AIM: To characterize the correlation between severity of hepatopulmonary syndrome (HPS) and degree of hepatic dysfunction,and to explore how intestinal endotoxemia (IETM) affects the development of HPS in cirrhotic ra...AIM: To characterize the correlation between severity of hepatopulmonary syndrome (HPS) and degree of hepatic dysfunction,and to explore how intestinal endotoxemia (IETM) affects the development of HPS in cirrhotic rats. METHODS: Male Wister rats were fed with a diet containing maize flour,lard,cholesterol,and alcohol and injected subcutaneously with CCl4 oil solution every two days for 8 wk to induce typical cirrhosis and development of HPS. The animals were also given a nitric oxide (NO) production inhibitor,Nω-nitro-L-arginine methyl ester (L-NAME) intraperitoneally,and an iNOS inhibitor,aminoguanidine hydrochloride (AG) via gavage daily from the end of the 4th wk to the end of the 6th or 8th wk,or a HO-1 inhibitor,zinc protoporphyrin (ZnPP) intraperitoneally 12 h prior to killing. Blood,liver and lung tissues were sampled. RESULTS: Histological deterioration of the lung paralleled to that of the liver in the cirrhotic rats. The number of pulmonary capillaries was progressively increased from 6.1 ± 1.1 (count/filed) at the 4th wk to 14.5 ± 2.4 (count/filed) at the 8th wk in the cirrhotic rats. Increased pulmonary capillaries were associated with increased blood levels of lipopolysaccharide (LPS)(0.31 ± 0.08 EU/mL vs control 0.09 ± 0.03 EU/mL),alanine transferase (ALT,219.1 ± 17.4 U/L vs control 5.9 ± 2.2 U/L) and portal vein pressure. Compared with normal control animals,the number of total cells in bronchoalveolar lavage fluid (BALF) of the cirrhotic rats at the 8th wk was not changed,but the number of macrophages and the ratio of macrophages to total cells were increased by nearly 2-fold,protein expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) started to increase significantly at the 4th wk,and reached its peak at the 8th wk in the lung of cirrhotic rats. The increase of iNOS expression appeared to be quicker than that of eNOS. NO2-/NO3-was also increased,which was correlated to the increase of iNOS (r = 0.7699,P < 0.0001) and eNOS (r = 0.5829,P < 0.002展开更多
The development of alcoholic liver disease (ALD) is a complex process involving both the parenchymal and non-parenchymal cells in the liver. Enhanced inflammation in the liver during ethanol exposure is an important c...The development of alcoholic liver disease (ALD) is a complex process involving both the parenchymal and non-parenchymal cells in the liver. Enhanced inflammation in the liver during ethanol exposure is an important contributor to injury. Kupffer cells, the resident macrophages in liver, are particularly critical to the onset of ethanol-induced liver injury. Chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharide via Toll-like receptor 4. This sensitization enhances production of inflammatory mediators, such as tumor necrosis factor-α and reactive oxygen species, that contribute to hepatocyte dysfunction, necrosis, apoptosis, and fibrosis. Impaired resolution of the inflammatory process probably also contributes to ALD. The resolution of inflammation is an active, highly coordinated response that can potentially be manipulated via therapeutic interventions to treat chronic inflammatory diseases. Recent studies have identif ied an adiponectin/interleukin-10/heme oxygenase-1 (HO-1) pathway that is profoundly effective in dampening the enhanced activation of innate immune responses in primary cultures of Kupffer cells, as well as in an in vivo mouse model of chronic ethanol feeding. Importantly, induction of HO-1 also reduces ethanol-induced hepatocellular apoptosis in this in vivo model. Based on these data, we hypothesize that the development of therapeutic agents to regulate HO-1 and its downstream targets could be useful in enhancing the resolution of inflammation during ALD and preventing progression of early stages of liver injury.展开更多
Hypoxiainducible factor1 and its specific target gene heme oxygenase1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hy poxiainducible factor1/heme oxyge...Hypoxiainducible factor1 and its specific target gene heme oxygenase1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hy poxiainducible factor1/heme oxygenase1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol （30 mg/kg） for 9 weeks. Morris water maze results showed that cognitive impairment gradually worsened as the cerebral ischemia proceeded. Immunohistochemistry, semiquantitative PCR and western blot analysis showed that hypoxiainducible factorla and heme oxygenase1 expression levels in creased after chronic cerebral ischemia, with hypoxiainducible factorla expression peaking at 3 weeks and heme oxygenase1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxiainducible factorla may upregulate heine oxygenase1 expression fol lowing chronic cerebral ischemia and that the hypoxiainducible factor1/heme oxygenase1 sig naling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, decreased hypoxiainducible factorla and heme oxygenase1 expression levels, and reduced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an antiapoptotic mechanism.展开更多
