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1.
Intestinal injury is a major cause of death after high-dose radiation exposure. The use of granulocyte-colony stimulating factor (G-CSF) to treat radiation injury has focused on enhancing recovery from hematopoietic radiation syndrome. We evaluated G-CSF for its ability to protect against radiation-induced intestinal injury in rat intestinal epithelial cells (IEC-6) and BALB/c mouse models. For in vitro tests, pre-radiation addition of G-CSF to IEC-6 prevented cytotoxicity and the loss of cell viability. Pre-radiation G-CSF treatment also reduced radiation-induced cleavage of caspase-3 and p53 in IEC-6. For in vivo tests, examination 12 h after abdominal irradiation showed that G-CSF-treated mice were protected against apoptosis of the jejunal crypts. G-CSF-treated mice also showed attenuated intestinal morphological changes 3.5 days after abdominal radiation (10 Gy). G-CSF also reduced the levels of proinflammatory cytokines interleukin-6 and tumor necrosis factor-α after radiation. This study showed that G-CSF may protect against radiation-induced intestinal damage through its anti-apoptotic and anti-inflammatory effects. These results suggest that G-CSF is promising candidate for protection against intestinal mucosal injury following irradiation.  相似文献   

2.
Zhang L  Kang W  Lei Y  Han Q  Zhang G  Lv Y  Li Z  Lou S  Liu Z 《Toxicology letters》2011,204(1):92-99
Only liver transplantation is currently available therapy for the patients with acute liver failure (ALF). This study was designed to determine whether administration of granulocyte colony-stimulating factor (G-CSF) has therapeutic efficacy in animals with ALF. Female Sprague-Dawley (SD) rats were intraperitoneally injected with a single dose of d-galactosamine (d-GalN, 1.4 g/kg) to induce ALF. After 2 h, the rats were randomized to receive G-CSF (50 μg/kg/day), or saline vehicle injection for 5 days. Rats were observed for survival and assessed for liver injury by serum alanine transaminase (ALT) measurement and histological analysis. CD34+ cells in bone marrow were assessed by flow cytometry. CD34+ cells and Ki-67+ hepatocytes in liver tissue were evaluated by immunohistochemistry. In the ALF model, 5-day survival after d-GalN injection was 33.3% (10/30), while G-CSF administration following d-GalN resulted in 53.3% (16/30) survival (p = 0.027). G-CSF treated rats had lower ALT level and less hepatic injury compared with saline vehicle rats. The increases of CD34+ cells in bone marrow and liver tissue and Ki-67+ cells in liver tissue in G-CSF treated rats were higher than those in saline rats. No correlation was observed between CD34+ cells and Ki-67+ hepatocytes in liver tissue in both G-CSF and vehicle rats. It is suggested that G-CSF increases survival rate, decreases liver injury and enhances hepatocyte proliferation in rats with d-GalN-induced ALF possibly through actions including but not limiting to CD34+ cell mobilization, and that G-CSF may be of potential value in treating ALF.  相似文献   

3.
Supplemental oxygen contributes to the development of bronchopulmonary dysplasia (BPD) in premature infants. In this investigation, we tested the hypothesis that prenatal treatment of pregnant mice (C57BL/6J) with the cytochrome P450 (CYP)1A1 inducer, ß-napthoflavone (BNF), will lead to attenuation of lung injury in newborns (delivered from these dams) exposed to hyperoxia by mechanisms entailing transplacental induction of hepatic and pulmonary CYP1A enzymes. Pregnant mice were administered the vehicle corn oil (CO) or BNF (40 mg/kg), i.p., once daily for 3 days on gestational days (17-19), and newborns delivered from the mothers were either maintained in room air or exposed to hyperoxia (> 95% O2) for 1-5 days. After 3-5 days of hyperoxia, the lungs of CO-treated mice showed neutrophil infiltration, pulmonary edema, and perivascular inflammation. On the other hand, BNF-pretreated neonatal mice showed decreased susceptibility to hyperoxic lung injury. These mice displayed marked induction of ethoxyresorufin O-deethylase (EROD) (CYP1A1) and methoxyresorufin O-demethylase (MROD) (CYP1A2) activities, and levels of the corresponding apoproteins and mRNA levels until PND 3 in liver, while CYP1A1 expression alone was augmented in the lung. Prenatal BNF did not significantly alter gene expression of pulmonary NAD(P)H quinone reductase (NQO1). Hyperoxia for 24-72 h resulted in increased pulmonary levels of the F2-isoprostane 8-iso-PGF, whose levels were decreased in mice prenatally exposed to BNF. In conclusion, our results suggest that prenatal BNF protects newborns against hyperoxic lung injury, presumably by detoxification of lipid hydroperoxides by CYP1A enzymes, a phenomenon that has implications for prevention of BPD in infants.  相似文献   

