatic iNOS protein expression and marked serum NO elevation was observed in the AdiNOS-treated group, without affecting endothelial nitric oxide synthase (eNOS) expression, before harvesting and after OLT. AdiNOS pretreatment markedly improved liver function assessed by serum aspartate aminotransferase/alanine aminotransferase levels and reduced liver necrosis formation. AdiNOS treatment also was associated with reduced ICAM-1 mRNA expression and neutrophil accumulation in the liver graft after OLT compared with untransfected or AdLacZ-treated group. Furthermore, AdiNOS delivery significantly improved transplant survival, compared with AdLacZ or saline controls. AdiNOS pretreatment did not attenuate I/R-induced apoptotic cell death in the liver graft. Administration of a selective inhibitor for iNOS abrogated the protection afforded by AdiNOS pretreatment. In conclusion, donor pretreatment with AdiNOS led to improved liver graft injury and posttransplantation survival. Downregulation of ICAM-1 mRNA and neutrophil infiltration may be associated with the mechanisms by which AdiNOS pretreatment confer the protection against transplant-associated hepatic I/R injury.

Adenoviridae↗
PubMed2006

Outcome of 1000 liver cancer patients evaluated at the UPMC Liver Cancer Center.

We evaluated 1000 consecutive patients with liver tumors at the University of Pittsburgh Medical Center (UPMC) Liver Cancer Center over the 4-year period from August 2000 to August 2004. Of the 1000 patients seen, 573 had primary liver cancer and 427 had metastatic cancer to the liver. The mean age of the patients evaluated was 62.2 years, and 61% were male. Treatment consisted of a liver surgical procedure (resection or radiofrequency ablation) in 369 cases (36.9%), hepatic intra-arterial regional therapy (transarterial chemoembolization or (90)yttrium microspheres) in 524 cases (52.4%), systemic chemotherapy in 35 cases (3.5%), and palliative care in 72 patients (7.2%). For treated patients, median survival was 884 days for those undergoing resection/radiofrequency ablation, compared to 295 days with regional therapy. These data indicate that over 90% of patients with liver cancer evaluated at a tertiary referral center can be offered some form of therapy. Survival rates are superior with a liver resection or ablation procedure, which is likely consistent with selection bias. Hepatocellular carcinoma was the most common tumor seen due to referral pattern and screening of hepatitis patients at a major liver transplant center. The most common reason for offering palliative care was hepatic insufficiency usually associated with cirrhosis.

Age Factors↗
PubMed2005

Hepatic ischemia/reperfusion injury involves functional TLR4 signaling in nonparenchymal cells.

Endogenous ligands from damaged cells, so-called damage-associated molecular pattern molecules, can activate innate immunity via TLR4 signaling. Hepatic warm ischemia and reperfusion (I/R) injury and inflammation is largely TLR4 dependent. We produced TLR4 chimeric mice to assess whether the TLR4-dependent injury required TLR4 expression on liver parenchymal or nonparenchymal cells. Chimeric mice were produced by adoptive transfer of donor bone marrow cells into irradiated recipient animals using reciprocal combinations of TLR4 wild-type (WT; C3H/HeOuj) and TLR4 mutant (C3H/HeJ) mouse bone marrow. Wild-type chimeric mice bearing TLR4 mutant hemopoietic cells and TLR4 mutant mice transplanted with their own bone marrow-derived cells were protected from hepatic I/R and exhibited decreased JNK and NF-kappaB activation compared with WT chimeric mice transplanted with their own bone marrow. In contrast, TLR4 mutant mice transplanted with TLR4 WT bone marrow were not protected from liver I/R and demonstrated pronounced increases in JNK and NF-kappaB activation when compared with autochthonous transplanted mutant mice. In addition, depletion of phagocytes taking up gadolinium chloride failed to provide any additional protection to TLR4 mutant mice, but substantially reduced damage in WT mice after hepatic I/R. Together, these results demonstrate that TLR4 engagement on actively phagocytic nonparenchymal cells such as Kupffer cells is required for warm I/R-induced injury and inflammation in the liver.

Animals↗
PubMed2005

The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion.

