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- Eguchi, Susumu, et al.
(författare)
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Loss and recovery of liver regeneration in rats with fulminant hepatic failure
- 1997
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Ingår i: Journal of Surgical Research. - 0022-4804 .- 1095-8673. ; 72:2, s. 112-122
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Tidskriftsartikel (refereegranskat)abstract
- We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobes necrosis. After this procedure, lack of regenerative response in the residual viable liver tissue (omental lobes) was associated with elevated plasma hepatocyte growth factor (HGF) and transforming growth factor beta (TGF-beta1) levels and delayed expression of HGF and c-met mRNA in the remnant liver. Here, we investigated whether syngeneic isolated hepatocytes transplanted in the spleen will prolong survival and facilitate liver regeneration in FHF rats. Inbred male Lewis rats were used. Group I rats (n = 46) received intrasplenic injection of 2 x 10(7) hepatocytes and 2 days later FHF was induced. Group II FHF rats (n = 46) received intrasplenic injection of saline. Rats undergoing partial hepatectomy of 68% (PH; n = 30) and a sham operation (SO; n = 30) served as controls. In 20 FHF rats (10 rats/group), survival time was determined. The remaining 72 FHF rats (36 rats/group) were used for physiologic studies (liver function and regeneration and plasma growth factor levels). In Group I rats survival was longer than that of Group II controls (73 +/- 22 hr vs. 33 +/- 9 hr; P < 0. 01). During the first 36 hr, Group I rats had lower blood ammonia, lactate, total bilirubin, PT, and PTT values, lower activity of liver enzymes, and higher monoethylglycinexylidide (MEGX) production than Group II rats. In Group I rats, livers increased in weight at a rate similar to that seen in PH controls and showed distinct mitotic and DNA synthetic activity (incorporation of bromodeoxyuridine and proliferation cell nuclear antigen expression). Plasma HGF and TGF-beta1 levels in these rats decreased and followed the pattern seen in PH rats; additionally, c-met expression in the remnant liver was accelerated. Hepatocyte transplantation prolonged survival in FHF rats and facilitated liver regeneration. Even though the remnant liver increased in weight four times reaching 30% of the original liver mass, the transplant-bearing rats expired due to inability of the regenerating liver to support the rat.
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| 2. |
- Hansbrough, John F., et al.
(författare)
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Neutrophil activation and tissue neutrophil sequestration in a rat model of thermal injury
- 1996
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 61:1, s. 17-22
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil (PMN) deposition in tissues (leukosequestration) after shock may produce local tissue injury from proteases and oxygen intermediaries which are released from sequestered PMNs. We quantified leukosequestration in tissues in burned rats using two methods of analysis: 1), measurement of lung myeloperoxidase (MPO); 2), measurement of radiolabeled PMNs and erythrocytes deposited in multiple tissues. After tracheostomy and venous cannulation, rats received 17% TBSA full-thickness contact burns and were resuscitated with 20 cc intraperitoneal saline. Lung PMNs were estimated by measuring MPO in lung tissue. PMN influx into lung, liver, spleen, gut, skin, muscle, kidney, and brain was determined by removing (preburn) and differentially radiolabeling PMNs (111In) and erythrocytes (51Cr), reinfusing cells 4.5 hr postburn, and measuring tissue radioactivity 5 hr postburn. Tissue edema was measured by determining extravasation of 125I-labeled albumin in tissues. Peripheral blood PMNs were analyzed for intracellular H2O2 content utilizing a fluorescent dye which reacts with H2O2 coupled with analysis of cell fluorescence by flow cytometry. MPO was elevated in lungs 8 hr postburn (P < 0.05). PMN influx into lung tissues was confirmed by histologic examination. Radioisotope studies demonstrated significant (P < 0.05) leukosequestration into lung, gut, kidney, skin, and brain tissues at 5 hr postburn. Respiratory burst activity of peripheral blood PMNs was increased 5 hr postburn (P < 0.05). Flow cytometric analysis indicated that peripheral blood PMNs were capable of producing markedly increased H2O2 levels 5 hr postburn. Tissue edema, manifested by radiolabeled albumin influx, was not seen in any tissues. Since others have shown that sequestration of metabolically active PMNs may induce remote tissue injury, therapies which block postburn leukosequestration may be able to improve clinical outcomes by limiting remote tissue injury.
