rhKD/APP对大鼠肝损伤保护作用的实验研究
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摘要
rhKD/APP是人源型蛋白酶抑制剂,与抑肽酶有43 %的同源性,作为一种丝氨酸蛋白酶抑制剂具有多种生物学功能。本研究对经过基因重组技术筛选出的稳定高效的工程菌株rhKD/APP在大鼠肝损伤的保护作用方面进行了多角度的研究。我们分别建立了大鼠D-氨基半乳糖肝损伤和大鼠肝脏缺血再灌注模型,观察rhKD/APP的干预治疗对不同原因导致的肝损伤是否有保护作用,并探讨rhKD/APP在其中可能的作用机制。实验结果表明: rhKD/APP对D-氨基半乳糖肝损伤和大鼠肝脏缺血再灌注模型,从血清酶学、肝重系数变化、组织病理形态学和超微结构改变方面,均可明显减轻肝损伤;研究结果同时提示,rhKD/APP的保护作用与增强氧自由基清除、抗脂质过氧化,抑制参与炎性反应的细胞因子的基因和蛋白表达,抑制肝细胞凋亡有关。
本实验首次证实了rhKD/APP对大鼠D-氨基半乳糖肝损伤和大鼠肝脏缺血再灌注损伤的保护作用;并首次从氧自由基、分子生物学及细胞凋亡角度深入探讨了rhKD/APP肝细胞保护作用机制。结果表明:rhKD/APP对大鼠肝损伤具有很好的保护作用,可以明显减轻急性肝损伤的程度,具有广泛的药用价值,给肝损伤保护提供了一种新的、有效的方法,具有广泛的应用前景。
There are various kinds of causative agents that will cause liver injury in different degree. These years the study about the mechanism of liver injury and its prevention have become the hot spot in biology and medical study in domestic and oversea. Protease inhibitors are a group of enzymes that exist in biological body and keep a dynamic equilibrium between proteases and their specific inhibitors. The protease inhibitors play an important role in regulating physiological process, such as coagulation, fibrinolysis, inflammatory response, cell migration, cell differentiation, complement activation and release of hormone of peptide and protein. BPTI( Bovine pancreatictrypsin inhibitor),or aprotinin, is a representative serine protease inhibitor of Kunitz family. It is a nonspecific and broad-spectrum serine protease inhibitor which affects known serine proteases. It can defend inflammatory reaction, formation of thrombus, improve microcirculation, and decrease the effect of oxygen free radicals, which have been used in clinic already.
But infusion of high doses of these nonmammalian inhibitor could result in immunologic reactions in patients undergoing by frequent use. So we need to find a substitute for BPTI which is preferable, small, potent and human-derived.The amyloidβ-protein precursor contains a domain homologous to Kunitz-type serine protease inhibitors. The sequence of hKD/APP which is consisted of 57 amino acids has 43% sequence identity with that of BPTI. The spatial conformation, reactive center of hKD/APP and its mechanism of function is much similar to that of BPTI. The isoforms of APP containing KD and hKD/APP show great ability to inhibit a variety of serine proteases. They are involed in coagulation, fibrinolysis, inflammatory response, complement activation and cell apoptosis, etc.
The pathological and physiological role of this protease inhibitor domains which concerns with abnormal metabolism of rhKD/APP are not well understood. So we need to produce large quantity of rhKD/APP to discover and study the possible mechanism on pharmacodynamics. The aim of this study is to investigate the protective effect of rhKD/APP on liver injury induced by D-GalN and hepatic ischemia/reperfusion of rats. And probable mechanism of this effect was discussed in the aspects of free radical, expression of cytokines mRNA and protein by immunohistochemistry and in situ hybridization technology, and cell apoptosis.
Part 1 The experimential study of the protective effect of rhKD/APP on liver injury induced by D-GalN of rats
Pathological model of hepatic injury of rats caused by D-GalN was set up . All rats were divided into 6 groups randomly, 10 in every group. rhKD/APP with different dosage were administrated (ip) to rats at daily on 7 day.Rats were injected with D-GalN at a dose of 600 mg?kg-1 body weight as a 10% saline solution and control ones with the same dose of saline ,4 h after the last injection of rhKD/APP.
1. The influence of rhKD/APP on levels of serum ALT、AST、ALP
The levels of serum ALT、AST、ALP were measured. The rats treated with rhKD/APP with different dosage exhibited that the amount of ALT、AST、ALP in blood serum were decreased.in different degree(P<0.01).
2. The influence of rhKD/APP on liver weight coefficent
Compared with the model control ,the liver weight coefficent decreased,but it has no statistical meaning in the groups of rats treated with rhKD/APP.