4.
Pulmonary toxicity induced by sulfur mustard and related vesicants is associated with oxidative stress. In the present studies we analyzed the role of reactive nitrogen species (RNS) generated via inducible nitric oxide synthase (iNOS) in lung injury and inflammation induced by vesicants using 2-chloroethyl ethyl sulfide (CEES) as a model. C57Bl/6 (WT) and iNOS −/− mice were sacrificed 3 days or 14 days following intratracheal administration of CEES (6 mg/kg) or control. CEES intoxication resulted in transient (3 days) increases in bronchoalveolar lavage (BAL) cell and protein content in WT, but not iNOS −/− mice. This correlated with expression of Ym1, a marker of oxidative stress in alveolar macrophages and epithelial cells. In contrast, in iNOS −/− mice, Ym1 was only observed 14 days post-exposure in enlarged alveolar macrophages, suggesting that they are alternatively activated. This is supported by findings that lung tumor necrosis factor and lipocalin Lcn2 expression, mediators involved in tissue repair were also upregulated at this time in iNOS −/− mice. Conversely, CEES-induced increases in the proinflammatory genes, monocyte chemotactic protein-1 and cyclooxygenase-2, were abrogated in iNOS −/− mice. In WT mice, CEES treatment also resulted in increases in total lung resistance and decreases in compliance in response to methacholine, effects blunted by loss of iNOS. These data demonstrate that RNS, generated via iNOS play a role in the pathogenic responses to CEES, augmenting oxidative stress and inflammation and suppressing tissue repair. Elucidating inflammatory mechanisms mediating vesicant-induced lung injury is key to the development of therapeutics to treat mustard poisoning.  相似文献   

5.
Chang JH  Zhang H  Guan FX  Wang YY  Li DG  Wu HY  Wang CC  Zhou CH  Zhai ZB  Lu L  Wang XC  Hou Q  Meng AM 《药学学报》2011,46(4):395-399
本研究主要观察p38抑制剂SB203580对小鼠辐射致死效应和小肠损伤的保护作用。在小鼠辐射致死效应实验中,随机分为对照组、照射组和照射给药组。对照组给予假照射,其他两组接受7.2Gy照射,照射给药组在照射前0.5 h腹腔注射给药,以后隔天给药(共5次),观察小鼠30天生存率。小肠损伤保护实验中分组和照射剂量相同。24 h后处死小鼠并取小肠组织进行HE及免疫组化染色。结果显示,照射给药组小鼠30天生存率比照射组提高40%。与照射组相比,照射给药组的小肠隐窝细胞p-p38、p53表达下降,凋亡细胞数量下降,Ki67表达升高,差异均有统计学意义(P<0.01)。结果表明,SB203580特异性抑制全身照射小鼠小肠隐窝细胞p38激活及p53表达升高,小肠隐窝细胞凋亡减少,增殖能力提高,30天小鼠生存率提高。提示SB203580对小鼠辐射致死效应和小肠损伤有一定保护作用,p38通路在辐射致死效应和辐射诱导小肠上皮细胞损伤中起着一定的作用。  相似文献   

6.
Procyanidins extracted with acetone–water from lotus (Nelumbo nucifera Gaertn.) seedpod (LSPCs) were evaluated for in vivo radioprotective activity against whole body gamma irradiation in Swiss albino mice. Pretreated with LSPCs 200 mg/kg by intragastric (i.g.) for 15 days was found to be the most effective dose in preventing radiation sickness, reducing radiation-induced mortality, increasing mean survival time and elevating radiation median lethal dose (LD50) from 8.9 to 10.5 Gy, indicating a dose modifying factor (DMF) of 1.18. Further, administered LSPCs at a dose of 200 mg/kg could effectively maintain spleen index close to normal, stimulate endogenous spleen colony forming units, promote the levels of red blood cells (RBC), white blood cells (WBC), platelets and hemoglobin in peripheral blood, and prevent spleen and skin damage in irradiated mice, reduce the level of radiation-induced micronucleated polychromatic erythrocytes in bone marrow, maintain the polychromatic erythrocytes (PCE) and normochromatic erythrocytes (NCE) ratio (P/N ratio) and significantly decrease bone marrow chromosomal damage. Alternatively, pretreated with LSPCs (200 mg/kg) significantly decreased the lipid peroxidation (LPO) level, and elevated the activities of endogenous antioxidant enzymes in liver after irradiation. Thus LSPCs possess a strong whole body radioprotective activity, and it may be used as a radioprotector.  相似文献   

