Takanori Hanada

Histopathological and immunohistochemical studies on arteritis induced by fenoldopam, a vasodilator, in rats

Fenoldopam, a dopaminergic (DA1) agonist, has been reported to induce medial necrosis and adventitial inflammatory response in the splanchnic arteries in rats. This study was carried out to clarify the detailed time course of the inflammatory responses, using antibodies for the inflammatory cell markers, CD3 (T cell), CD20 (B cell) and ED-1 (macrophage), and inflammatory serum factors, IgG, IgM and C3. Rats were administered fenoldopam for 24 hours by intravenous infusion. Histopathologically, medial necrosis with hemorrhage was observed at the end of infusion, but it almost disappeared on day 7 post-infusion. Adventitial inflammatory responses with ED-1-, CD3- and CD20-positive cells were very slight at the end of infusion, became prominent with marked fibrosis on days 3 and 5, decreased on day 7, and subsided on day 14. The serum factors were first present in the area of medial necrosis, then shifted to the subendothelial space or cytoplasm of smooth muscle cells, and disappeared on day 14 post-infusion. Gaps in the external elastic lamina were observed on days 3 and 5 post-infusion, and IgG and IgM were present outside the gaps in the adventitia. These results provided us with more detailed information on the inflammatory responses following medial damage induced by vasodilators.

Effects of fructose-induced hypertriglyceridemia on hepatorenal toxicity of acetaminophen in rats

The mode of hepatorenal toxicity of acetaminophen (AAP) was compared between fructose-induced hyper-triglyceridemic and normal rats. The hypertriglyceridemic and normal rats received a single dose of AAP (0, 750 and 900 mg/kg ip) at week 5 of fructose-treatment. At 24 hrs after AAP-dosing, they were sacrificed and examined blood biochemically and histopathologically. Hepatotoxicity as indicated by an increase in plasma ALT and AST activities and centrilobular necrosis of hepatocytes was more severe in the normal rats than in the hypertriglyceridemic ones. In contrast, nephrotoxicity as indicated by an increase in plasma urea nitrogen content and necrosis of epithelial cells in the proximal straight tubules was more severe in the hypertriglyceridemic rats than in normal ones. Thus, in the fructose-induced hypertriglyceridemic rats, as compared with normal ones, hepatotoxicity of AAP became apparently less severe, whereas nephrotoxicity of AAP became significantly more severe.

Antioxidants suppress nitrofurazone-induced proliferation of hepatocytes.

On administration to rats at a subtoxic dose, the antibiotic nitrofurazone (NF) has been shown to increase hepatocyte DNA synthesis and liver weight in a dose-dependent manner, with no histological or biochemical evidence of cell damage or necrosis. Free radicals are implicated in NF metabolism, as well as in the DNA synthesis or cell proliferation induced by a number of other chemicals. In the present study, NF was given alone or concomitantly with the antioxidants N-acetylcysteine or cyanidanol. Antioxidants prevent the effects of free radicals. Co-administration decreased hepatocyte proliferation to the same level as the control. This suppression of NF-induced hepatocyte proliferation by antioxidants therefore strongly suggests that free radical production is involved in this process.

Acute Parietal and Chief Cell Changes Induced by a Lethal Dose of Lipopolysaccharide in Mouse Stomach before Thrombus Formation

The common lipopolysaccharide (LPS)-induced gastric lesions, such as erosions or ulcers, have been investigated in depth. Little is known, however, about the acute gastric lesions following a high dose of LPS. In a time-course study, ICR female mice were given a high subcutaneous dose of LPS (50 mg/kg). Mice were sacrificed at 4, 6, 12, and 24 hours after dosing and were assessed histopathologically for acute gastric lesions. The major gastric changes were seen in the fundic region and included vacuolar degeneration of parietal cells and apoptosis of chief cells. The vacuole in parietal cells was apparent as early as 4 hours postinjection (PI), and apoptosis of chief cells was apparent at 12 hours PI. Thrombus formation, in contrast, was not seen until 24 hours PI. No erosion, ulcer, or hemorrhage was seen in any gastric region in any of the treated animals at 24 hours PI. These results indicate that a subcutaneous high dose of LPS in mice causes vacuolar degeneration of parietal cells and apoptosis of chief cells before thrombus formation or subsequent ulcerative lesions.