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). mRNA expression of eNOS and iNOS was highly consistent with their protein expression. CONCLUSION: Progression and severity of HPS as indicated by both increased pulmonary capillaries and histological changes are closely associated with LPS levels and progression of hepatic dysfunction as indicated by increased levels of ALT and portal vein pressure. Intestinal endotoxemia plays a central role in the development of HPS in the cirrhotic rat model by inducing NO and/or CO.展开更多
AIM： To investigate the dysfunction of the immunological barrier of the intestinal mucosa during endotoxemia and to elucidate the potential mechanism of this dysfunction. METHODS： Male Wistar rats were randomly dist...AIM： To investigate the dysfunction of the immunological barrier of the intestinal mucosa during endotoxemia and to elucidate the potential mechanism of this dysfunction. METHODS： Male Wistar rats were randomly distributed into two groups： control group and lipopolysaccharide （LPS） group. Endotoxemia was induced by a single caudal venous injection of LPS. Animals were sacrificed in batches 2, 6, 12 and 24 h after LPS infusion. The number of microfold （M）-cells, dendritic cells （DCs）, CD4＋ T cells, CD8＋ T cells, regulatory T （Tr） cells and IgA＋ B cells in the intestinal mucosa were counted after immunohistochemical staining. Apoptotic lymphocytes were counted after TUNEL staining. The levels of interleukin （IL）-4, interferon （IFN）-γ, and forkhead box P3 （Foxp3） in mucosal homogenates were measured by ELISA. The secretory IgA （sIgA） content in the total protein of one milligram of small intestinal mucus was detected using a radioimmunological assay.RESULTS： This research demonstrated that LPS-induced endotoxemia results in small intestinal mucosa injury. The number of M-cells, DCs, CD8~ T cells, and IgA~ B cells were decreased while Tr cell and apoptotic lymphocyte numbers were increased significantly. The number of CD4＋ T cells increased in the early stages and then slightly decreased by 24 h. The level of IL-4 significantly increased in the early stages and then reversed by the end of the study period. The level of IFN-T increased slightly in the early stages and then decreased markedly by the 24 h time point. Level of Foxp3 increased whereas sIgA level decreased.CONCLUSION： Mucosal immune dysfunction forms part of the intestinal barrier injury during endotoxemia. The increased number and function of Tr cells as well as lymphocyte apoptosis result in mucosal immunode- ficiency.展开更多
The paper provides a basic review of intestinal microflora and its importance in liver diseases. The intestinal microflora has many important functions, above all to maintain the microbial barrier against established ...The paper provides a basic review of intestinal microflora and its importance in liver diseases. The intestinal microflora has many important functions, above all to maintain the microbial barrier against established as well as potential pathogens. Furthermore, it influences the motility and perfusion of the intestinal wall, stimu- lates the intestinal immune system and therefore also the so-called common mucosal immune system, reducing bacterial translocation and producing vitamins. Immune homeostasis at mucosal level results from a controlled response to intestinal luminal antigens. In liver cirrhosis, there are many changes in its function, mostly an increase in bacterial overgrowth and translocation. In this review, probiotics and their indications in hepatology are generally discussed. According to recent knowledge, these preparations are indicated in clinical practice only for cases of hepatic encephalopathy. Probiotics are able to decrease the permeability of the intestinal wall, and decrease bacterial translocation and endotoxemia in animal models as well as in clinical studies, which is extremely important in the prevention of complications of liver cirrhosis and infection after liver transplantation. Probiotics could limit oxidative and inflammatory liver damage and, in some situations, improve the histological state, and thus non-alcoholic steatohepatitis could be considered as another possible indication.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). mRNA expression of eNOS and iNOS was highly consistent with their protein expression. CONCLUSION: Progression and severity of HPS as indicated by both increased pulmonary capillaries and histological changes are closely associated with LPS levels and progression of hepatic dysfunction as indicated by increased levels of ALT and portal vein pressure. Intestinal endotoxemia plays a central role in the development of HPS in the cirrhotic rat model by inducing NO and/or CO.
基金Supported by Beijing Municipal Science & Technology Commission Major Scitech Program,No.H020920050130
文摘AIM： To investigate the dysfunction of the immunological barrier of the intestinal mucosa during endotoxemia and to elucidate the potential mechanism of this dysfunction. METHODS： Male Wistar rats were randomly distributed into two groups： control group and lipopolysaccharide （LPS） group. Endotoxemia was induced by a single caudal venous injection of LPS. Animals were sacrificed in batches 2, 6, 12 and 24 h after LPS infusion. The number of microfold （M）-cells, dendritic cells （DCs）, CD4＋ T cells, CD8＋ T cells, regulatory T （Tr） cells and IgA＋ B cells in the intestinal mucosa were counted after immunohistochemical staining. Apoptotic lymphocytes were counted after TUNEL staining. The levels of interleukin （IL）-4, interferon （IFN）-γ, and forkhead box P3 （Foxp3） in mucosal homogenates were measured by ELISA. The secretory IgA （sIgA） content in the total protein of one milligram of small intestinal mucus was detected using a radioimmunological assay.RESULTS： This research demonstrated that LPS-induced endotoxemia results in small intestinal mucosa injury. The number of M-cells, DCs, CD8~ T cells, and IgA~ B cells were decreased while Tr cell and apoptotic lymphocyte numbers were increased significantly. The number of CD4＋ T cells increased in the early stages and then slightly decreased by 24 h. The level of IL-4 significantly increased in the early stages and then reversed by the end of the study period. The level of IFN-T increased slightly in the early stages and then decreased markedly by the 24 h time point. Level of Foxp3 increased whereas sIgA level decreased.CONCLUSION： Mucosal immune dysfunction forms part of the intestinal barrier injury during endotoxemia. The increased number and function of Tr cells as well as lymphocyte apoptosis result in mucosal immunode- ficiency.
文摘The paper provides a basic review of intestinal microflora and its importance in liver diseases. The intestinal microflora has many important functions, above all to maintain the microbial barrier against established as well as potential pathogens. Furthermore, it influences the motility and perfusion of the intestinal wall, stimu- lates the intestinal immune system and therefore also the so-called common mucosal immune system, reducing bacterial translocation and producing vitamins. Immune homeostasis at mucosal level results from a controlled response to intestinal luminal antigens. In liver cirrhosis, there are many changes in its function, mostly an increase in bacterial overgrowth and translocation. In this review, probiotics and their indications in hepatology are generally discussed. According to recent knowledge, these preparations are indicated in clinical practice only for cases of hepatic encephalopathy. Probiotics are able to decrease the permeability of the intestinal wall, and decrease bacterial translocation and endotoxemia in animal models as well as in clinical studies, which is extremely important in the prevention of complications of liver cirrhosis and infection after liver transplantation. Probiotics could limit oxidative and inflammatory liver damage and, in some situations, improve the histological state, and thus non-alcoholic steatohepatitis could be considered as another possible indication.
