人参二醇皂苷对内毒素休克和对失血—内毒素二次打击大鼠肝脏损伤的保护作用及机制的研究
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摘要
本文分别观察了人参二醇皂苷对内毒素休克和对失血-内毒素二次打击大鼠肝脏损伤的保护作用,并探讨其机制。结果显示:人参二醇皂苷(PDS)与地塞米松类似,可降低血液黏度,改善微循环,减少氧自由基产生,抑制AST、ALT、ALP、CK、LDH 等血清酶的释放,具有良好的抗休克的作用。进一步的研究发现,PDS 能够抑制内毒素休克和二次打击大鼠肝脏组织CD14 的过度表达、提高I-κB mRNA 的表达水平,减少NF-κB 入核,使含κB 序列的基因转录减弱,进而抑制TNF、IL6 和IL18 的表达,即减少了促炎因子的大量释放,又避免了抗炎因子过量产生所导致的免疫抑制,是实现机体自稳调节的分子机制; PDS 还有调节LPS 导致的AQP8 、9 、1 表达失调的作用。上述发现证明了人参二醇皂苷对肝脏细胞的保护作用,国内外尚未见类似报道,为人参二醇皂苷的开发和临床应用奠定了基础。
The reason that traumatic or infectious shocks as well as others progressed into refractory shocks were related with severe obstruction of microcirculation and severe ischemia-anoxia, caused by disseminated or diffused intravascular coagulation (DIC) besides, with destruction of intestinal mucosal barrier, immune dysfunction and subsequent shifting of bacteria and endotoxin into the blood. After LPS entered blood, they bond to circulating LPS-binding protein (LBP) of which belonging to acute phase protein, and formed LPS-LBP complex which subsequently combined with cell membrane receptor of monocytes and macrophages, CD14 that, in turn, triggered the intracellular signaling transduction pathway mediated by LPS receptor and produced the consequence of intracellular responses including the phosphorylation and degradation of the inhibitory protein IκBαwhich originally presented in the cytoplasm combined with the inactive NF-κB. NF-κB was then activated and released from IκBα, and shifted to the nucleus and bond to κB motif of the target genes, in turn inducing gene expression and a number of inflammatory cytokines produced. When inflammation response failed to be self-controlled because of the overproduction of inflammatory mediators, self-destroyed systemic inflammatory response syndrome (SIRS) induced, which would be the
leading cause of multiple system organ failure (MSOF).
This paper aims at observation of the protective effects of PDS on the liver of two kinds of shocks by building up the pathological models of LPS induced endotoxic shock and hemorrhage–lipopolysaccharides induced two-hit Wistar rats, and exploring the signal transduction system mediated by LPS receptor.
1. The protective effects and mechanism of PDS on liver injury of endotoxic shock in rats
Adult wistar rats were divided randomly into 4 groups: the control group (CTR group) ; the LPS shock model group (LPS group, 5mg/kg) ; Dexamethasone pretherapy +LPS group (DEX group, 2mg/Kg);Panaxadiol saponins pretherapy +LPS group (PDS group, 25mg/Kg). LPS was administered by sublingual vein injection to build up the model of endotoxic shock. When blood pressure reduced to 2/3 of the baseline it was regarded as the start of shock.. DEX and PDS were injected intraperitoneally 10 min before LPS administered. Animals were executed 240min after LPS administered.The results are as follows:
1.1 PDS had the same protective effect as DEX to endotoxic shock rats:①Steadily and permanently improved mean arterial blood pressure( MABP). ②The blood viscosity in DEX group and PDS groups were all significantly lower under various shear rates than that in LPS group. It suggested that PDS had the effect of decreasing blood viscosity, significant improving of microcirculation. ③The levels of serum AST,ALT etc were the highest in LPS group among four groups, and the levels of serum enzyme in PDS and DEX groups were significantly lower compared with that in LPS group; these showed the protective effects of PDS on hepatic cell membrane. ④The technology of reverse transcriptase-polymerase chain reaction (RT-PCR) was used to assay the expression of hepatic AQP1 mRNA : The expression of hepatic AQP1 mRNA in LPS group was significantly lower than that in
Control, DEX and PDS groups; the expression of AQP1mRNA in PDS group was close to that in Control group. The above results hinted that PDS had protective effect on endothelium of capillary vessels in liver. ⑤The protective effect to the histology of liver: The injury of liver tissue was found with light microscope after LPS administered 4h. In LPS group there were expansion and congestion with the central vein of hepatic lobule, and nuclear diffluence, disappearance, and heavy staining in cytoplasm of hepatocytes around the central vein of hepatic lobule; Kupffer cells hyperplasia actively also could be seen in sinusoids. The above signs in PDS and DEX groups were significantly slighter than LPS group. PDS had the same protective effect as DEX to morphology of hepatic cells in endotoxic shock rats.
