-A large-scale toxicogenomcis database has now been constructed in the Toxicogenomics Project in Japan (TGP). To facilitate the analytical procedures for such large-scale microarray data, we developed a simple one-dimensional score, named TGP1 which expresses the trend of the changes in expression of biomarker genes as a whole. To evaluate the usefulness of the TGP1 score, microarray data of rat liver and rat hepatocytes deposited in the TGP database were scored for three biomarker gene sets, i.e., carcinogenesis-related, PPARα-regulated and glutathione depletion-related gene sets. The TGP1 scoring system gave reasonable results, i.e., the scores for carcinogenesis-related genes were high in omeprazole-, chlorpromazine-, hexachlorobenzene-, sulfasalazine-and Wy-14,643-treated rat livers, that for PPARα-regulated genes were high in clofibrate-, Wy-14,643-, gemfibrozil-, benzbromarone-and aspirintreated rat livers as well as rat hepatocytes, and for glutathione deficiency-related genes were high in omeprazole-, bromobenzene-, acetaminophen-and coumarin-treated rat liver. We concluded that the TGP1 score is useful for surveying the expression changes in multiple biomarker gene sets for a large-scale toxicogenomics database, which would reduce the time of doing conventional multivariate statistical analysis. In addition, the TGP1 score can be applied to screening of compatible biomarker gene sets between rat liver and rat hepatocytes, like PPARα-regulated gene sets, which will allow us to develop an appropriate in vitro system for drug safety assessment in vivo.
The effect on the adhesion of endothelial cells of immobilization of adhesion proteins onto a microporous polypropylene hollow fiber membrane for a conventional artificial lung was investigated with the aim of constructing a hybrid artificial lung bearing endothelial cells on the modified membrane. The membrane was modified by adsorption or covalent bonding of adhesion proteins of fibronectin, gelatin, or Pronectin. The density of adherent cells on the membrane modified by adsorption of or covalent bonding with fibronectin reached 1 x 10(5) cells/cm(2) after 1 day of incubation, which corresponds to the confluent cell density in a conventional culture dish, while the cell densities on the membranes modifieds with gelatin and Pronectin were 1-5 x 10(4) cells/cm(2) and 0.5-1 x 10(4) cells/cm(2), respectively. The loading of hydrodynamic shear force (0.23 N/m(2)) for 30 min to the membranes bearing endothelial cells had little effect on the density of adhered cells. The membrane covalently bonded with fibronectin could well maintain a high cell density even after the loading of a higher shear force of 1.15 N/m(2) for 180 min, however, at this level of shear force 49% of adhered cells on the fibronectin-adsorbed membrane were lost after 30 min. A partial cardiopulmonary bypass in rats employing the hybrid artificial lung model composed of a polypropylene hollow fiber membrane covalently bonded with fibronectin and endothelial cell adhesion showed the inhibition of tumor necrosis factor-Alpha release and an increase in IL-10 concentration in the circulating blood compared with that employing an artificial lung without cells. Long-term partial cardiopulmonary bypass employing the hybrid artificial lung model should be studied further.
The effect of plasma discharge treatment of a microporous polypropylene hollow-fiber membrane commonly used for gas exchange in a conventional artificial lung on the adhesion of endothelial cells was investigated with the aim of constructing a hybrid artificial lung bearing endothelial cells on the membrane. The initial adhesion density and growth rate of the cells on the membrane were markedly increased following plasma discharge treatment (13.56MHz, 30W) of the membrane for 5 to 20rain in the presence of 0.05 mmHg of various gases, such as ammonia, oxygen, and water vapor. Treatment of the membrane with ammonia for 5min resulted in the highest increase in the cell adhesion density on 5 days from 1.4 • 10 z to 2.0 • 10 3 cells/cm 2, and the cell density reached 5.0 • 10 3 cells/cm 2 after cultivation for 14 days. Increasing the inoculum cell concentration from 3.3 • 105 to 3.2 • 106 cells/ml resulted in an initial cell adhesion of 0.9 • 105 cells/cm 2, even after 1 day. It was observed under a microscope that the cells were distributed uniformly to cover almost all of the surface area of the membrane. After the plasma discharge treatment, the permeability of the membrane to water increased to 9% of that of a polyethylene hollow fiber having pore diameters larger than 0.4 ~tm.
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