Effect of an antimitotic agent colchicine on thioacetamide hepatotoxicity.

In an earlier study we established that timely and adequate tissue repair response following the administration of a six-fold dose-range of thioacetamide (TA; 50, 150, and 300 mg/kg) prevented progression of injury and led to recovery and animal survival. Delayed and attenuated repair response after the 600 mg/kg TA dose resulted in a marked progression of injury and 100% lethality. The objective of the present study was to further scrutinize this concept in an experimental protocol in which we hypothesized that a selective ablation of the tissue repair response should lead to lethality from the nonlethal, moderately toxic doses of 150 and 300 mg/kg TA. In this study we investigated the effect of the antimitotic agent colchicine (CLC, 1 mg/kg) on the outcome of TA hepatotoxicity. Male Sprague-Dawley rats (175-225 g) were injected intraperitoneally (ip) with 150 and 300 mg/kg TA. We assessed liver injury by serum enzyme elevations and histopathology. Tissue regeneration response was measured by 3H-thymidine incorporation into hepatonuclear DNA and by proliferating cell nuclear antigen (PCNA) assay. S-Phase stimulation, as indicated by 3H-thymidine incorporation, was noted at 36 and 48 hr following the administration of 150 mg/kg TA, whereas with the 300 mg/kg TA S-phase stimulation was elicited at 48 hr following treatment. Therefore, two doses of CLC (30 hr and 42 hr, 1 mg/kg, ip) were administered to the 150 mg/kg treated group while a single dose of CLC (42 hr, 1 mg/kg, ip) was administered to the 300 mg/kg group. CLC treatment resulted in 100% lethality in both groups. Thus, CLC administration converted nonlethal doses into lethal doses. The 150 mg/kg TA dose was then chosen to further investigate the underlying mechanism. Rats treated with TA alone recovered from injury by 36-48 hr while CLC treatment resulted in a progression of injury as indicated by serum enzyme elevation and histopathology. Tissue repair, as evidenced by 3H-thymidine incorporation and PCNA studies explained this dichotomy. Antimitotic intervention with CLC resulted in a significantly diminished repair response leading to unrestrained progression of injury and lethality even from nonlethal doses. This model demonstrates the critical role of tissue repair response in determining the final outcome of toxicity.     

Colchicine antimitosis abolishes resiliency of postnatally developing rats to chlordecone-amplified carbon tetrachloride hepatotoxicity and lethality.

We have previously reported that rats are resilient to the hepatotoxic and lethal combination of chlordecone (CD) and carbon tetrachloride (CCl4) during early postnatal development. The overall findings pointed to stimulated cell division and tissue repair mechanisms as the underlying cause of resistance. The objective of the current study was to investigate if the antimitotic effect of colchicine (CLC) abolishes this resiliency to CD + CCl4 by inhibiting ongoing and stimulated cell division. We used 45-day-old rats in this study because this age group exhibited partial sensitivity to CD + CCl4 in our previous studies. Male Sprague-Dawley rats were treated with a single low intraperitoneal dose of CCl4 (100 microl/kg) or corn oil after exposure to either 10 ppm CD in the diet or a normal diet (ND) for 15 days. CLC (1 mg/kg) was administered 6 or 30 hr after CCl4 to ND or CD rats, respectively. Administration of CLC resulted in increased CCl4-induced mortality from 25% to 85% in rats pretreated with CD, in contrast to 100% survival in ND rats. Liver injury was assessed by plasma alanine transaminase (ALT) and sorbitol dehydrogenase (SDH) elevations as well as by histopathology. Hepatocellular regeneration was assessed by 3H-thymidine (3H-T) incorporation into hepatonuclear DNA and proliferating cell nuclear antigen (PCNA) studies during 0-96 hr after CCl4. Administration of CLC to ND + CCl4 rats resulted in a slight delay in cell division and tissue repair, as indicated by 3H-T incorporation and PCNA, thereby leading to prolonged liver injury as revealed by elevations in plasma ALT, SDH, and histopathological lesions. In contrast, CLC administration to CD + CCl4-treated rats further delayed and diminished cell division by 80%, which led to unrestrained progression of CCl4-induced liver injury, resulting in 85% mortality. These findings underscore the importance of ongoing and toxicant-stimulated cell division and tissue repair mechanisms in hepatotoxicity, and the need for the inclusion of age factors in risk assessment of exposure to environmental and other chemicals.     

