One hundred and eleven cases of multiple focal to massive hepatic necrosis were noted out of 202 guinea pigs, aged between 4 and 23 weeks, purchased from 3 different Japanese breeding colonies. Guinea pigs with hepatic lesions showed no abnormal clinical symptoms. The occurrence of lesions peaked at 5 weeks of age in males, and 10 weeks of age in females. Grossly, yellowish white lesions, up to 10 mm in diameter, were observed singly or scattered in the liver. Histopathologically, the commonest lesions consisted of coagulative necrosis or vacuolation of hepatocytes in the central area, and macrophage/lymphocyte infiltration and regeneration of bile ducts around the peripheral area. The cytoplasm of the necrotic hepatocytes and macrophages often contained mineral granules, which were thought to be the dystrophic mineralization and associated with a concomitant occurrence of chronic nephropathy. The other organs examined revealed no significant lesions related to the hepatic lesions. Light and electron microscopic examinations failed to uncover causal organisms; an experimental infection by inoculation of extract from the guinea pig hepatic lesions to immuno-suppressed mice failed to cause hepatic lesions.

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Renal tubulointerstitial lesions were investigated in F344 rats which were treated with 1 mg/kg b.w. of mercuric chloride (HgCl₂) one (day 0) and three times (days 0, 2 and 4), and killed at days 2, 4, and 6 and at days 6, 8, 10, and 20, respectively. Mild to moderate necrosis (at day 2) and subsequent regeneration (at day 4) were found in the epithelial cells of the straight portion of the proximal tubules in the cortico-medullary junction. At and after day 6, slight fibrosis with slight mononuclear cell infiltration was observed around the affected and dilated tubules. These mononuclear cells were mainly composed of ED1-, CD8-, and α-SMA-positive cells. The level of TGF-β1 mRNA evaluated by RT-PCR slightly increased, and TGF-β1-immunoreactivity was seen along the brush borders as well as in the basal cytoplasm of the epithelial cells. In comparison with the results of our previous reports in BN rats (J Toxicol Pathol 1998; 11: 241-248, Int J Exp Pathol 1999; 80: 125-132), the nature of renal tubulointerstitial lesions was almost similar but the severity of them was apparently milder in F344 rats.

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Vascular endothelial growth factor (VEGF) is a dimeric glycoprotein that specifically increases vascular permeability and stimulates angiogenesis. Recently we demonstrated a high level of VEGF and VEGF mRNA expression in N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat bladder carcinomas with abundant fenestrated capillaries. We speculated that the expression of VEGF might be involved in the induction or maintenance of capillary fenestration, and examined ultrastructurally the morphological alteration of blood capillaries in BBN-induced rat bladder carcinoma following the administration of neutralizing antibody against VEGF. Five minutes after administration, the fenestrated endothelial cell ratio and the number of fenestrae decreased significantly, and continued to decrease with time reaching a minimum at 10 minutes after administration. The ratio thereafter gradually increased and at 30 minutes returned to its control condition. These results showed the specific inhibition of VEGF bioactivity potently induced to close the capillary fenestrations. We can suggest that VEGF synthesized by BBN-induced rat bladder carcinoma cells specifically induces and maintains the tumor capillary fenestrations.

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In this study we examined the susceptibility of three sister inbred strains of mice, NON/Shi, CTS/Shi, and NOD/Shi to the urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in an attempt to optimize our model for tumor induction and spontaneous metastasis. The animals were given BBN at a dose of 0.05% in drinking water for 8 weeks and then maintained without further treatment until week 24 when the renal pelvis and urinary bladder were examined microscopically. The incidences of renal pelvic and urinary bladder carcinomas in NON/Shi, CTS/Shi, and NOD/Shi were 13/25 (52%) and 11/25 (44%), 3/19 (16%) and 12/19 (63%), and 0/24 (0%) and 1/24 (4%), respectively. Metastasis to lungs was only observed in renal pelvic carcinoma-bearing NON/Shi mice at an incidence of 77%. Invasion of the prostate and/or intraperitoneal dissemination were observed in urinary bladder carcinoma-bearing NON/Shi and CTS/Shi mice at incidences of 18% and 25%, respectively. BBN intake was highest in NON/Shi mice but urinary concentrations of the carcinogen and its ω-oxidative metabolite, N-butyl-N-(3-carboxypropyl) nitrosamine did not differ among the three strains. These results indicate that NON/Shi is the most sensitive of the three strains to carcinogenic effects of BBN on the urinary tract, particularly renal pelvis, and therefore the most suitable for our spontaneous metastasis model.

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The present study deals with the effects of 5-azacytidine (5AzC) on the lymphoid and hematopoietic tissues in adult mice. Seven-week-old, male BALB/c mice were injected with 5AzC (100 mg/kg) intraperitoneally, and the thymus, spleen, and bone marrow were examined for cellular proliferative activity and apoptotic changes. In 5AzC-treated mice, the number of proliferative cell nuclear antigen (PCNA)-positive cells began to decrease at 6 hours after treatment (AT) in the thymic cortex and bone marrow, and at 12 hours AT in the splenic white pulp. The number of TUNEL-positive cells strikingly increased up to 24 hours AT in the thymic cortex, to 12 hours AT in the splenic white pulp, and to 6 hours AT in the bone marrow, and decreased thereafter in all tissues. The number of immature myeloid and erythroid cells in the bone marrow decreased after 5AzC-treatment. Electron microscopic study revealed nuclear condensation and fragmentation in pyknotic or karyorrhectic thymic lymphocytes. DNA electrophoresis of the thymus and bone marrow from 5AzC-treated mice at 12 hours AT showed a typical ladder formation. These findings indicate the apoptotic effect of 5AzC on dividing lymphoid and hematopoietic cells even in adult mice.

