That Ho cells in rat liver express desmin was confirmed by immunohistochemical technique. Consequently, changes of desmin-positive cells, lysozyme-positive cells and fibronectin were further studied in experimental ci...That Ho cells in rat liver express desmin was confirmed by immunohistochemical technique. Consequently, changes of desmin-positive cells, lysozyme-positive cells and fibronectin were further studied in experimental cirrhosis of rat. It was found that desmln- positive cells, with the transitional feature between Ito cells and myofibroblasts or fibrobiasts under electron microscope, increased in number and expression of desmin in the necrotic areas as well as in the cellular fibrous septa, but decreased in number in the fibrous septa except those areas closed to the edges of the septa. These results suggested that Ito cells, myofibroblasts and fibroblasts might belong to the same cellular system and play an important role in the pathogenesis of cirrhosis. Meanwhile, it was also noted that changes of both fibronectin and lysozymepositive cells were correlated with those of desmin-positive cells. These provide evidence in vivo that flbronectin and Kupffer cells might exert certain effects on the migration and proliferation of Ito cells in liver cirrhosis.展开更多
Thrombocytopenia is a common complication in liver disease and can adversely affect the treatment of liver cirrhosis,limiting the ability to administer therapy and delaying planned surgical/diagnostic procedures becau...Thrombocytopenia is a common complication in liver disease and can adversely affect the treatment of liver cirrhosis,limiting the ability to administer therapy and delaying planned surgical/diagnostic procedures because of an increased risk of bleeding.Multiple factors,including splenic sequestration,reduced activity of the hematopoietic growth factor thrombopoietin,bone marrow suppression by chronic hepatitis C virus infection and anti-cancer agents,and antiviral treatment with interferon-based therapy,can contribute to the development of thrombocytopenia in cirrhotic patients.Of these factors,the major mechanisms for thrombocytopenia in liver cirrhosis are(1)platelet sequestration in the spleen;and(2)decreased production of thrombopoietin in the liver.Several treatment options,including platelet transfusion,interventional partial splenic embolization,and surgical splenectomy,are now available for severe thrombocytopenia in cirrhotic patients.Although thrombopoietin agonists and targeted agents are alternative tools for noninvasively treating thrombocytopenia due to liver cirrhosis,their ability to improve thrombocytopenia in cirrhotic patients is under investigation in clinical trials.In this review,we propose a treatment approach to thrombocytopenia according to our novel concept of splenic volume,and we describe the current management of thrombocytopenia due to liver cirrhosis.展开更多
AIM:To investigate the significance of Thrombospondin-1 (TSP-1) expression and its relationship with angiogenesis during experimental fibrosis. METHODS:Cirrhosis was induced in male Wistar rats by intraperitoneal admi...AIM:To investigate the significance of Thrombospondin-1 (TSP-1) expression and its relationship with angiogenesis during experimental fibrosis. METHODS:Cirrhosis was induced in male Wistar rats by intraperitoneal administration of diethyl nitrosamine (DEN). The serial sections from liver tissues were stained with anti-CD34 and anti-TSP-1 antibodies before being quantitated by light microscopy. RESULTS:Our results showed that of TSP-1 expression gradually increases according to the severity of fibrosis (GroupⅠvs group Ⅱ, Group Ⅲ and Group Ⅳ;Group Ⅱ vs group Ⅲ and group Ⅳ;group Ⅲ vs group Ⅳ, P < 0.05). Moreover, TSP-1 expression was found to be correlated with angiogenesis (P < 0.05). CONCLUSION:The correlative evidence of the link between TSP-1 and fibrosis or angiogenesis provided by this study suggests that besides its role as a strong promoter of transforming growth factor-β1 (TGF-β1), TSP-1 might have an additional role in liver fibrogenesis by stimulating angiogenesis and this protein could be a potential target to prevent fibrogenesis in chronic inflammatory diseases of the liver.展开更多
AIM: To observe the regulatory effect of Chinese herbal medicine on peritoneal lymphatic stomata and its significance in treating ascites in liver fibrosis model mice. METHODS: Two Chinese herbal composite prescriptio...AIM: To observe the regulatory effect of Chinese herbal medicine on peritoneal lymphatic stomata and its significance in treating ascites in liver fibrosis model mice. METHODS: Two Chinese herbal composite prescriptions were used separately to treat the carbon tetrachloride-induced mouse model of liver fibrosis. The histo-pathologic changes of the liver sections (HE and VG stainings) were observed. The peritoneal lymphatic stomata was detected by scanning electron microscopy and computer image processing. The changes of urinary volume and sodium ion concentration were measured. RESULTS: In the model group, lots of fibrous tissue formed in liver and extended into the hepatic lobules to separate them incompletely. In the treated and prevention groups, the histo-pathologic changes of liver was rather milder, only showed much less fibrous tissue proliferation in the hepatic lobules. The peritoneal lymphatic stomata enlarged with increased density in the experimental groups (diameter: PA, 3.07 +/- 0.69 microm; PB, 2.82 +/- 0.37 microm; TA, 3.25 +/- 0.82 microm and TB, 2.82 +/- 0.56 microm; density: PA, 7.11 +/- 1.90 stomata.1000 microm(-2); PB, 8.76 +/- 1.45 stomata.1000 microm(-2); TA, 6.55 +/- 1.44 stomata.1000 microm(-2)and TB, 8.76+/-1.79 stomata.1000 microm(-2)), as compared with the model group (diameter: 2.00+/-0.52 microm density: 4.45+/-1.05 stomata.1000 microm(-2)). After treatment, the urinary volume and sodium ion excretion increased in the experimental groups (PA, 231.28+/-41.09 mmol.L(-1); PB, 171.69 +/- 27.48 mmol.L(-1) and TA, 231.44 +/- 34.12 mmol.L(-1)), which were significantly different with those in the model group (129.33 +/- 36.75 mmol.L(-1)). CONCLUSION: Chinese herbal medicine has marked effects in alleviating liver fibrosis, regulating peritoneal lymphatic stomata, improving the drainage of ascites from peritoneal cavity and causing increase of urinary volume and sodium ion excretion to reduce the water and sodium retention, and thus have favorable therapeutic effect in treating ascites.展开更多