1.2 The effect of PDS on signal transduction pathway mediated by LPS receptor of liver in endotoxic shock rats
The results of study on several important factors involved in signaling include: ①the expression of CD14 mRNA and protein in LPS group was the highest among four groups as assayed by RT-PCR and western blotting, respectively, while that in DEX and PDS groups it was significantly lower than that in LPS group. The result of Immunohistochemistry showed that Hepatic cell stained with CD14 Ab and Kupffer cells membrane had positive pigmentation in sinusoids; the number of dyed Kupffer cells in LPS group was more than that both in DEX and PDS groups. The above results proved that LPS strongly induced the expression of CD14, but PDS inhibited the expression of CD14. ②The hepatic expression of IκBαmRNA in LPS group was significantly lower than that in PDS and DEX groups , PDS up regulated IκBαmRNA expression in liver. ③PDS inhibited protein expression of NF-κB p65 and NF-κB p50 in cell nucleus: The Western Blotting result showed that, the expression of NF-κB p65 and NF-κB p50 in LPS group were significantly strengthened, the expression in PDS groups having the same tendency as in DEX group was weaker compared with that in LPS group.
1.3. The effect of PDS on down regulate expression of cytokines and production of NOS induced by NF-κB in liver of endotoxic shock rats: ①The expression of hepatic TNFαand IL-6 mRNA: Both expression of TNFαand IL-6 mRNA in LPS group were higher than that in PDS and DEX groups. ②The expression of hepatic IL-18 mRNA and protein: The expression of IL-18 mRNA and protein in LPS group were significantly higher than that in PDS and DEX groups; PDS and DEX had the same effect of down regulated expression of IL-18 mRNA and protein. ③The content of NO2-/NO3-and NOS activity in serum in LPS group was significantly higher than that in PDS and DEX group after endotoxic shock 240 min. These result suggested that PDS and DEX had the same effect to lessen the production of NO·in serum and counteract peroxidization of lipid.
In summary, the protective effects of PDS on endotoxic shock rats: PDS had the same effect as DEX to steadily and permanently maintain mean arterial blood pressure, to lessen serum enzyme release, and strengthen the expression of AQP1, and mitigate the injury of modality and structure in liver. the possible protective mechanisms of PDS were ①decreasing blood viscosity, and improving microcirculation, and elevating blood and oxygen supply under state of endotoxic shock. ②regulating the over expression of signaling transduction pathway mediated by LPS receptor, enhancing self-limitation of production of promoted inflammatory factors and avoiding self-destroyed systemic inflammatory response syndrome (SIRS) induced by overrunning of inflammatory mediators.
2. The protective effect and mechanism of PDS on the liver injury of two-hit rats with hemorrhage -LPS
In order to simulate condition of hemorrhagic shock and subsequently endotoxin (LPS) shift into blood, two-hit models of rats were replicated by resuscitation with 1/2 shed blood plus 2 vol of saline by slow reperfusion after hemorrhagic shock 1h and then LPS (2mg/Kg) injected intraperitoneally.
DEX(2mg/Kg) and PDS(25mg/Kg) were injected intraperitoneally in HLD and HLP groups10 min before LPS administered . Animals were execute at 6h after LPS injected. Adult wistar rats (230g-250g) were randomly divided into 4 groups : the sham operational group(S group); the two-hit groups with hemorrhage-lipopolysaccharides ( hemorrhagic shock/ resuscitation with shed blood and lipopolysaccharides administered, HL group);the Dexamethasone preventive therapy group ( the hemorrhagic shock/ resuscitation / Dexamethasone and lipopolysaccharides administered group, HLD group);the panaxadiol saponins preventive therapy group( the hemorrhagic shock/ resuscitation / panaxadiol saponins and lipopolysaccharides administered group ,HLP group).
2.1The protection of PDS to liver in two-hit rats with hemorrhage-LPS:
2.1.1 PDS had the same effect as DEX on inhibition of release of serum enzymes AST, ALT, ALP, CK and LDH, on protection of hepatic cell membrane and mitigation of cholestasis.