3. The influence of rhKD/APP on changes of liver hisopathology
Under light microscopy , the extent of hepatic tissue damage caused by D-GalN , including necrosis and hydropic swelling of hepatocytes and inflammatory cell infiltration, were decreased in the groups treated with rhKD/APP with different dosage .
4. The influence of rhKD/APP on histological changes of liver under electronic microscopy
Under electronic microscopy , the extent of swelling of cell body and endotheliocyte were decreased in the groups treated with rhKD/APP with different dosage.The swelling of chondrosome and cavitation in the intracytoplasm were also decreased. The nuclear became normal.
5. The influence of rhKD/APP on levels of MDA、SOD、GSH-PX in tissue
The activities of SOD, GSH-PX and the content of MDA in liver tissue were measured. In model rats, the activities of SOD and GSH-PX were all decreased and the content of MDA was significantly increased (P<0.01) compared with the controls. After treated with the rhKD/APP, the activities of SOD, GSH-PX were significantly increased, while the content of MDA were obviously decreased (P<0.01). These results showed that pretreatment with rhKD/APP could reduce oxygen free radicals and reinforce elimination.
6. The influence of rhKD/APP on expression of TNF-α、IFN-γmRNA and protein in tissue
The expression of TNF-α、IFN-γmRNA and protein in tissue was determined by immunohistochemistry and in situ hybridization technology. The results showed that after treated with rhKD/APP, expression of TNF-α、IFN-γmRNA and protein in tissue was significantly reduced compared with model group(P<0.01).The results have shown that rhKD/APP has the protective effect through inhibiting the inflammatory process.
7. The influence of rhKD/APP on apoptosis of D-GalN induced liver injury of rats
Hematoxylin-Eosin (HE) staining, in situ end-labeling of nuclear DNA fragmentation (TUNEL) were employed to determine the level of apoptosis. The increase numbers of TUNEL-positive staining cells were significantly observed in model. The immunoreactivity was inhibited by rhKD/APP(P<0.01). It indicated that rhKD/APP could protect liver cells through inhibting the cell apoptosis.
Part 2 The experimential study of the protective effect of rhKD/APP on liver ischemia-reperfusion injury of rats
Pathological model of liver ischemia-reperfusion injury of rats was set up . All rats were divided into 6 groups randomly, 10 in every group. Rats were pretreated with rhKD/APP 30min before operation and then subjected to liver ischemia/reperfusion injury induced by a left and middle hepatic artery oCClusion. Rats were killed after 40min ischemia and 3h reperfusion.
1. The influence of rhKD/APP on levels of serum ALT、AST、ALP
The levels of serum ALT、AST、ALP were measured. The rats treated with rhKD/APP with different dosage exhibited that the amount of ALT、AST、ALP in blood serum were decreased in different degree(P<0.01).
2. The influence of rhKD/APP on liver weight coefficient
Compared with the model control ,the liver weight coefficient decreased, but it has no statistical meaning in the groups of rats treated with rhKD/APP.
3. The influence of rhKD/APP on histological changes of liver under light microscopy
Under light microscopy , the extent of hepatic tissue damaged , including necrosis and hydropic swelling of hepatocytes and inflammatory cell infiltration, were decreased in the groups treated with rhKD/APP with different dosage .
4. The influence of rhKD/APP on histological changes of liver under electronic microscopy
Under electronic microscopy , the extent of swelling of cell body and endotheliocyte were decreased in the groups treated with rhKD/APP with different dosage.The swelling of chondrosome and cavitation in the intracytoplasm were also decreased. The nuclear became normal.
5. The influence of rhKD/APP on levels of MDA、SOD、GSH-PX in tissue
The activities of SOD, GSH-PX and the content of MDA in liver tissue were measured. After treated with the rhKD/APP, the activities of SOD, GSH-PX were significantly increased, while the content of MDA were obviously decreased (P<0.01). These results showed that pretreatment with rhKD/APP could reduce oxygen free radicals and reinforce elimination.
6. The influence of rhKD/APP on levels of TNF-α、IFN-γmRNA and protein in tissue
The expression of TNF-α、IFN-γmRNA and proteinin tissue was determined by immunohistochemistry and in situ hybridization. The results showed that after treated with rhKD/APP, expression of TNF-α、IFN-γmRNA and protein in tissue wassignificantly reduced compared with model group(P<0.01).The results have shown that rhKD/APP has the protective effect through inhibiting the inflammatory process.
7. The influence of rhKD/APP on apoptosis of liver ischemia-reperfusion injury of rats
TUNEL were employed to determine the level of apoptosis. The numbers of TUNEL-positive staining cells were significantly decreased in the rats pretreated with rhKD/APP(P<0.01). It indicated that rhKD/APP could protect liver cells through inhibting the cell apoptosis.
