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1.
Dig Dis Sci ; 51(11): 2102-12, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17024574

ABSTRACT

Neutrophil elastase, which enhances intercellular adhesion molecule-1 (ICAM-1) expression in endothelial cells, plays an important role in ischemia/reperfusion injury. Here, we investigated signal transduction of ICAM-1 expression in endothelial cells stimulated by neutrophil elastase. Pretreatment of animals with the neutrophil elastase inhibitor, ONO-5046.Na significantly decreased the number of neutrophils or Mac-1(+) (CD11b/CD18) cells in ischemic liver lobes after reperfusion. ICAM-1 expression in the rat endothelial cell line (WK-5) was significantly upregulated after stimulation with neutrophil elastase, but this reaction was inhibited by the neutrophil elastase inhibitor ONO-5046.Na. ICAM-1 mRNA expression, which is induced by neutrophil elastase in a dose-dependent manner, was repressed by the alpha1-protease inhibitor. ICAM-1 expression, stimulated by neutrophil elastase, was partially reduced by a diacylglycerol kinase inhibitor and protein kinase C inhibitor, but was completely inhibited by a phospholipase C inhibitor, cytosolic Ca(2+) chelator, calmodulin antagonist, and nuclear transcription factor kappa B inhibitor. Binding of (125)I-neutrophil elastase to WK-5 cells was competitively inhibited by the addition of unlabeled neutrophil elastase. The neutrophil elastase inhibitor significantly reduces ICAM-1 expression and Mac-1(+) cell accumulation in ischemic liver lobes after reperfusion. Neutrophil elastase stimulates ICAM-1 expression in endothelial cells by intracellular signal transduction via activation of diacylglycerol kinase, protein kinase C, phospholipase C, Ca(2+)-calmodulin, and nuclear transcription factor kappa B.


Subject(s)
Endothelial Cells/metabolism , Intercellular Adhesion Molecule-1/metabolism , Leukocyte Elastase/physiology , Signal Transduction/physiology , Animals , Blotting, Northern , Dose-Response Relationship, Drug , Glycine/analogs & derivatives , Glycine/pharmacology , Immunohistochemistry , Leukocyte Elastase/antagonists & inhibitors , Male , RNA, Messenger/analysis , Rats , Rats, Wistar , Signal Transduction/drug effects , Sulfonamides/pharmacology , alpha 1-Antitrypsin/pharmacology
2.
J Surg Res ; 135(1): 52-60, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16716354

ABSTRACT

BACKGROUND: The pre-transplant administration of donor antigens to recipients is reported to prolong transplanted organ survival. We investigated the effect of pre-transplant intraportal administration of recipient blood on rat hepatic allograft survival. MATERIALS AND METHODS: Male LEW (RT1l) and ACI (RT1a) rats were used as transplant recipients and donors, respectively. Before transplantation, donors were transfused with recipient blood. Experimental animals were divided into groups as follows: group I, no treatment; group II, pre-treatment with recipient blood via the penile vein 7 days before transplantation; group III, pre-treatment with recipient blood via the portal vein 5 days before transplantation; and group IV, pre-treatment with recipient blood via the portal vein 7 days before transplantation. Serum interferon (IFN)-gamma concentrations were measured post-operatively. RESULTS: Animals in group I survived a mean of 10.1 +/- 0.7 days. The survival of groups II and III was 10.6 +/- 1.6 and 13.1 +/- 0.9 days, respectively. The survival rate in group IV was prolonged significantly to 33.7 +/- 2.6 days. Serum concentrations of IFN-gamma were increased significantly in group IV, as compared with group I. The ratio of OX76+CD4+ or OX76+CD8+ T cells to OX76-CD4+ or OX76-CD8+ T cells was greater in group IV, as compared group I. OX76+CD8+ T cells from hepatic allografts in group IV expressed IFN-gamma and interleukin (IL)-10, but not IL-2 mRNA. Apoptotic hepatic infiltrates were greater in group IV, as compared to group I. CONCLUSION: The cytokine profile of donor CD8+ T cells from allografts treated by the intraportal administration of recipient blood is associated with apoptosis of graft-infiltrating cells and the prolonged survival of hepatic allografts in rats.


Subject(s)
Blood Transfusion , Graft Survival/immunology , Liver Transplantation , Lymphocyte Transfusion , Transplantation Conditioning/methods , Animals , Apoptosis , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/transplantation , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/transplantation , Flow Cytometry , Interferon-gamma/genetics , Interleukin-10/genetics , Interleukin-2/genetics , Liver/pathology , Liver/surgery , Male , Portal Vein , RNA, Messenger/analysis , Rats , Rats, Inbred ACI , Rats, Inbred Lew , Transplantation, Homologous
3.
J Surg Res ; 124(1): 29-37, 2005 Mar.
Article in English | MEDLINE | ID: mdl-15734476