7.
Cholestasis is a pathological common component of numerous liver diseases that results in hepatotoxicity, inflammation, and cirrhosis when untreated. While the predominant hypothesis in cholestatic liver injury remains hepatocyte apoptosis due to direct toxicity of hydrophobic bile acid exposure, recent work suggests that the injury occurs through inflammatory necrosis. In order to resolve this controversy, we used novel plasma biomarkers to assess the mechanisms of cell death during early cholestatic liver injury. C57Bl/6 mice underwent bile duct ligation (BDL) for 6–72 h, or sham operation. Another group of mice were given d-galactosamine and endotoxin as a positive control for apoptosis and inflammatory necrosis. Plasma levels of full length cytokeratin-18 (FL-K18), microRNA-122 (miR-122) and high mobility group box-1 protein (HMGB1) increased progressively after BDL with peak levels observed after 48 h. These results indicate extensive cell necrosis after BDL, which is supported by the time course of plasma alanine aminotransferase activities and histology. In contrast, plasma caspase-3 activity, cleaved caspase-3 protein and caspase-cleaved cytokeratin-18 fragments (cK18) were not elevated at any time during BDL suggesting the absence of apoptosis. In contrast, all plasma biomarkers of necrosis and apoptosis were elevated 6 h after Gal/End treatment. In addition, acetylated HMGB1, a marker for macrophage and monocyte activation, was increased as early as 12 h but mainly at 48–72 h. However, progressive neutrophil accumulation in the area of necrosis started at 6 h after BDL. In conclusion, these data indicate that early cholestatic liver injury in mice is an inflammatory event, and occurs through necrosis with little evidence for apoptosis.  相似文献   

8.
Exposure of mice to perfluorooctanoate (PFOA) evokes pronounced hepatomegaly along with significant alterations in both the histological structure and immune status of the liver. The present study was designed to evaluate the effects of this perfluorochemical on immune-mediated liver damage. In this connection, the influence of both sub-acute (10 days), moderate-dose (0.002% w/w = 3 ± 0.7 mg/kg body weight/day) and short-term (28 days), low-dose (0.00005% w/w = 70 ± 2 μg/kg body weight/day) dietary pretreatment with PFOA on the development of concanavalin A (Con A)-induced liver damage in mice was examined. With sub-acute, moderate, but not short-term, low-dose exposure, PFOA aggravated the acute liver damage caused by Con A, i.e., elevated serum levels of transaminases and led to more pronounced damage of hepatic tissue. This aggravation was associated with significantly enhanced hepatic level of interleukin-6 (IL-6), but unaltered hepatic levels of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ) and interleukin-4 (IL-4). Moreover, hepatic DNA fragmentation was not changed by sub-acute exposure to the moderate-dose. Our findings imply that exposure to PFOA may sensitize hepatic parenchymal cells to other toxicants that activate the hepatic immune system and thereby aggravate liver injury during acute inflammation.  相似文献   

9.
Continuous exposure to high concentrations of hexavalent chromium [Cr(VI)] in drinking water results in intestinal tumors in mice but not rats. Concentration-dependent gene expression effects were evaluated in female F344 rat duodenal and jejunal epithelia following 7 and 90 days of exposure to 0.3-520 mg/L (as sodium dichromate dihydrate, SDD) in drinking water. Whole-genome microarrays identified 3269 and 1815 duodenal, and 4557 and 1534 jejunal differentially expressed genes at 8 and 91 days, respectively, with significant overlaps between the intestinal segments. Functional annotation identified gene expression changes associated with oxidative stress, cell cycle, cell death, and immune response that were consistent with reported changes in redox status and histopathology. Comparative analysis with B6C3F1 mouse data from a similarly designed study identified 2790 differentially expressed rat orthologs in the duodenum compared to 5013 mouse orthologs at day 8, and only 1504 rat and 3484 mouse orthologs at day 91. Automated dose-response modeling resulted in similar median EC50s in the rodent duodenal and jejunal mucosae. Comparative examination of differentially expressed genes also identified divergently regulated orthologs. Comparable numbers of differentially expressed genes were observed at equivalent Cr concentrations (μg Cr/g duodenum). However, mice accumulated higher Cr levels than rats at ≥ 170 mg/L SDD, resulting in a ~ 2-fold increase in the number of differentially expressed genes. These qualitative and quantitative differences in differential gene expression, which correlate with differences in tissue dose, likely contribute to the disparate intestinal tumor outcomes.  相似文献   

10.
On the basis of the recent report that granulocyte colony-stimulating factor (G-CSF) administration after rats’ partial orthotopic liver transplantation greatly improved survival rate and liver regeneration of partial graft, we here evaluated the effect of intermittent administration of G-CSF on fibrosis formation induced by carbon tetrachloride (CCl4). Bone marrow chimeric female C57BL/6 mice were treated with G-CSF at days 1, 7, 14, 21, and 28 after CCl4 challenge. At day 35 after CCl4 administration, we found that G-CSF treatment significantly reduced CCl4-induced liver damage and collagen deposition. In addition, levels of hepatic hydroxyproline and serum fibrosis markers in mice receiving G-CSF administration after CCl4 challenge were significantly lower compared to those of control mice. Histological examination suggested that hepatic damage recovery was much better in these G-CSF-treated mice. Immunofluorescence and fluorescence in situ hybridization (FISH) analysis revealed that donor cells engrafted into host liver, had epithelium-like morphology and expressed albumin, although at low frequency. These results suggest that intermittent G-CSF treatment might initiate endogenous hepatic tissue regeneration in response to CCl4 injury and ameliorate its fibrogenic effects.  相似文献   

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