Conclusions:The results showed that rhKD/APP has protective effect on liver injury induced by D-GalN and hepatic ischemia/reperfusion of rats. rhKD/APP can improve the liver fuction, reduce liver weight ,relieve the extent of hepatic tissue damage , including necrosis and hydropic swelling of hepatocytes and inflammatory cell infiltration.And there is a dose–dependent on its protective effect. rhKD/APP can obviously reduce oxygen free radicals and reinforce oxygen free radicals elimination. rhKD/APP can obviously inhibit the inflammatory process . rhKD/APP can inhibit the cell apoptosis . Through those mechanisms, rhKD/APP may have the protective effect of liver injury.
本实验首次证实了rhKD/APP对大鼠D-氨基半乳糖肝损伤和大鼠肝脏缺血再灌注损伤的保护作用;并首次从氧自由基、分子生物学及细胞凋亡角度深入探讨了rhKD/APP肝细胞保护作用机制。结果表明:rhKD/APP对大鼠肝损伤具有很好的保护作用,可以明显减轻急性肝损伤的程度,具有广泛的药用价值,给肝损伤保护提供了一种新的、有效的方法,具有广泛的应用前景。
There are various kinds of causative agents that will cause liver injury in different degree. These years the study about the mechanism of liver injury and its prevention have become the hot spot in biology and medical study in domestic and oversea. Protease inhibitors are a group of enzymes that exist in biological body and keep a dynamic equilibrium between proteases and their specific inhibitors. The protease inhibitors play an important role in regulating physiological process, such as coagulation, fibrinolysis, inflammatory response, cell migration, cell differentiation, complement activation and release of hormone of peptide and protein. BPTI( Bovine pancreatictrypsin inhibitor),or aprotinin, is a representative serine protease inhibitor of Kunitz family. It is a nonspecific and broad-spectrum serine protease inhibitor which affects known serine proteases. It can defend inflammatory reaction, formation of thrombus, improve microcirculation, and decrease the effect of oxygen free radicals, which have been used in clinic already.
But infusion of high doses of these nonmammalian inhibitor could result in immunologic reactions in patients undergoing by frequent use. So we need to find a substitute for BPTI which is preferable, small, potent and human-derived.The amyloidβ-protein precursor contains a domain homologous to Kunitz-type serine protease inhibitors. The sequence of hKD/APP which is consisted of 57 amino acids has 43% sequence identity with that of BPTI. The spatial conformation, reactive center of hKD/APP and its mechanism of function is much similar to that of BPTI. The isoforms of APP containing KD and hKD/APP show great ability to inhibit a variety of serine proteases. They are involed in coagulation, fibrinolysis, inflammatory response, complement activation and cell apoptosis, etc.
The pathological and physiological role of this protease inhibitor domains which concerns with abnormal metabolism of rhKD/APP are not well understood. So we need to produce large quantity of rhKD/APP to discover and study the possible mechanism on pharmacodynamics. The aim of this study is to investigate the protective effect of rhKD/APP on liver injury induced by D-GalN and hepatic ischemia/reperfusion of rats. And probable mechanism of this effect was discussed in the aspects of free radical, expression of cytokines mRNA and protein by immunohistochemistry and in situ hybridization technology, and cell apoptosis.
Part 1 The experimential study of the protective effect of rhKD/APP on liver injury induced by D-GalN of rats
Pathological model of hepatic injury of rats caused by D-GalN was set up . All rats were divided into 6 groups randomly, 10 in every group. rhKD/APP with different dosage were administrated (ip) to rats at daily on 7 day.Rats were injected with D-GalN at a dose of 600 mg?kg-1 body weight as a 10% saline solution and control ones with the same dose of saline ,4 h after the last injection of rhKD/APP.
1. The influence of rhKD/APP on levels of serum ALT、AST、ALP
The levels of serum ALT、AST、ALP were measured. The rats treated with rhKD/APP with different dosage exhibited that the amount of ALT、AST、ALP in blood serum were decreased.in different degree(P<0.01).
2. The influence of rhKD/APP on liver weight coefficent
Compared with the model control ,the liver weight coefficent decreased,but it has no statistical meaning in the groups of rats treated with rhKD/APP.
3. The influence of rhKD/APP on changes of liver hisopathology
Under light microscopy , the extent of hepatic tissue damage caused by D-GalN , including necrosis and hydropic swelling of hepatocytes and inflammatory cell infiltration, were decreased in the groups treated with rhKD/APP with different dosage .
4. The influence of rhKD/APP on histological changes of liver under electronic microscopy
Under electronic microscopy , the extent of swelling of cell body and endotheliocyte were decreased in the groups treated with rhKD/APP with different dosage.The swelling of chondrosome and cavitation in the intracytoplasm were also decreased. The nuclear became normal.