载硒酵母对小鼠化学性肝损伤的影响

观察不同剂量（３０，６０，９０ｍｇ／ｋｇ）载硒酵母（ｓｅｌｍｉｎｍ－ｅｎｒｉｃｈｅｄｙｅａｓｔ，ＳＥＹ）ｉｇ７天对ＣＣｌ４和Ｄ－Ｇａｌ－Ｎ引起的化学性肝损伤的保护作用。结果发现：ＳＥＹ６０ｍｇ／ｋｇ可降低ＣＣｌ４所致血清ＡＬＴ的升高，各剂量组均可降低Ｄ－Ｇａｌ－Ｎ所致血清ＡＬＴ和ＡＳＴ的升高，ＳＥＹ３０ｍｇ／ｋｇ可减轻Ｄ－Ｇａｌ－Ｎ所致肝病理损伤，各剂量组ＳＥＹ均可降低Ｄ－Ｇａｌ－Ｎ所致肝匀浆ＭＤＡ含量升高。提示ＳＥＹ在一定程度上可减轻ＣＣｌ４和Ｄ－Ｇａｌ－Ｎ的化学性损伤，其作用机制可能与抗氧化作用有关。     

不同新辅助化疗方案治疗局部晚期乳腺癌的疗效比较

目的探讨新辅助化疗不同的治疗方案对局部晚期乳腺癌的患者的疗效。方法72例接受新辅助化疗的乳腺癌(ⅢA期)患者随机分为3组:即TA组(n=24)(紫杉醇联合吡柔比星):TXL 135 mg/m2静滴,d1,THP 40 mg/m2静推,d2。CAF组(n=24)(吡柔比星联合环磷酰胺,5-氟尿嘧啶):THP 40 mg/m2静推,d1,CTX 600 mg/m2,静推,d1.8,5-FU 12 mg/kg,d1-5,静滴。CMF组(n=24)(环磷酰胺联合5-氟尿嘧啶,氨甲喋呤):CTX 600 mg/m2静推d1.8,5-FU 12 mg/kg,静滴,d1-5,MTX 0.4 mg/kg,d1,静推。21 d为一个周期,2个周期后对乳腺癌原发病灶及腋窝淋巴结状态进行观察及分析。结果TA组总有效率为83%,CAF组总有效率为63%,CMF组总有效率25%。TA组与CMF组相比较有显著差异(P<0.05),CAF组与CMF组相比较有显著差异(P<0.05),TA组与CAF组相比较无统计学意义(t=0.022,P>0.05)。结论TA组和CAF组在局部晚期的乳腺癌新辅助治疗的过程中疗效满意,毒副反应可以耐受,值得推广。     

Chronic Prosopis Glandulosa Treatment Blunts Neutrophil Infiltration and Enhances Muscle Repair after Contusion Injury

The current treatment options for soft tissue injuries remain suboptimal and often result in delayed/incomplete recovery of damaged muscle. The current study aimed to evaluate the effects of oral Prosopis glandulosa treatment on inflammation and regeneration in skeletal muscle after contusion injury, in comparison to a conventional treatment. The gastrocnemius muscle of rats was subjected to mass-drop injury and muscle samples collected after 1-, 3 h, 1- and 7 days post-injury. Rats were treated with P. glandulosa (100 mg/kg/day) either for 8 weeks prior to injury (up until day 7 post-injury), only post-injury, or with topically applied diclofenac post-injury (0.57 mg/kg). Neutrophil (His48-positive) and macrophage (F4/80-positive) infiltration was assessed by means of immunohistochemistry. Indicators of muscle satellite cell proliferation (ADAM₁₂) and regeneration (desmin) were used to evaluate muscle repair. Chronic P. glandulosa and diclofenac treatment (p < 0.0001) was associated with suppression of the neutrophil response to contusion injury, however only chronic P. glandulosa treatment facilitated more effective muscle recovery (increased ADAM₁₂ (p < 0.05) and desmin (p < 0.001) expression), while diclofenac treatment had inhibitory effects on repair, despite effective inhibition of neutrophil response. Data indicates that P. glandulosa treatment results in more effective muscle repair after contusion.     