2.1.2 The effect of PDS on expression of AQP8,9,1 in liver: ①The results of Fluorescence-based Real-Time PCR assay showed that , the level of expression of hepatic AQP8 in HL group was the lowest among groups and had a significant difference compared with S, HLD and HLP groups; the level of expression of hepatic AQP 9 mRNA in HL and HLD groups were low, and the level of expression in HLP group was appreciably increasing. ②Application of western blotting assay to test the expression of hepatic AQP8, 9 protein: the expression of AQP8 protein in HL group was significantly lower than that in S group, the expression in HLD and HLP groups were significantly higher than that in HL group, especially in HLP group. The expression of AQP9 protein in HL and HLD groups were significantly lower than that in S group, the expression of AQP9 protein in HLP group was close to that in S group. ③Both PDS and DEX didn’t have protective effect on the expression of hepatic AQP1mRNA. AQP1 expressed mainly on membrane of endothelium of capillary vessels in liver, the membrane of endothelium had
been hurt at stage of hemorrhagic shock, PDS and DEX were gaven after resuscitation, so it couldn’t show the visible protective effect of PDS.
2.1.3 The protective effect of PDS on structure and ultrastructure of liver: with the observation of light microscope , there was obvious injury of hepatocyte with spot necrosis and nuclear diffluence, disappearance, and lymphocyte and monocyte infiltration can be seen in hepatic lobule, and fatty degeneration of hepatocyte also could been seen, the expansion and congestion of the central vein of hepatic lobule, manifolded inflammatory cells in central vein of hepatic lobule all were seen, active hyperplasia of Kupffer cells could also be seen in sinusoids in LPS group. The above signs in HLP groups and HLD group were significantly slighter than that in HL group. With observation of scanning electron microscope, in LPS group there were the degeneration and necrosis of hepatocytes including abnormity nucleus, faintness karyotheca, the swelling of mitochondria and rough surfaced endoplasmic reticulum, and increased lipid drops and lysosomes in cytoplasm; and there were also gotten thin microvilli on the surface of hepatocyte facing the space of sinusoid. There were cavitated necrosis of cells in sinusoid including damaged cytomembrane, cavitated nucleus and cytoplast, and swelled and cavitated mitochondria in Kupffer cells. The above signs in HLP and HLD groups were significantly slighter than that in HL group.
2.2 The effects of PDS to the signaling pathway mediated by LPS receptors in two-hit rats
Similar to endotoxic shock , ①after LPS injected intraperitoneally 6 h ,the expression of CD14 mRNA and protein in HL group was higher than that in S group, while that in HLP group was a little bit lower than that in HL group. ②The expression of IκB in HL group is significantly lower than that in S group, while that in HLP group was close to S group and higher than that in HL group; therefore speculation was be given that PDS had the protective effects on inhibitory protein IκB from degradation. ③The expression of NF-κB p65 in HL group is significantly strengthened while in HLP and HLD groups were getting weak but higher than that of S group. ④The effect of
The reason that traumatic or infectious shocks as well as others progressed into refractory shocks were related with severe obstruction of microcirculation and severe ischemia-anoxia, caused by disseminated or diffused intravascular coagulation (DIC) besides, with destruction of intestinal mucosal barrier, immune dysfunction and subsequent shifting of bacteria and endotoxin into the blood. After LPS entered blood, they bond to circulating LPS-binding protein (LBP) of which belonging to acute phase protein, and formed LPS-LBP complex which subsequently combined with cell membrane receptor of monocytes and macrophages, CD14 that, in turn, triggered the intracellular signaling transduction pathway mediated by LPS receptor and produced the consequence of intracellular responses including the phosphorylation and degradation of the inhibitory protein IκBαwhich originally presented in the cytoplasm combined with the inactive NF-κB. NF-κB was then activated and released from IκBα, and shifted to the nucleus and bond to κB motif of the target genes, in turn inducing gene expression and a number of inflammatory cytokines produced. When inflammation response failed to be self-controlled because of the overproduction of inflammatory mediators, self-destroyed systemic inflammatory response syndrome (SIRS) induced, which would be the
leading cause of multiple system organ failure (MSOF).
This paper aims at observation of the protective effects of PDS on the liver of two kinds of shocks by building up the pathological models of LPS induced endotoxic shock and hemorrhage–lipopolysaccharides induced two-hit Wistar rats, and exploring the signal transduction system mediated by LPS receptor.