目的:本文旨在在体外水平上研究瑞巴派特与血红素氧合酶1(hemeoxygenase 1,HO-1)相互作用,从而抑制药物所致的胃黏膜上皮细胞损伤的作用.方法:将处于对数生长期的细胞分为4组,分别为空白组、损伤组、低浓度组以及高浓度组.分别给予单纯...目的:本文旨在在体外水平上研究瑞巴派特与血红素氧合酶1(hemeoxygenase 1,HO-1)相互作用,从而抑制药物所致的胃黏膜上皮细胞损伤的作用.方法:将处于对数生长期的细胞分为4组,分别为空白组、损伤组、低浓度组以及高浓度组.分别给予单纯损伤处理或添加预保护处理,使用细胞增殖检测法、免疫印迹蛋白检测法等对细胞增殖功能、HO-1的蛋白表达以及细胞内丙二醛(malondialdehyde,M D A)和超氧化物歧化酶(s u p e r o x i d e dismutase,SOD)的含量进行测定.结果:细胞增殖实验中,空白组、损伤组以及药物处理组(低浓度和高浓度)存活率分别为97.22%±2.01%,60.33%±1.88%、72.34%±1.03%,组间差异均具有统计学意义(P<0.05);损伤组的MDA含量升高,而经药物预处理后,MDA含量下降为1.88 nmol/m g±0.13 n m o l/m g和1.55 n m o l/m g±0.16n m o l/m g,与损伤组比较差异有统计学意义(t=9.567、7.332,P=0.009、0.032).药物进行处理后,低浓度组和高浓度组SOD分别提高为(10.23 U/mg±1.77 U/mg)和(12.09U/mg±2.01 U/mg),与损伤组相比差异均有统计学意义(P<0.05);HO-1经过免疫印迹蛋白检测技术检测损伤组的蛋白稍高于对照组,经药物处理后HO-1的表达量明显升高(0.88±0.10 vs 0.34±0.03,1.34±0.28 vs 0.88±0.10).统计学处理后显示两组间差异均有统计学意义,且具有剂量依赖性(t=5.869、9.122,P=0.017、0.008).结论:瑞巴派特可激活HO-1抑制氧化应激反应,从而减轻药物引起的对GES-1细胞的损伤作用.展开更多
基金Supported by the Awards to University Academic Leaders Granted by the Government of Shanxi Province of China to Hui-Ying Zhang and partially by the US National Institute of Health, NIAAA, Grant R01 AA014428 to Cheng Ji
文摘AIM: To characterize the correlation between severity of hepatopulmonary syndrome (HPS) and degree of hepatic dysfunction,and to explore how intestinal endotoxemia (IETM) affects the development of HPS in cirrhotic rats. METHODS: Male Wister rats were fed with a diet containing maize flour,lard,cholesterol,and alcohol and injected subcutaneously with CCl4 oil solution every two days for 8 wk to induce typical cirrhosis and development of HPS. The animals were also given a nitric oxide (NO) production inhibitor,Nω-nitro-L-arginine methyl ester (L-NAME) intraperitoneally,and an iNOS inhibitor,aminoguanidine hydrochloride (AG) via gavage daily from the end of the 4th wk to the end of the 6th or 8th wk,or a HO-1 inhibitor,zinc protoporphyrin (ZnPP) intraperitoneally 12 h prior to killing. Blood,liver and lung tissues were sampled. RESULTS: Histological deterioration of the lung paralleled to that of the liver in the cirrhotic rats. The number of pulmonary capillaries was progressively increased from 6.1 ± 1.1 (count/filed) at the 4th wk to 14.5 ± 2.4 (count/filed) at the 8th wk in the cirrhotic rats. Increased pulmonary capillaries were associated with increased blood levels of lipopolysaccharide (LPS)(0.31 ± 0.08 EU/mL vs control 0.09 ± 0.03 EU/mL),alanine transferase (ALT,219.1 ± 17.4 U/L vs control 5.9 ± 2.2 U/L) and portal vein pressure. Compared with normal control animals,the number of total cells in bronchoalveolar lavage fluid (BALF) of the cirrhotic rats at the 8th wk was not changed,but the number of macrophages and the ratio of macrophages to total cells were increased by nearly 2-fold,protein expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) started to increase significantly at the 4th wk,and reached its peak at the 8th wk in the lung of cirrhotic rats. The increase of iNOS expression appeared to be quicker than that of eNOS. NO2-/NO3-was also increased,which was correlated to the increase of iNOS (r = 0.7699,P < 0.0001) and eNOS (r = 0.5829,P < 0.002
基金Supported by (in part) NIH Grants No. RO1AA0011975Supported by (in part) NIH Grants No. R56AA001975Supported by (in part) NIH Grants No. RO1AA011876
文摘The development of alcoholic liver disease (ALD) is a complex process involving both the parenchymal and non-parenchymal cells in the liver. Enhanced inflammation in the liver during ethanol exposure is an important contributor to injury. Kupffer cells, the resident macrophages in liver, are particularly critical to the onset of ethanol-induced liver injury. Chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharide via Toll-like receptor 4. This sensitization enhances production of inflammatory mediators, such as tumor necrosis factor-α and reactive oxygen species, that contribute to hepatocyte dysfunction, necrosis, apoptosis, and fibrosis. Impaired resolution of the inflammatory process probably also contributes to ALD. The resolution of inflammation is an active, highly coordinated response that can potentially be manipulated via therapeutic interventions to treat chronic inflammatory diseases. Recent studies have identif ied an adiponectin/interleukin-10/heme oxygenase-1 (HO-1) pathway that is profoundly effective in dampening the enhanced activation of innate immune responses in primary cultures of Kupffer cells, as well as in an in vivo mouse model of chronic ethanol feeding. Importantly, induction of HO-1 also reduces ethanol-induced hepatocellular apoptosis in this in vivo model. Based on these data, we hypothesize that the development of therapeutic agents to regulate HO-1 and its downstream targets could be useful in enhancing the resolution of inflammation during ALD and preventing progression of early stages of liver injury.