The dose-response relationship of trichlorfon neurotoxicity in hens.

Trichlorfon [dimethyl 1-hydroxy-2,2,2-trichloroethyl phosphonate (Dipterex)], an organophosphorus pesticide, has been implicated in producing neuropathy in various species. Adult hens were given oral or subcutaneous doses ranging from 50 to 300 mg/kg. The animals were observed for up to 24 hr after dosing for acute toxicological effects and through a 30-day period for development of ataxia and paralysis. Neurotoxic esterase (NTE) activity was measured in whole-brain homogenates 24 hr after each dosing regimen and at 29–35 days after dosing. Tissue samples were taken at 29–35 days after treatment for histologic examination of brain, spinal cord, and sciatic nerve. The level of muscarinic and nicotinic actions of trichlorfon was dependent on both dose and route of administration. In general, the level of response increased as the dose was elevated. Oral doses greater than 100 mg/kg produced more severe acute toxicologic effects than the corresponding sc dose. Signs of neurologic dysfunction were seen 12–18 days after dosing, and it was evident that functional impairment reached its peak at a marginal level despite increases in the amount of trichlorfon given. NTE activity was definitely diminished 24 hr after trichlorfon treatment. At the highest dose (200, 100 mg/kg, sc, given 3 days apart) NTE was inhibited 63%. Doses of trichlorfon (50 or 100 mg/kg, oral, sc) which are near the LD₅₀ (LD₅₀ in hen, 75 mg/kg, oral, ip) resulted in no or marginal inhibition of neurotoxic esterase (0 to 20%). The minimal levels of NTE inhibition at doses near the LD₅₀ are consistent with the marginal neurologic dysfunction. A 20–30% inhibition of NTE at about 30 days after a large dose of trichlorfon (200, 100 mg/kg, sc, given 3 days apart) was noted; however, in hens given lower doses of the chemical the level of NTE activity at 30 days was within the range of normal activity. A multifocal neuropathy at about 1 month after dosing affecting both the central and peripheral nervous system was seen. Minimal degenerative changes were detected in the cerebellum, brainstem, and striata as well as in the sciatic nerve in hens given 100 mg/kg trichlorfon.     

硫代乙酰胺建立大鼠急性肝损伤模型探讨

目的探讨用硫代乙酰胺（Thioacetamide,TAA）制作大鼠急性肝损伤模型时选择TAA的合适剂量、指标检测的最佳时间点以及大鼠的适宜性别。方法一次性腹腔注射不同剂量的TAA制作大鼠急性肝损伤模型,检测血清谷草转氨酶（AST）、谷丙转氨酶（ALT）值及肝脏病理学变化。结果TAA200mg／kg的剂量组血清ALT、AST值显著升高,病理学显示肝细胞变性坏死,而且肝脏病理变化均一。各组雌性鼠的各项指标均不如雄性鼠明显。结论在本实验条件下TAA200mg／kg的剂量最佳,雄性鼠优于雌性鼠．给药后24小时急性肝损伤最明显。     

硫代乙酰胺建立大鼠急性肝损伤模型探讨

目的探讨用硫代乙酰胺(Thioacetamide,TAA)制作大鼠急性肝损伤模型时选择TAA的合适剂量、指标检测的最佳时间点以及大鼠的适宜性别。方法一次性腹腔注射不同剂量的TAA制作大鼠急性肝损伤模型,检测血清谷草转氨酶(AST)、谷丙转氨酶(ALT)值及肝脏病理学变化。结果TAA200mg/kg的剂量组血清ALT、AST值显著升高,病理学显示肝细胞变性坏死,而且肝脏病理变化均一。各组雌性鼠的各项指标均不如雄性鼠明显。结论在本实验条件下TAA200mg/kg的剂量最佳,雄性鼠优于雌性鼠,给药后24小时急性肝损伤最明显。     