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Renal interstitial fibrosis induced in F344 rats by an intraperitoneal, single dose of cisplatin (6 mg/kg body weight) was pathologically investigated. Renal tubules showing nuclear alterations and desquamation of epithelial cells were seen in the cortico-medullary junction from day 1 after dosing; these changes became more prominent on days 3 and 5. On days 7 to 13, regenerating renal epithelial cells replaced the injured epithelial cells, and the fibrosis progressed around the affected renal tubules. During the early stages (days 1-5), apoptotic epithelial cells, demonstrable by TUNEL method, appeared, and then, macrophages phagocytizing apoptotic bodies were seen in late stages (days 7-13). Macrophages and myofibroblasts (a fibrogenic cell) were significantly increased in number on days 3-5, and the numbers retained high levels by day 13. The macrophages and some renal tubular epithelial cells reacted immunohistochemically to TGF-β1, a fibrogenic factor. Macrophages were also immunoreactive to inducible nitric oxide (iNOS), and macrophages and regenerating epithelial cells showed positive reactions with histochemistry to NADPH-diaphorase, a co-enzyme of iNOS; these findings indicate that nitric oxide formed through iNOS might have participated in epithelial apoptosis, in addition to direct induction of apoptosis by cisplatin. Abnormal depositions of extracellular matrices such as collagens (types I, III and IV), fibronectin and laminin were seen in fibrotic areas and around the affected renal tubules. Based on data obtained in the present study, a possible pathogenesis of cisplatin-induced rat renal interstitial fibrosis was discussed.

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To investigate the modifying effects of cinnamaldehyde (CNMA) on the development of lung proliferative lesions, male transgenic mice carrying the human prototype c-Ha-ras gene (rasH2 mice) were given a single intraperitoneal injection of 250 mg/kg urethane (UR) or saline (vehicle control), followed by a diet containing 0.5% CNMA or basal diet, respectively, for 26 weeks. Their non-transgenic CB6F1 littermates (non-Tg mice) were also treated in the same manner. In rasH2 mice, alveolar/bronchiolar hyperplasias were observed in all treated groups including untreated controls, and adenomas were induced in the treated groups except for CNMA-alone group. However, there were no significant intergroup differences in the incidences and multiplicities of these lesions. In addition, although carcinomas were found in both UR-alone and UR+CNMA groups, there was no significant differences in the incidences and multiplicities between them. In non-Tg mice, alveolar/bronchiolar hyperplasias were observed in both untreated control and UR+CNMA groups with no significant differences in the incidences and multiplicities. Adenomas were induced in all treated groups except for CNMA-alone group in non-Tg mice, the incidences and multiplicities were lower than those in rasH2 mice and no significant intergroup differences were observed. There were no significant intergroup differences between UR-alone and UR+CNMA groups in the PCNA labeling indices of adenomas or carcinomas and the areas of adenomas or carcinomas to whole examined area of lungs. The present results suggest that the CNMA treatment under the present experimental conditions does not influence on the development of lung proliferative lesions induced by urethane in both rasH2 mice and non-Tg mice.

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In order to examine the effect of clofibrate on cell population in hepatocytes, clofibrate at dose levels of 30, 100, or 300 mg/kg were given orally to male rats for 7 consecutive days. Hepatomegaly was observed at dose levels of 100 mg/kg and above, which resulted from hepatocytic proliferation and enzyme induction. Although there was no change in the level of apoptosis, the levels of cell proliferation at different dosages were reduced to less than that of the control levels, following the withdrawal of treatment. The mechanism and the biological significance of mitoinhibition, following the withdrawal were not elucidated in our study. Consequently, it might be the similar mechanism of mitoinhibition in chronic treatment of clofibrate.

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Silver (Ag)-staining nucleolar organizer region (NOR) proteins are closely related to the cell cycle and reflect proliferative activity. In this study, we examined morphological changes of AgNORs in both glutathione S-transferase placental form (GST-P) positive foci and background parenchyma of rat liver by double staining. To induce GST-P positive foci, eight male F344 rats were given a single injection of diethylnitrosamine (20 mg/kg b.w., i.p.), and fed a diet containing 0.01% 2-acetylaminofluorene in diet from weeks 2 to 4 and subjected to 2/3 partial hepatectomy at week 3. At the end of week 5, liver sections were processed for double staining of GST-P and AgNOR. No statistically significant difference was observed for the number of AgNORs between GST-P positive foci and background parenchyma. However, areas of AgNORs relative to nuclear area (dot-to-nuclei ratio) in GST-P positive foci were significantly increased and the roundness was decreased as compared to values for surrounding hepatocytes. Frequencies of cells with big and bizarre (low roundness) dots were elevated in GST-P positive foci. Hence, our data suggest that AgNOR area and shape rather than number may reflect cell proliferation more acurately, so that assessment of these parameters may be useful for evaluating the biological nature of preneoplastic lesions.

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Spontaneous multifocal calcification in the stomach was found in a 15-month-old male beagle dog. There were no abnormalities in behavior. Most of the calcified foci were seen in the lamina propria of the necks of fundic glands. These foci were round-shaped and had a lamellated structure, and they were surrounded by fibroblasts, macrophages, and connective tissue. The calcified foci were not associated with neutrophil or lymphocyte infiltration. The gastric gland occasionally shows a small number of calcified foci in healthy dogs. The findings in the present case are characterized by multifocal calcium deposition without disturbance of blood mineral levels.

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