High-mobility group box 1 (HMGB1) is a nuclear factor that is released extracellularly as a late mediator of lethality in sepsis as well as after necrotic, but not apoptotic, death. Here we demonstrate that in contrast to the delayed role of HMGB1 in the systemic inflammation of sepsis, HMGB1 acts as an early mediator of inflammation and organ damage in hepatic ischemia reperfusion (I/R) injury. HMGB1 levels were increased during liver I/R as early as 1 h after reperfusion and then increased in a time-dependent manner up to 24 h. Inhibition of HMGB1 activity with neutralizing antibody significantly decreased liver damage after I/R, whereas administration of recombinant HMGB1 worsened I/R injury. Treatment with neutralizing antibody was associated with less phosphorylation of c-Jun NH(2)-terminal kinase and higher nuclear factor-kappaB DNA binding in the liver after I/R. Toll-like receptor 4 (TLR4)-defective (C3H/Hej) mice exhibited less damage in the hepatic I/R model than did wild-type (C3H/HeOuj) mice. Anti-HMGB1 antibody failed to provide protection in C3H/Hej mice, but successfully reduced damage in C3H/Ouj mice. Together, these results demonstrate that HMGB1 is an early mediator of injury and inflammation in liver I/R and implicates TLR4 as one of the receptors that is involved in the process.

Animals↗
PubMed2005

90Y microsphere treatment of unresectable liver metastases: changes in 18F-FDG uptake and tumour size on PET/CT.

PURPOSE: The intra-arterial administration of 90Y microspheres is a new palliative treatment option for unresectable liver metastases. The aim of this study was to quantitatively assess changes in FDG uptake and tumour size following 90Y microsphere treatment (SIR-Spheres) using 18F-fluorodeoxyglucose (FDG) PET/CT imaging. METHODS: Five patients with unresectable liver metastases who had failed multiple prior chemotherapy regimens received seven 90Y microsphere treatments to a single liver lobe. All patients underwent a baseline PET/CT scan prior to treatment, as well as up to four follow-up PET/CT scans. The tumour area of 30 liver metastases was measured on CT and the FDG uptake was semiquantitatively assessed by calculation of standardised uptake values (SUVs). A total of 18 FDG-PET/CT scans were performed. RESULTS: The SUVs in the 30 treated liver metastases decreased from 6.5+/-2.3 at baseline to 4.2+/-1.8 after the first follow-up PET/CT scan (p=0.001). In contrast, the SUVs of untreated metastases increased slightly from 7.2+/-2.3 to 8.0+/-0.8. There was no difference in FDG uptake in treated versus untreated normal liver tissue. Using a previously defined threshold of 20% decrease in SUV from baseline to determine response, 20 out of 30 liver metastases were considered to have responded at the first follow-up PET/CT scan approximately 1 month after treatment. In these metastases, the SUV decreased by 47+/-12%, compared with a slight increase by 5.9+/-19% in ten non-responding metastases (p=0.0001). The changes in tumour size did not correlate with changes in FDG uptake. On the first follow-up PET/CT scan, the tumour area on CT increased by 3.1+/-57% in treated metastases compared with 23.3+/-32% in untreated metastases. A wide range of post-treatment changes of target lesions was observed on CT, including an increase in the size of hypodense lesions, necrotic features and complete resolution of CT abnormalities. CONCLUSION: The metabolic information obtained from FDG-PET/CT seems to provide a more accurate and earlier assessment of therapy response following 90Y microsphere treatment than does the anatomical CT information.

Adult↗
PubMed2005

Ethyl pyruvate ameliorates liver ischemia-reperfusion injury by decreasing hepatic necrosis and apoptosis.