Mutagenicity studies of saccharin in mice

Summary Genetic effects of saccharin were studied in mice by the dominant lethal test and the cytological analysis of changes induced in the stage of spermatogonia formation.Male mice were treated intraperitoneally with a single dose of 1000 mg/kg BW or repeated doses of 5 × × 200 mg/kg BW at 24 hr intervals, or 5 × 50 mg/kg BW, 5 × 100 mg/kg BW and 5 × 200 mg/kg BW at 12 hr intervals.The highest frequency of dominant lethals was found in the group treated with 5 × 200 mg/kg BW at 12 hr intervals. Following the relationship between the dose and the frequency of dominant lethals, the incidence of dominant lethals increased with increasing dose levels of saccharin. A cytological analysis of chromosome rearrangements in spermatogonia revealed that a dose of 5 × 200 mg saccharin/kg BW given at 12 hr intervals produced 1.6% translocations and 4.5% separated X and Y chromosomes or univalents.Summing up the results of the dominant lethal test and those of the cytological analysis of spermatocytes in mice with results obtained on Drosophila melanogaster, Vicia faba and Chinese hamster cell line, it is possible to conclude that saccharin is a mutagenic compound inducing both point mutations and chromosome aberrations.     

二甲基甲酰胺急性肝损伤与肝脏谷胱甘肽的关系

目的 研究二甲基甲酰胺（DMF）所致急性肝损伤规律及其与肝脏谷胱甘肽（GSH）的关系。方法 以600、1200、1800mg/kgDMF分别给小鼠腹腔染毒,分析血清山梨醇醇脱氢酶（SDH）、丙氨酸转氨酶（ALT）及肝脏GSH的变化,观察病理改变;高剂量DMF染毒后,再经口连续投入N－乙酰半胱氨酸（NAC）,与未投药组比较。结果 低、中、高3个剂量组的小鼠血清SDH、ALT分别在染毒后24、36、48h达高峰,2项指标高峰值与DMF剂量呈正相关（r＝0．951,r＝0．997）,各染毒组肝脏GSH的损耗均早于血清酶的升高,分别在染毒后8、12、24h降至最低,最低值与DMF剂量呈负相关(r＝－0．854）。经口投入NAC后,血清SDH、ALT活力的升高及肝脏GSH的损耗及病理改变均明显减轻,差异有显著性（前2项指标P＜0．01,后1项指标P＜0．05）。结论 DMF急性损伤有剂量－效应和时间－效应关系,随着染毒剂量增加、肝损伤加重、损伤高峰出现时间延迟,毒作用机制与肝脏GSH含量降低有关。     

Protective Effect of Eurotium cristatum Fermented Loose Dark Tea and Eurotium cristatum Particle on MAPK and PXR/AhR Signaling Pathways Induced by Electronic Cigarette Exposure in Mice

Electronic-cigarette smoke (eCS) has been shown to cause a degree of oxidative stress and inflammatory damage in lung tissue. The aim of this study was to evaluate the repair mechanism of Eurotium cristatum fermented loose dark tea (ECT) and Eurotium cristatum particle metabolites (ECP) sifted from ECT after eCS-induced injury in mice. Sixty C57BL/6 mice were randomly divided into a blank control group, an eCS model group, an eCS + 600 mg/kg ECP treatment group, an eCS + 600 mg/kg ECT treatment group, an eCS + 600 mg/kg ECP prevention group, and an eCS + 600 mg/kg ECT prevention group. The results show that ECP and ECT significantly reduced the eCS-induced oxidative stress and inflammation and improved histopathological changes in the lungs in mice with eCS-induced liver injury. Western blot analysis further revealed that ECP and ECT significantly inhibited the eCS-induced upregulation of the phosphorylation levels of the extracellular Regulated protein Kinases (ERK), c-Jun N-terminal kinase (JNK) and p38mitogen-activated protein kinases (p38MAPK) proteins, and significantly increased the eCS-induced downregulation of the expression levels of the pregnane X receptor (PXR) and aryl hydrocarbon receptor (AhR) proteins. Conclusively, these findings show that ECP and ECT have a significant repairing effect on the damage caused by eCS exposure through the MAPK and PXR/AhR signaling pathways; ECT has a better effect on preventing eCS-induced injury and is suitable as a daily healthcare drink; ECP has a better therapeutic effect after eCS-induced injury, and might be a potential therapeutic candidate for the treatment of eCS-induced injury.     

