Leukotriene inhibitors modulate hepatic injury induced by lipopolysaccharide-activated macrophages.

In an attempt to elucidate the effect of lipoxygenase inhibitors on hepatic injury, we investigated D-galactosamine (GalN)-treated C57BL/6 mice receiving an intravenous (i.v.) injection of lipopolysaccharide (LPS)-activated autologous spleen cells. As compared with control spleen cells, the number of monocytes in the spleen cells isolated from LPS-treated mice and their oxidative free radical production increased markedly. Oxygen radical production by the dish-adherent cells (macrophage-rich population) was enhanced a further 4-fold. Although hepatotoxicity was not demonstrated in mice treated with 20 mg GalN alone, marked hepatic injury was found in the GalN-treated mice with a supplementation of LPS-activated spleen cells. The dish-adherent cells aggravated this hepatic injury, in contrast to minor hepatotoxicity by the nonadherent cells. Oxygen radical production by LPS-activated spleen cells was markedly reduced by the lipoxygenase inhibitors (azelastine, ketotifen and AA861). Hepatotoxicity was scarcely detected in the GalN-treated mice with a supplementation of the LPS-activated spleen cells which had been previously treated with lipoxygenase inhibitors. From these results, LPS-activated spleen macrophages contributed to hepatic injury induced by GalN, and lipoxygenase inhibitors which reduced oxygen radical production by the activated cells, protected against macrophage-induced hepatic injury in mice.

The pathogenesis of graft-versus-host reaction in the intrahepatic bile duct. An immunohistochemical study.

Although intrahepatic bile duct injury following bone marrow transplantation is considered to be one feature of graft-versus-host disease, its developmental mechanism has not been clarified. In order to elucidate this aspect, an immunohistochemical study of the liver following human allogeneic bone marrow transplantation was made. Cytotoxic T lymphocytes (Tc) and natural killer cells (NK) were found in contact with intrahepatic bile duct epithelial cells showing degeneration and necrotic changes. These findings suggested a cytotoxic effect of these cells on bile duct epithelial cells. Abnormal expression of HLA class II (DR) antigen was recognized in intrahepatic bile duct epithelial cells following bone marrow transplantation. Cell injury was prominent in cells with weak DR antigen expression, whereas the cells demonstrating conspicuous expression appeared almost normal. There results suggest that abnormal expression of DR antigen plays an important role in the development of GVHD of the intrahepatic bile duct.

Intrahepatic bile duct injury following bone marrow transplantation. Analysis of pathological features based on three-dimensional and histochemical observation.

A specific bile duct injury is frequently observed in the liver following bone marrow transplantation. The materials used for study consisted of liver specimens obtained from 7 autopsy cases and 2 biopsies. The pathological lesions were analyzed by reconstruction of serial sections and by immunohistochemical examination. Injury following bone marrow transplantation occurred most frequently in bile ducts right after the canalicular-ductular junction to ducts having an outer diameter of 50-60 mu, being especially prominent in those less than 30 mu in diameter. They preserved their continuity and there was neither complete destruction nor loss of bile ducts as seen in primary biliary cirrhosis. Immunohistochemical examination showed predominancy of suppressor T lymphocytes around ducts and they were frequently found adjacent to epithelial cells of bile ducts. C3 components and HLA-DR antigens were confirmed to be localized in ductular epithelia in the area where injury took place. Although their localization and site of injury did not necessarily coincide, the participation of an immunologic mechanism against injury cannot be denied. Evidence of a relation between ductular injury and cytomegalovirus infection could not be obtained.

Hodgkin's disease--a histochemical study with special emphasis on the character of Hodgkin's cell and Reed-Sternberg cell.

Enzyme histochemical and immunohistochemical study was carried out on 16 cases of Hodgkin's disease in order to elucidate the origin of Hodgkin's cell and Reed-Sternberg cell. Both Hodgkin's cell and Reed-Sternberg cell do not have tumor markers such as lysosome enzyme, alpha-fetoprotein, and fibronectin, and these cells do not form either Es or EoxACm rosettes. A great number of cells in most cases contained intracytoplasmic immunoglobulin and showed gamma-glutamyl transpeptidase activity on the cell membrane and in cytoplasm. Since gamma-glutamyl transpeptidase is an enzyme related to the transport of amino acid into cell, it is assumed that there is an intake of amino acid in these cells followed by synthesis of protein. Enzyme histochemically, both Hodgkin's cells and Reed-Sternberg cells resemble multiple myeloma cells rather than B-cells in acute lymphocytic leukemia and chronic lymphocytic leukemia and T-cells or monocytes.