BACKGROUND: Hepatic ischemia-reperfusion injury (I/R) occurs in the settings of transplantation, trauma, and elective liver resections. Reactive oxygen species (ROS) have been shown to play a major role in organ I/R injury. Pyruvate, a key intermediate in cellular metabolism, is an effective scavenger of ROS. The purpose of this study was to test the hypothesis that ethyl pyruvate (EP), a soluble pyruvate derivative, is effective in preventing hepatic I/R injury. METHODS: Lewis rats underwent 60 minutes of partial warm hepatic ischemia. Three doses of EP dissolved in lactated Ringer's solution or lactated Ringer's solution (LR) alone were given by intravenous injection. Serum and tissue samples were obtained at 1 to 24 hours postreperfusion. RESULTS: Serum transaminases, degree of hepatic necrosis, and neutrophil infiltration were all significantly decreased in the EP-treated rats compared with control animals. The amount of hepatic lipid peroxidation was also significantly decreased in EP-treated animals. Both circulating levels and hepatic expression of inflammatory cytokines were significantly decreased in the EP-treated animals. Furthermore, EP inhibited activation of extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase mitogen-activated protein kinases, as well as nuclear factor-kappaB, signaling pathways involved in cytokine release. Treatment with EP also inhibited hepatic apoptosis. CONCLUSION: EP has a protective effect on hepatic I/R injury, mediated in part by decreasing lipid peroxidation, down-regulation of inflammatory mediators, and inhibition of apoptosis. Strategies using this additive to LR solution should be considered in clinical settings of ischemic liver injury to decrease organ damage.

Animals↗
PubMed2005

Proxy ratings of health related quality of life in patients with hepatocellular carcinoma.

The present study prospectively assessed consistency of ratings of health-related quality of life between patients with hepatocellular carcinoma and two types of proxy raters, family caregivers and oncologist care providers. Patients and proxies completed the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) at baseline prior to treatment (82 patients plus proxies), at 3-months (32 patients plus proxies), and 6-months follow up (16 patients plus proxies) after diagnosis. Patient and proxy demographic data and patient medical data were also collected. At baseline, significant intra-class correlations (ICC) were found for patient--caregiver ratings of physical, social/family, and functional well-being, additional concerns (symptoms, side effects), and overall health related quality of life (HRQL); for patient--care provider ratings of physical well-being; and for caregiver--care provider ratings of physical and emotional well-being. At 3-months follow-up, the most significant number of ICCs were recorded across all three rater pairs. Significant consistencies were found for overall HRQL, and all subscale scores except for social and family well-being. The fewest significant ICCs were found at the 6-month follow-up, and were for patient--caregiver ratings of physical and functional well-being, and additional concerns; and for caregiver--care provider ratings on overall HRQL. These results suggest that family caregivers are adequate proxies of patient physical and functional well-being and additional concerns throughout the patient's illness, more so than oncologist care providers. Further research is warranted with larger samples.

Adult↗
PubMed2005

Carbon monoxide inhalation ameliorates cold ischemia/reperfusion injury after rat liver transplantation.

BACKGROUND: Carbon monoxide (CO), a product of heme degradation by heme oxygenase, induces cytoprotection against ischemia/reperfusion (I/R) injury in a variety of organs such as the heart, lung, kidney, and small intestine. We examined whether CO would protect liver grafts against cold I/R injury associated with transplantation. METHODS: Orthotopic liver transplantation (OLT) was performed in syngeneic Lewis rats with 18 hours preservation in cold University of Wisconsin solution. Recipients were exposed to air or CO (100 ppm) for 1 hour before and 24 hours after OLT. Recipients were sacrificed 0.5 to 48 hours post-transplant. RESULTS: CO inhalation significantly decreased serum aspartate aminotransferase and alanine aminotransferase levels and suppressed hepatic necrosis formation and neutrophil accumulation at 6 to 48 hours after OLT, compared with air control. The expressions of tumor necrosis factor alpha, intercellular adhesion molecule 1, and inducible nitric oxide synthase messenger RNA in the liver graft were significantly inhibited in the CO-treated group at 1 hour after reperfusion. Hepatic nuclear factor-kappaB activation did not differ between the groups. CONCLUSIONS: The results demonstrate that exogenous CO treatment suppresses early proinflammatory gene expression and neutrophil infiltration, and efficiently ameliorates hepatic I/R injury. The possible mechanism by which CO protects the liver against cold I/R does not seem to be associated with downregulation of the nuclear factor-kappaB-signaling pathway.

Administration, Inhalation↗