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| 3. |
- Sturesson, C, et al.
(författare)
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Hepatic inflow occlusion increases the efficacy of interstitial laser-induced thermotherapy in rat
- 1997
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 71:1, s. 67-72
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Tidskriftsartikel (refereegranskat)abstract
- Interstitial laser-induced thermotherapy (ILT) destroys tumors thermally, ILT was performed for treatment of liver tumors in rats to investigate the effect of hepatic inflow occlusion on temperature distribution and lesion size. Tumors were irradiated for 20 min with near-infrared light from a neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, The laser light at a power of 1.5 W was delivered through a plane-cut optical fiber, the tip of which was placed in the tumor. Rats in group I received ILT without interruption of hepatic blood flow. Those in group II received ILT during hepatic inflow occlusion. Liver temperatures were measured during treatment. After 3 days the animals were sacrificed and the size of the lesions was measured. Occlusion of the hepatic inflow during ILT increased the maximum lesion diameter, as measured at the liver surface, by 47%. Linear interpolation between the temperatures measured at 6 and 12 mm distance from the fiber tip revealed that the temperature at the necrotic border just before the end of treatment was approximately 45 degrees C in both the occluded and nonoccluded groups, indicating that the hepatic inflow occlusion caused no increase in tissue thermal sensitivity, This study shows that occlusion of the hepatic in-flow during interstitial laser-induced thermotherapy causes a significant increase in lesion size, which could have implications for the treatment of hepatic tumors. (C) 1997 Academic Press.
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| 4. |
- Suk Suh, K, et al.
(författare)
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Bioartificial liver treatment in rats with fulminant hepatic failure : effect on DNA binding activity of liver-enriched and growth-associated transcription factors
- 1999
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 0022-4804 .- 1095-8673. ; 85:2, s. 243-250
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Tidskriftsartikel (refereegranskat)abstract
- Background. We earlier described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobe necrosis. In FHF rats, lack of regeneration of the residual liver was associated with delayed expression of HGF and HGF receptor c-met and elevated blood HGF and TGF-β1 levels. We then found that intrasplenic hepatocyte transplantation prolonged survival in FHF rats and triggered hepatocyte proliferation in the native liver. The latter effect was associated with accelerated expression of HGF and c-met mRNA in the liver and lowering of blood HGF and TGF-β1 levels. In the present study we show that in FHF rats, treatment with a bioartificial liver (BAL) had similar effects.Materials and methods. FHF was induced in inbred Lewis rats and after 4 h, Group 1 rats were subjected to a 4-h whole blood perfusion through the BAL loaded with 3 × 108 microcarrier-attached syngeneic hepatocytes, whereas Group 2 control rats were treated with the BAL containing microcarriers only.Results. Compared to sham-BAL-treated rats, the test rats lived longer (28 ± 5 vs 17 ± 2 h; P = 0.0005), had better coagulation parameters, maintained higher body core temperature, and showed decreased plasma TGF-β1 levels. In addition, their liver remnants were HGF positive and showed increased DNA binding of transcription factors engaged in the modulation of hepatocyte proliferation (e.g., STAT3) and liver-specific gene expression (e.g., HNF1, HNF4, C/EBP).Conclusions. This study demonstrates that hepatocyte-based extracorporeal support not only can provide metabolic support by increasing the available functional liver mass but also is capable of modifying humoral and molecular mechanisms which are responsible for proliferation and organ-specific functions of residual hepatocytes.
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| 9. |
- Bäckbro, Kristina, et al.
(författare)
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Unexpected binding mode of a cyclic sulfamide HIV-1 protease inhibitor
- 1997
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 40:6, s. 898-902
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Tidskriftsartikel (refereegranskat)abstract
- Two cyclic, C2-symmetric HIV-1 protease inhibitors, one sulfamide and one urea derivative, both comprising phenyl ether groups in the P1/P1‘ positions, were cocrystallized with HIV-1 protease, and the crystal structures were determined to 2.0 Å resolution. The structure of the urea 2 showed a conformation similar to that reported for the related urea 3 by Lam et al., while the sulfamide 1 adopted an unanticipated conformation in which the P1‘ and P2‘ side chains were transposed.
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