5. The influence of rhKD/APP on levels of MDA、SOD、GSH-PX in tissue
The activities of SOD, GSH-PX and the content of MDA in liver tissue were measured. In model rats, the activities of SOD and GSH-PX were all decreased and the content of MDA was significantly increased (P<0.01) compared with the controls. After treated with the rhKD/APP, the activities of SOD, GSH-PX were significantly increased, while the content of MDA were obviously decreased (P<0.01). These results showed that pretreatment with rhKD/APP could reduce oxygen free radicals and reinforce elimination.
6. The influence of rhKD/APP on expression of TNF-α、IFN-γmRNA and protein in tissue
The expression of TNF-α、IFN-γmRNA and protein in tissue was determined by immunohistochemistry and in situ hybridization technology. The results showed that after treated with rhKD/APP, expression of TNF-α、IFN-γmRNA and protein in tissue was significantly reduced compared with model group(P<0.01).The results have shown that rhKD/APP has the protective effect through inhibiting the inflammatory process.
7. The influence of rhKD/APP on apoptosis of D-GalN induced liver injury of rats
Hematoxylin-Eosin (HE) staining, in situ end-labeling of nuclear DNA fragmentation (TUNEL) were employed to determine the level of apoptosis. The increase numbers of TUNEL-positive staining cells were significantly observed in model. The immunoreactivity was inhibited by rhKD/APP(P<0.01). It indicated that rhKD/APP could protect liver cells through inhibting the cell apoptosis.
Part 2 The experimential study of the protective effect of rhKD/APP on liver ischemia-reperfusion injury of rats
Pathological model of liver ischemia-reperfusion injury of rats was set up . All rats were divided into 6 groups randomly, 10 in every group. Rats were pretreated with rhKD/APP 30min before operation and then subjected to liver ischemia/reperfusion injury induced by a left and middle hepatic artery oCClusion. Rats were killed after 40min ischemia and 3h reperfusion.
1. The influence of rhKD/APP on levels of serum ALT、AST、ALP
The levels of serum ALT、AST、ALP were measured. The rats treated with rhKD/APP with different dosage exhibited that the amount of ALT、AST、ALP in blood serum were decreased in different degree(P<0.01).
2. The influence of rhKD/APP on liver weight coefficient
Compared with the model control ,the liver weight coefficient decreased, but it has no statistical meaning in the groups of rats treated with rhKD/APP.
3. The influence of rhKD/APP on histological changes of liver under light microscopy
Under light microscopy , the extent of hepatic tissue damaged , including necrosis and hydropic swelling of hepatocytes and inflammatory cell infiltration, were decreased in the groups treated with rhKD/APP with different dosage .
4. The influence of rhKD/APP on histological changes of liver under electronic microscopy
Under electronic microscopy , the extent of swelling of cell body and endotheliocyte were decreased in the groups treated with rhKD/APP with different dosage.The swelling of chondrosome and cavitation in the intracytoplasm were also decreased. The nuclear became normal.
5. The influence of rhKD/APP on levels of MDA、SOD、GSH-PX in tissue
The activities of SOD, GSH-PX and the content of MDA in liver tissue were measured. After treated with the rhKD/APP, the activities of SOD, GSH-PX were significantly increased, while the content of MDA were obviously decreased (P<0.01). These results showed that pretreatment with rhKD/APP could reduce oxygen free radicals and reinforce elimination.
6. The influence of rhKD/APP on levels of TNF-α、IFN-γmRNA and protein in tissue
The expression of TNF-α、IFN-γmRNA and proteinin tissue was determined by immunohistochemistry and in situ hybridization. The results showed that after treated with rhKD/APP, expression of TNF-α、IFN-γmRNA and protein in tissue wassignificantly reduced compared with model group(P<0.01).The results have shown that rhKD/APP has the protective effect through inhibiting the inflammatory process.
7. The influence of rhKD/APP on apoptosis of liver ischemia-reperfusion injury of rats
TUNEL were employed to determine the level of apoptosis. The numbers of TUNEL-positive staining cells were significantly decreased in the rats pretreated with rhKD/APP(P<0.01). It indicated that rhKD/APP could protect liver cells through inhibting the cell apoptosis.
Conclusions:The results showed that rhKD/APP has protective effect on liver injury induced by D-GalN and hepatic ischemia/reperfusion of rats. rhKD/APP can improve the liver fuction, reduce liver weight ,relieve the extent of hepatic tissue damage , including necrosis and hydropic swelling of hepatocytes and inflammatory cell infiltration.And there is a dose–dependent on its protective effect. rhKD/APP can obviously reduce oxygen free radicals and reinforce oxygen free radicals elimination. rhKD/APP can obviously inhibit the inflammatory process . rhKD/APP can inhibit the cell apoptosis . Through those mechanisms, rhKD/APP may have the protective effect of liver injury.
引文
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