人参皂苷Rg1对小鼠免疫性肝损伤保护作用

目的探讨人参皂苷Rg1对小鼠免疫性肝损伤的保护作用及机制。方法实验设Rg1高、中、低剂量(60、30、15 mg/kg), 灌胃给予15 d, 尾静脉注射20 mg/kg刀豆蛋白A制备免疫性肝损伤小鼠模型;采用自动生化分析仪测定小鼠血清中谷草转氨酶(AST)、谷丙转氨酶(ALT)活性;酶联免疫吸附实验测定小鼠血清中肿瘤坏死因子(TNF-α)、干扰素(IFN-γ)水平, 并进行肝组织病理学观察。结果与对照组比较, 模型组小鼠血清中AST、ALT含量[分别为(235.5±79.9)、(262.1±63.9)U/L]及TNF-α、IFN-γ水平[分别为(46.3±13.3)、(165.3±86.1)pg/mL]明显升高(P<0.01);与模型组比较, 高剂量Rg1组小鼠血清中AST、ALT含量[分别为(57.1±19.9)、(44.1±16.2)U/L]及TNF-α、IFN-γ水平[(12.9±6.1)、(55.06±29.5)pg/mL] 明显下降(P<0.01);组织学观察显示, Rg1各剂量组小鼠肝损伤程度明显轻于模型组。结论Rg1对小鼠免疫性肝损伤具有一定保护作用, 其机制可能与降低炎性细胞因子、减轻T淋巴细胞毒性作用有关。     

Cross-tolerance between ethanol and chlordiazepoxide

Drug-induced hypothermia was used to investigate drug tolerance and cross-tolerance. C57BL/6J mice, which were injected with a single dose of chlordiazepoxide (CDP; 30 mg/kg) one day before and reinjected with an equivalent dose of CDP the next day, did not develop tolerance to the drug. However, ethanol-pretreated (3.5 g/kg, 24 hr earlier) mice, when injected with CDP (30 mg/kg), showed cross-tolerance to CDP. The cross-tolerance was short-lived (less than 48 hr). On the other hand, CDP-pretreated mice (30 mg/kg, 24 hr earlier) did not show cross-tolerance to ethanol. The lack of a reciprocating effect of CDP-pretreatment was not likely to be due to the difference in initial dosage between ethanol and CDP. It may be due to different rates of tolerance development or different mechanisms of actions between CDP and ethanol. Mice chronically treated with ethanol also showed a similar degree of cross-tolerance to CDP compared to those exposed to an acute dose of ethanol.     

Characterization of acute 4,4'-methylene dianiline hepatotoxicity in the rat.

Methylene dianiline (DDM) is a chemical intermediate in the production of isocyanates and other industrial chemicals, and it is hepatotoxic in humans. The acute hepatotoxicity of orally administered DDM was characterized in rats. Rats receiving DDM (25-225 mg/kg, per os) demonstrated a dose-dependent elevation in serum alanine aminotransferase activity, g-glutamyltransferase activity, and serum bilirubin concentration. DDM also caused a decrease in bile flow and an elevation in liver weight. Significant changes in these markers of liver injury occurred between 8 and 12 hr after a single, oral administration of DDM. Histologically, DDM caused multifocal, necrotizing hepatitis with neutrophil infiltration. Changes in the portal regions consisted of bile ductular necrosis, portal edema, neutrophil infiltration, mild fibrin exudation, and segmental necrotizing vasculitis. The role of cytochrome P450 monooxygenase (MO)-mediated metabolism in DDM hepatotoxicity was evaluated using the MO inhibitors, aminobenzotriazole and SKF-525A and the MO inducers phenobarbital and beta-naphthoflavone. Aminobenzotriazole provided protection from DDM-induced hepatotoxicity, whereas SKF-525A had no effect. The effect of phenobarbital pretreatment depended on the dose of DDM administered. At a dose of DDM that produced a maximal hepatotoxic response, phenobarbital did not influence hepatotoxicity. However, phenobarbital pretreatment provided protection against the hepatotoxic effects of a lower dose of DDM. beta-naphthoflavone pretreatment had a more modest effect on DDM-induced hepatic insult. These results demonstrate that DDM causes acute hepatotoxicity in the rat that is dose and time dependent. Results using inducers and inhibitors of MO suggest that DDM requires bioactivation to exert toxicity; however, the relationship between metabolism and toxicity may be complex.     