1. The protective effects and mechanism of PDS on liver injury of endotoxic shock in rats
Adult wistar rats were divided randomly into 4 groups: the control group (CTR group) ; the LPS shock model group (LPS group, 5mg/kg) ; Dexamethasone pretherapy +LPS group (DEX group, 2mg/Kg);Panaxadiol saponins pretherapy +LPS group (PDS group, 25mg/Kg). LPS was administered by sublingual vein injection to build up the model of endotoxic shock. When blood pressure reduced to 2/3 of the baseline it was regarded as the start of shock.. DEX and PDS were injected intraperitoneally 10 min before LPS administered. Animals were executed 240min after LPS administered.The results are as follows:
1.1 PDS had the same protective effect as DEX to endotoxic shock rats:①Steadily and permanently improved mean arterial blood pressure( MABP). ②The blood viscosity in DEX group and PDS groups were all significantly lower under various shear rates than that in LPS group. It suggested that PDS had the effect of decreasing blood viscosity, significant improving of microcirculation. ③The levels of serum AST,ALT etc were the highest in LPS group among four groups, and the levels of serum enzyme in PDS and DEX groups were significantly lower compared with that in LPS group; these showed the protective effects of PDS on hepatic cell membrane. ④The technology of reverse transcriptase-polymerase chain reaction (RT-PCR) was used to assay the expression of hepatic AQP1 mRNA : The expression of hepatic AQP1 mRNA in LPS group was significantly lower than that in
Control, DEX and PDS groups; the expression of AQP1mRNA in PDS group was close to that in Control group. The above results hinted that PDS had protective effect on endothelium of capillary vessels in liver. ⑤The protective effect to the histology of liver: The injury of liver tissue was found with light microscope after LPS administered 4h. In LPS group there were expansion and congestion with the central vein of hepatic lobule, and nuclear diffluence, disappearance, and heavy staining in cytoplasm of hepatocytes around the central vein of hepatic lobule; Kupffer cells hyperplasia actively also could be seen in sinusoids. The above signs in PDS and DEX groups were significantly slighter than LPS group. PDS had the same protective effect as DEX to morphology of hepatic cells in endotoxic shock rats.
1.2 The effect of PDS on signal transduction pathway mediated by LPS receptor of liver in endotoxic shock rats
The results of study on several important factors involved in signaling include: ①the expression of CD14 mRNA and protein in LPS group was the highest among four groups as assayed by RT-PCR and western blotting, respectively, while that in DEX and PDS groups it was significantly lower than that in LPS group. The result of Immunohistochemistry showed that Hepatic cell stained with CD14 Ab and Kupffer cells membrane had positive pigmentation in sinusoids; the number of dyed Kupffer cells in LPS group was more than that both in DEX and PDS groups. The above results proved that LPS strongly induced the expression of CD14, but PDS inhibited the expression of CD14. ②The hepatic expression of IκBαmRNA in LPS group was significantly lower than that in PDS and DEX groups , PDS up regulated IκBαmRNA expression in liver. ③PDS inhibited protein expression of NF-κB p65 and NF-κB p50 in cell nucleus: The Western Blotting result showed that, the expression of NF-κB p65 and NF-κB p50 in LPS group were significantly strengthened, the expression in PDS groups having the same tendency as in DEX group was weaker compared with that in LPS group.
1.3. The effect of PDS on down regulate expression of cytokines and production of NOS induced by NF-κB in liver of endotoxic shock rats: ①The expression of hepatic TNFαand IL-6 mRNA: Both expression of TNFαand IL-6 mRNA in LPS group were higher than that in PDS and DEX groups. ②The expression of hepatic IL-18 mRNA and protein: The expression of IL-18 mRNA and protein in LPS group were significantly higher than that in PDS and DEX groups; PDS and DEX had the same effect of down regulated expression of IL-18 mRNA and protein. ③The content of NO2-/NO3-and NOS activity in serum in LPS group was significantly higher than that in PDS and DEX group after endotoxic shock 240 min. These result suggested that PDS and DEX had the same effect to lessen the production of NO·in serum and counteract peroxidization of lipid.
In summary, the protective effects of PDS on endotoxic shock rats: PDS had the same effect as DEX to steadily and permanently maintain mean arterial blood pressure, to lessen serum enzyme release, and strengthen the expression of AQP1, and mitigate the injury of modality and structure in liver. the possible protective mechanisms of PDS were ①decreasing blood viscosity, and improving microcirculation, and elevating blood and oxygen supply under state of endotoxic shock. ②regulating the over expression of signaling transduction pathway mediated by LPS receptor, enhancing self-limitation of production of promoted inflammatory factors and avoiding self-destroyed systemic inflammatory response syndrome (SIRS) induced by overrunning of inflammatory mediators.