基金supported by the Natural Science Fundation of Jilin Province in China, No.200705272
文摘Hypoxiainducible factor1 and its specific target gene heme oxygenase1, are involved in acute cerebral ischemia. However, very few studies have examined in detail the changes in the hy poxiainducible factor1/heme oxygenase1 signaling pathway in chronic cerebral ischemia. In this study, a rat model of chronic cerebral ischemia was established by permanent bilateral common carotid artery occlusion, and these rats were treated with intragastric cilostazol （30 mg/kg） for 9 weeks. Morris water maze results showed that cognitive impairment gradually worsened as the cerebral ischemia proceeded. Immunohistochemistry, semiquantitative PCR and western blot analysis showed that hypoxiainducible factorla and heme oxygenase1 expression levels in creased after chronic cerebral ischemia, with hypoxiainducible factorla expression peaking at 3 weeks and heme oxygenase1 expression peaking at 6 weeks. These results suggest that the elevated levels of hypoxiainducible factorla may upregulate heine oxygenase1 expression fol lowing chronic cerebral ischemia and that the hypoxiainducible factor1/heme oxygenase1 sig naling pathway is involved in the development of cognitive impairment induced by chronic cerebral ischemia. Cilostazol treatment alleviated the cognitive impairment in rats with chronic cerebral ischemia, decreased hypoxiainducible factorla and heme oxygenase1 expression levels, and reduced apoptosis in the frontal cortex. These findings demonstrate that cilostazol can protect against cognitive impairment induced by chronic cerebral ischemic injury through an antiapoptotic mechanism.
文摘目的:本文旨在在体外水平上研究瑞巴派特与血红素氧合酶1(hemeoxygenase 1,HO-1)相互作用,从而抑制药物所致的胃黏膜上皮细胞损伤的作用.方法:将处于对数生长期的细胞分为4组,分别为空白组、损伤组、低浓度组以及高浓度组.分别给予单纯损伤处理或添加预保护处理,使用细胞增殖检测法、免疫印迹蛋白检测法等对细胞增殖功能、HO-1的蛋白表达以及细胞内丙二醛(malondialdehyde,M D A)和超氧化物歧化酶(s u p e r o x i d e dismutase,SOD)的含量进行测定.结果:细胞增殖实验中,空白组、损伤组以及药物处理组(低浓度和高浓度)存活率分别为97.22%±2.01%,60.33%±1.88%、72.34%±1.03%,组间差异均具有统计学意义(P<0.05);损伤组的MDA含量升高,而经药物预处理后,MDA含量下降为1.88 nmol/m g±0.13 n m o l/m g和1.55 n m o l/m g±0.16n m o l/m g,与损伤组比较差异有统计学意义(t=9.567、7.332,P=0.009、0.032).药物进行处理后,低浓度组和高浓度组SOD分别提高为(10.23 U/mg±1.77 U/mg)和(12.09U/mg±2.01 U/mg),与损伤组相比差异均有统计学意义(P<0.05);HO-1经过免疫印迹蛋白检测技术检测损伤组的蛋白稍高于对照组,经药物处理后HO-1的表达量明显升高(0.88±0.10 vs 0.34±0.03,1.34±0.28 vs 0.88±0.10).统计学处理后显示两组间差异均有统计学意义,且具有剂量依赖性(t=5.869、9.122,P=0.017、0.008).结论:瑞巴派特可激活HO-1抑制氧化应激反应,从而减轻药物引起的对GES-1细胞的损伤作用.