Temporal patterns of brain cholinesterase activities of white-footed mice (Peromyscus leucopus) following dosing with diazinon or parathion

Brain cholinesterase (ChE) activities were determined for white-footed mice (Peromyscus leucopus) orally dosed with either diazinon (18.8 mg/kg body weight) or parathion (10 mg/kg body weight). Following treatment with diazinon, a latent period of approximately six hr elapsed during which time ChE activity was relatively unaffected. After the latent phase, ChE activity rapidly declined to a minimum 12 hr after dosing. After 48 hr, ChE activity recovered to levels only slightly below that of the controls. The response of both male and female white-footed mouse brain ChE to dosing with parathion was similar to that exhibited by animals dosed with diazinon. ChE activities declined rapidly at 6 hr and reached a minimum 24 hr after dosing. ChE activity of treated animals was comparable to that of controls 48 hr after treatment. Brain ChE activities of treated female white-footed mice were significantly lower (P<0.05) than those of treated males.     

Strong acute toxicity, severe hepatic damage, renal injury and abnormal serum electrolytes after intravenous administration of cadmium fluoride in rats

Cadmium fluoride (CdF) is commonly used as an insulator for ulta high speed mass telecommunications equipment, and there is a considerable risk that industrial workers will inhale CdF particles. Despite the possibility that acute exposure can cause harmful systemic effects, there are no studies to date that address the health consequences of acute CdF exposure. This study therefore aimed to determine the acute lethal dose of CdF and its effects on various target organs, including the liver and kidney. We also determined the effect of CdF on serum electrolytes and acid-base balance. The effective lethal dose was determined and dose-response study was conducted after intravenous administration of CdF in rats. The 24 h LD(50) of CdF was determined to be 3.29 mg/kg. The dose-response study used doses of 1.34, 2.67, 4.01 mg/kg CdF. Saline or sodium fluoride solution were used for controles. Severe hepatocellular injury was induced at doses greater than 2.67 mg/kg, as demonstrated by AST and ALT activities greater than 1,500 IU/l in rats injected with a dose of 4.01 mg/kg. Acute renal failure was induced at doses greater than 2.67 mg/kg. Decreased serum Ca, increased serum K and metabolic acidosis were induced at a dose of 4.01 mg/kg. Decreased serum Ca was caused by exposure to ionized F. CdF has the strongest lethal and hepatic toxicity among all Cd containing compounds.     

1-(2,4-Dichlorobenzyl)-1 H-lndazole-3-Carboxylic Acid (DICA), an Exfoliative Antispermatogenic Agent in the Rat

The oral administration of 50 mg DICA/kg at nine weekly or four monthly intervals produced partially reversible infertility in male rats as judged by the results of serial mating and testicular histology. Oral 500 mg DICA/kg doses administered at the same intervals produced permanent sterility. Single oral doses of 50 or 500 mg DICA/kg elevated mean FSH concentrations on days 2, 3, and 7 but did not affect LH or testosterone. Mean plasma concentration peaked at 74 μg/ml 4 hr after a 50 mg/kg dose of uniformly tritiated DICA; 24 hr later, it had declined rapidly to 5.5 μg/ml. The drug did not have a strong affinity for any tissue studied including the testis. DICA-induced exfoliation of immature germ cells was first observed 4 hr after administration and led to significantly reduced testis weights by day 2. Neither single doses of 10-250 mg DICA/kg nor five daily doses of 10-100 mg DICA/kg reduced seminal vesicle, ventral prostate, or body weights of male rats. Chronic weekly DICA administration did reduce mean seminal vesicle weight. These studies have shown that DICA is an effective, partially reversible antifertility agent that directly affects the rat testis.     