2. The protective effect and mechanism of PDS on the liver injury of two-hit rats with hemorrhage -LPS
In order to simulate condition of hemorrhagic shock and subsequently endotoxin (LPS) shift into blood, two-hit models of rats were replicated by resuscitation with 1/2 shed blood plus 2 vol of saline by slow reperfusion after hemorrhagic shock 1h and then LPS (2mg/Kg) injected intraperitoneally.
DEX(2mg/Kg) and PDS(25mg/Kg) were injected intraperitoneally in HLD and HLP groups10 min before LPS administered . Animals were execute at 6h after LPS injected. Adult wistar rats (230g-250g) were randomly divided into 4 groups : the sham operational group(S group); the two-hit groups with hemorrhage-lipopolysaccharides ( hemorrhagic shock/ resuscitation with shed blood and lipopolysaccharides administered, HL group);the Dexamethasone preventive therapy group ( the hemorrhagic shock/ resuscitation / Dexamethasone and lipopolysaccharides administered group, HLD group);the panaxadiol saponins preventive therapy group( the hemorrhagic shock/ resuscitation / panaxadiol saponins and lipopolysaccharides administered group ,HLP group).
2.1The protection of PDS to liver in two-hit rats with hemorrhage-LPS:
2.1.1 PDS had the same effect as DEX on inhibition of release of serum enzymes AST, ALT, ALP, CK and LDH, on protection of hepatic cell membrane and mitigation of cholestasis.
2.1.2 The effect of PDS on expression of AQP8,9,1 in liver: ①The results of Fluorescence-based Real-Time PCR assay showed that , the level of expression of hepatic AQP8 in HL group was the lowest among groups and had a significant difference compared with S, HLD and HLP groups; the level of expression of hepatic AQP 9 mRNA in HL and HLD groups were low, and the level of expression in HLP group was appreciably increasing. ②Application of western blotting assay to test the expression of hepatic AQP8, 9 protein: the expression of AQP8 protein in HL group was significantly lower than that in S group, the expression in HLD and HLP groups were significantly higher than that in HL group, especially in HLP group. The expression of AQP9 protein in HL and HLD groups were significantly lower than that in S group, the expression of AQP9 protein in HLP group was close to that in S group. ③Both PDS and DEX didn’t have protective effect on the expression of hepatic AQP1mRNA. AQP1 expressed mainly on membrane of endothelium of capillary vessels in liver, the membrane of endothelium had
been hurt at stage of hemorrhagic shock, PDS and DEX were gaven after resuscitation, so it couldn’t show the visible protective effect of PDS.
2.1.3 The protective effect of PDS on structure and ultrastructure of liver: with the observation of light microscope , there was obvious injury of hepatocyte with spot necrosis and nuclear diffluence, disappearance, and lymphocyte and monocyte infiltration can be seen in hepatic lobule, and fatty degeneration of hepatocyte also could been seen, the expansion and congestion of the central vein of hepatic lobule, manifolded inflammatory cells in central vein of hepatic lobule all were seen, active hyperplasia of Kupffer cells could also be seen in sinusoids in LPS group. The above signs in HLP groups and HLD group were significantly slighter than that in HL group. With observation of scanning electron microscope, in LPS group there were the degeneration and necrosis of hepatocytes including abnormity nucleus, faintness karyotheca, the swelling of mitochondria and rough surfaced endoplasmic reticulum, and increased lipid drops and lysosomes in cytoplasm; and there were also gotten thin microvilli on the surface of hepatocyte facing the space of sinusoid. There were cavitated necrosis of cells in sinusoid including damaged cytomembrane, cavitated nucleus and cytoplast, and swelled and cavitated mitochondria in Kupffer cells. The above signs in HLP and HLD groups were significantly slighter than that in HL group.
2.2 The effects of PDS to the signaling pathway mediated by LPS receptors in two-hit rats
Similar to endotoxic shock , ①after LPS injected intraperitoneally 6 h ,the expression of CD14 mRNA and protein in HL group was higher than that in S group, while that in HLP group was a little bit lower than that in HL group. ②The expression of IκB in HL group is significantly lower than that in S group, while that in HLP group was close to S group and higher than that in HL group; therefore speculation was be given that PDS had the protective effects on inhibitory protein IκB from degradation. ③The expression of NF-κB p65 in HL group is significantly strengthened while in HLP and HLD groups were getting weak but higher than that of S group. ④The effect of
引文
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