ABSTRACT

Donor dendritic cells (DC) migrate into the recipient spleen after hepatic transplantation. Immunological unresponsiveness to rat hepatic allografts can be induced by prior donor-specific blood transfusion (DST). We investigated homing receptor phenotype and splenic distribution of donor DC after allografting and DST. Immunostaining revealed OX62+ cells in the splenic red pulp of animals receiving pre-transplant DST but only in the white pulp of untreated animals. Most OX62 cells were positive for OX76. There were two subsets of DC in the spleen, CD45RChighOX62+ and CD45RClowOX62+ cells. RT-PCR revealed that CD45RClowOX62+ cells expressed interleukin (IL)-10, while CD45RChighOX62+ cells expressed IL-2 and low levels of IL-10 mRNA. CD45RChighOX62+ cells strongly expressed CCR5 and CCR7, compared with weak expression in CD45RClowOX62+ cells. The Epstein-Barr virus-induced molecule 1 (EBI-1) ligand chemokine (ELC/MIP3beta) was expressed mainly within the splenic white pulp. Mucosal vascular addressin-cell adhesion molecule-1 (MAdCAM-1) was expressed in the marginal zone and white pulp, but expression of splenic MAdCAM-1 was down-regulated in DST-treated animals. L-selectin (CD62L), the ligand for MAdCAM-1, was strongly expressed on CD45RChighOX62+ cells but not on CD45RClowOX62+ cells. In conclusion, differential splenic migration of CCR5lowCCR7lowCD62Llow CD45RClow DC expressing Th2-type cytokines is associated with immunological unresponsiveness to rat hepatic allografts.


Subject(s)
Cell Movement/immunology , Dendritic Cells/immunology , Liver Transplantation/immunology , Spleen/immunology , Transplantation Tolerance/immunology , Animals , Antigens, Differentiation/immunology , Blood Transfusion , Immunoglobulins/immunology , L-Selectin/immunology , Leukocyte Common Antigens/immunology , Male , Models, Animal , Mucoproteins/immunology , Rats , Rats, Inbred Strains , Receptors, CCR5/immunology , Receptors, CCR7 , Receptors, Chemokine/immunology , Receptors, Lymphocyte Homing/immunology , Transplantation, Homologous/immunology
4.
J Surg Res ; 120(1): 73-82, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15172192

ABSTRACT

BACKGROUND: Fatty split-liver and living-related liver transplantation is associated with massive hepatocellular necrosis during acute rejection. Uncoupling protein (UCP)-2 is a potential regulator of energy expenditure and ATP production. We investigated the role of UCP-2 and the effects of a metalloprotease inhibitor, Y-39083, on hepatocellular injury in fatty liver allografts in rats. MATERIALS AND METHODS: Rats were treated for 6 weeks with high-ethanol or isocalic dextrose-containing liquid diets that caused characteristic pericentral lipid accumulation. Alcoholic or nonalcoholic fatty livers from ACI (RT1a) rats were transplanted into LEW (RT1l) rats orthotopically. Hepatic necrosis was determined histologically following liver transplantation. UCP-2 mRNA levels in the hepatic allograft and in primary cultured hepatocytes from fatty liver stimulated by tumor necrosis factor (TNF)-alpha were determined. Y-39083 was administered to recipient rats continuously at 5 mg/kg/day using an osmotic infusion mini-pump. RESULTS: The acute rejection index on day 5 posttransplant in alcoholic and nonalcoholic fatty donor livers was higher than in lean grafts. Massive hepatocyte necrosis was more prominent in alcoholic than nonalcoholic fatty liver allografts and was not seen in lean allografts. UCP-2 transcripts in both alcoholic and nonalcoholic fatty liver allografts were higher than in lean allografts. Serum TNF-alpha concentrations in recipient rats with either fatty liver allograft were greater than in animals with lean allografts. In vitro UCP-2 mRNA levels in primary cultured hepatocytes from both alcoholic and nonalcoholic fatty livers increased more after stimulation with TNF-alpha than those from lean livers. In vitro TNF-alpha production by Kupffer cells isolated from alcohol-induced fatty liver allografts on day 3 posttransplant was greater than those from lean allografts. Y-39083 significantly reduced serum concentrations of TNF-alpha and prevented massive hepatocellular necrosis in rats with both alcoholic and nonalcoholic fatty liver allografts. CONCLUSION: Liver grafts with steatosis up-regulated UCP-2. TNF-alpha further enhanced UCP-2 transcripts, inducing massive hepatocellular necrosis during acute rejection. Posttransplantation necrosis may be prevented by metalloprotease inhibitors.


Subject(s)
Fatty Liver/metabolism , Hepatocytes/drug effects , Liver Transplantation , Liver/drug effects , Membrane Transport Proteins/biosynthesis , Mitochondrial Proteins/biosynthesis , Animals , Fatty Liver/pathology , Fatty Liver/surgery , Graft Rejection/metabolism , Hepatocytes/pathology , Ion Channels , Kupffer Cells/drug effects , Kupffer Cells/metabolism , Liver/pathology , Necrosis , Rats , Tissue Inhibitor of Metalloproteinases/pharmacology , Transplantation, Homologous , Tumor Necrosis Factor-alpha/biosynthesis , Uncoupling Protein 2 , Up-Regulation/drug effects
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