The protective effect of glycyrrhizin against injury of the liver caused by ischemia-reperfusion

Effects of glycyrrhizin (GR) on an injury of the liver caused by ischemia-reperfusion in rats were determined. In the liver ischemia-reperfusion model, levels of serum AST, ALT and LDH, lipid peroxides in the liver tissue, and blood superoxide dismutase activity were significantly increased. On the contrary, total glutathione content in the liver tissue was decreased. When rats were given GR 100 mg/kg for 10 days, GR suppressed the elevation of the lipid peroxide level, serum AST, ALT, LDH level, and the decrease in glutathione content during the period of reperfusion. The suppressive effect of GR was similar with that of -tocopherol (VE). GR showed neither 1,1-diphenyl-2-picrylhydrazyl (DPPH) nor 5,5-dimethyl-1-pyrroline-N-oxide (DMPO)-OOH radical-trapping ability, but exhibited DMPO-OH radical-trapping action, while, VE exhibited both DPPH and DMPO-OOH radical-trapping ability. These results indicate that the hydroxyl radical trapping action of GR is the likely mechanism suppressing liver injury caused by ischemia-reperfusion.     

Lipopolysaccharide-induced hepatic injury is enhanced by polychlorinated biphenyls.

After intravenous administration of bacterial lipopolysaccharide (LPS) to rats, polymorphonuclear neutrophils (PMNs) rapidly accumulate in the liver, and midzonal hepatic necrosis is prominent by 6 hr. PMNs are required for the development of hepatic injury in rats. Certain polychlorinated biphenyls (PCBs) can activate PMNs, resulting in production of superoxide anion (O2-.) and release of cytolytic factors from granules. This raises the possibility that PCB exposure might enhance PMN-mediated tissue injury, such as LPS-induced hepatotoxicity. We treated female Sprague-Dawley rats with a minimally toxic dose of LPS in saline (2 mg/kg, intravenous) and 90 min later exposed them to Aroclor 1248 (50 mg/kg, intraperitoneal), a mixture of PCBs. The animals were killed 6 hr after LPS administration, and hepatic injury was assessed. Neither LPS nor Aroclor 1248 alone produced liver injury. Co-treatment with LPS and Aroclor 1248 resulted in pronounced liver injury as demonstrated from increased activities of alanine aminotransferase and isocitrate dehydrogenase in plasma. Histological evaluation indicated increased severity of hepatic necrosis in rats receiving both LPS and Aroclor 1248. Hepatic accumulation of PMNs, normally observed after LPS, was not altered by co-exposure to PCBs. Aroclor 1248 stimulated rat PMNs in vitro to produce O2-. and to degranulate. In addition, PMN-mediated cytotoxicity to isolated rat hepatocytes in culture was increased upon addition of Aroclor 1248. PCBs activate PMNs in vitro and increase PMN-dependent hepatocellular damage in vitro and after LPS treatment in vivo. PCBs may act in vivo as an additional inflammatory stimulus to activate PMNs to become cytotoxic, resulting in increased tissue injury.     

急性百草枯中毒血清细胞因子的动态变化

目的观察细胞因子白细胞介素(IL)-1β、IL-6、IL-10、肿瘤坏死因子-α(TNF-α)在急性百草枯中毒动物模型中的变化规律,探讨百草枯中毒急性肺损伤的作用机制。方法72只Wistar大鼠随机分为对照组及百草枯高剂量染毒组(120mg／kg)、中剂量染毒组(60mg／kg)、低剂量染毒组(30 mo／kg),分为8、24、72 h 3个观察时段,观察不同剂量组在染毒后不同时间大鼠静脉血细胞因子IL-1β、IL-6、IL-10、TNF-α的动态变化。结果8、24、72 h各剂量组细胞因子的水平均增加,24、72 h组与对照组比较,差异均有统计学意义(P<0．05或P<0．01)。72 h高剂量组各指标与同时间点低剂量组比较,差异有统计学意义(P<0．05)。72 h高、中、低3个剂量组与8 h时间点比较,差异有统计学意义(P<0．05)。随染毒浓度的增加,细胞因子水平逐渐增加。随时间的延长,细胞因子的水平也逐渐增加,存在一定的线性趋势,在整个实验过程中表现出动态的变化。结论在百草枯中毒急性肺损伤机制中细胞因子IL-1β、IL-6、IL-10、TNF-α可能起到了重要作用。