Suppressive Effects of Antioxidant DA-9601 on Hepatic Fibrosis in Rats / 대한간학회지

BACKGROUND/AIMS: Oxidative stress is one of the important underlying mechanisms of hepatic fibrosis. DA-9601, the ethanol extracts of Artemisia asiatica, has been reported to possess strong antioxidative and cytoprotective actions. We tried to evaluate whether antioxidant can ameliorate dimethylnitrosamine (DMN)-induced hepatic fibrosis. METHODS: Rat hepatic fibrosis was induced by intraperitoneal administrations of 10 mg DMN six times. Additionally, rats of one group were started daily with DA-9601 30 mg/kg containing diets and another group was fed a pellet diet containing DA-9601 100 mg/kg. The immunohistochemical studies for collagen, alpha-smooth muscle actin (alpha-SMA), and fibronectin, the measurements of hepatic malondialdehyde (MDA) and collagens, and the changes of liver function profiles were performed. Hepatic stellate cells (HSC) were isolated and in vitro effects of DA-9601 on HSC activations were measured. RESULTS: DA-9601 significantly attenuated the loss of body weights (p<0.05), the reduction of liver wet weights (p<0.05), and the elevation of liver enzymes provoked by DMN administrations. DMN injections caused the severe fibrosis of portal tract, hepatic inflammation, and significant oxidative damages, but DA-9601 treatment significantly reduced the mean scores of hepatic fibrosis, the amounts of hepatic collagens, and hepatic MDA levels. The prominent decreases in the expressions of collagens type I and III, alpha-SMA, and fibronectin or hepatic inflammations were observed in DA-9601-treated groups dose-dependently and similar efficacy was also proven in in vitro HSC experiment. CONCLUSIONS: DA-9601 effectively protected rat liver tissues against the DMN-induced hepatic fibrosis. Antioxidant could be considered as a supplementary therapeutic for alleviating the hepatic fibrosis.

Radiation-Induced Proctitis in Rat and Role of Nitric Oxide / 대한방사선종양학회지

PURPOSE: Proctitis is one of acute complications encountered when radiotherapy was applied to the pelvis. Radiation-induced proctitis represents similar microscopic findings that are observed in inflammatory bowel disease (IBD). Nitric oxide (NO) plays an important role in the inflammatory process and many data suggest a close relationship between NO production and gastrointestinal inflammation. This study was aimed to establish the optimal radiation dose for radiation-induced proctitis in rat and to find a relationship between radiation proctitis and NO production. MATERIALS AND METHODS: Female Wistar rats, weighing from 150 to 220 g, received various doses(10-30 Gy) of radiation to the rectum. On the 5th and 10th day after irradiation, rectal specimens were evaluated grossly and microscopically. In addition, the degree of NO production by irradiation dose was evaluated by study with NOS expression and nitrite production in the irradiated rectal tissue. To evaluate relationship between radiation proctitis and NO, we administered aminoguanidine, iNOS inhibitor and L-arginine, substrate of NOS to rats from 2 days before to 7 days after the irradiation. RESULTS: There were obvious gross and histological changes after 17.5 Gy or higher radiation dose but not with 15 Gy or less radiation dose. Twenty Gy or higher dose of radiation caused Grade 4 damage in most of rectal specimens which were more likely to be related to the late complications such as fibrosis, rectal bleeding and rectal obstruction. A single fraction of 17.5 Gy to the rat rectum is considered to be an optimal dose to produce commonly experienced proctitis in the clinic. The result demonstrated that severity of microscopic damage of rectal mucosa from irradiation significantly correlated with iNOS overexpression. However, administration of iNOS inhibitor or substrate of iNOS did not influence the degree of rectal damage. CONCLUSION: A single fraction of 17.5 Gy irradiation to the rat rectum considered to be an optimal dose for radiation induced proctitis model. These results indicated that an excess production of NO contributes to pathogenesis of radiation-induced proctitis in part but was not the direct cause of rectal damage.

A rat model for radiation-induced proctitis

Radiation proctitis is a frequent acute complication encountered with pelvic irradiation. This study was aimed at establishing the optimal radiation dose for radiation-induced proctitis in rats. Female Wistar rats were used. The rectal specimens were examined morphologically at 5th and 10th day following 10-30 Gy irradiation in single fraction. With increasing dose, mucosal damage became worse, and there was a prominent reaction after > or =15 Gy. We selected 17.5 Gy as an optimal dose for radiation proctitis and examined specimens at day 1-14 and at week 4, 6, 8, and 12 after 17.5 Gy. The rectal mucosa revealed characteristic histological changes with time. An edema in lamina propria started as early as 1-2 days after irradiation and progressed into acute inflammation. On day 7 and 8, regeneration was observed with or without ulcer. Four weeks later, all regeneration processes have been completed with end result of either fibrosis or normal appearing mucosa. This study showed that the radiation injury of the rectum in rat develops in dose-dependent manner as it has reported in previous studies and suggested that 17.5 Gy in single fraction is the optimum dose to evaluate the protective effect of various medications for radiation proctitis in face of the clinical situation.