AIM： To investigate the change of bone parameters in a new model of experimentally induced liver cirrhosis and hepatocellular carcinoma （HCC） in growing rats. METHODS： Fischer-344 rats （n = 55） were used. Carbon...AIM： To investigate the change of bone parameters in a new model of experimentally induced liver cirrhosis and hepatocellular carcinoma （HCC） in growing rats. METHODS： Fischer-344 rats （n = 55） were used. Carbon tetrachloride （CCh）, phenobarbital （PB）, and a single diethylnitrosamine （DEN） injection were used. Animals were killed at wk 8 and 16. Bone mineral content, femoral length, cortical index （quotient of cortical thickness and whole diameter） and ultimate bending load （Fmax） of the femora were determined. The results in animals treated with DEN＋PB＋CCh （DPC, n = 21） were com- pared to those in untreated animals （UNT, n = 14） and in control group treated only with DEN＋PB （DP, n = 20）. RESULTS： Fatty liver and cirrhosis developed in each DPC-treated rat at wk 8 and HCC was presented at wk 16. No skeletal changes were found in this group at wk 8, but each parameter was lower （P〈0.05 for each） at wk 16 in comparison to the control group. Neither fatty liver nor cirrhosis was observed in DP-treated animals at any time point. Femoral length and Fmax values were higher （P〈0.05 for both） in DP-treated animals at wk 8 compared to the UNT controls. However, no difference was found at wk 16. CONCLUSION： Experimental liver cirrhosis and HCC are accompanied with inhibited skeletal growth, reduced bone mass, and decreased mechanical resistance in growing rats. Our results are in concordance withthe data of other studies using different animal models. A novel finding is the transiently accelerated skeletal growth and bone strength after a 8-wk long phenobarbital treatment following diethylnitrosamine injection.展开更多
AIM: To evaluate the effects of varying ischemic durations on cirrhotic liver and to determine the safe upper limit of repeated intermittent hepatic inflow occlusion. METHODS: Hepatic ischemia in cirrhotic rats was in...AIM: To evaluate the effects of varying ischemic durations on cirrhotic liver and to determine the safe upper limit of repeated intermittent hepatic inflow occlusion. METHODS: Hepatic ischemia in cirrhotic rats was induced by clamping the common pedicle of left and median lobes after non-ischemic lobes resection. The cirrhotic rats were divided into six groups according to the duration and form of vascular clamping: sham occlusion (SO), intermittent occlusion for 10 (IO-10), 15(IO-15), 20(IO-20) and 30(IO-30) minutes with 5 minutes of reflow and continuous occlusion for 60 minutes (CO-60). All animals received a total duration of 60 minutes of hepatic inflow occlusion. Liver viability was investigated in relation of hepatic adenylate energy charge (EC). Triphenyltetrazollum chloride (TTC) reduction activities were assayed to qualitatively evaluate the degree of irreversible hepatocellular injury. The biochemical and morphological changes were also assessed and a 7-day mortality was observed. RESULTS: At 60 minutes after reperfusion following a total of 60 minutes of hepatic inflow occlusion, EC values in IO-10 (0.749 +/- 0.012) and IO-15 (0.699 +/- 0.002) groups were rapidly restored to that in SO group (0.748 +/- 0.016), TTC reduction activities remained in high levels (0.144 +/- 0.002 mg/mg protein, 0.139 +/- 0.003 mg/mg protein and 0.121 +/- 0.003 mg/mg protein in SO, IO-10 and IO-15 groups, respectively). But in IO-20 and IO-30 groups, EC levels were partly restored (0.457 +/- 0.023 and 0.534 +/- 0.027) accompanying with a significantly decreased TTC reduction activities (0.070 +/- 0.005 mg/mg protein and 0.061 +/- 0.003 mg/mg protein). No recovery in EC values (0.228 +/- 0.004) and a progressive decrease in TTC reduction activities (0.033 +/- 0.002 mg/mg protein) were shown in CO-60 group. Although not significantly different, the activities of the serum aspartate aminotransferase (AST) on the third postoperative day (POD(3)) and POD(7) and of the serum alanine aminotransferase (ALT) on POD(3) in CO-60 group remained higher than that in intermittent occlusion groups. Moreover, a 60% animal mortality rate and more severe morphological alterations were also shown in CO-60 group. CONCLUSION: Hepatic inflow occlusion during 60 minutes for liver resection in cirrhotic rats resulted in less hepatocellular injury when occlusion was intermittent rather than continuous. Each period of 15 minutes was the safe upper limit of repeated intermittent vascular occlusion that the cirrhotic liver could tolerate without undergoing irreversible hepatocellular injury.展开更多
AIM: To study the anti-hepatofibrosis mechanism of Bie Jia Jian oral liquid (BOL). METHODS: The model was induced by subcutaneous injection of CCl(4). BOL was administered and the change of serum hyaluronic acid (HA) ...AIM: To study the anti-hepatofibrosis mechanism of Bie Jia Jian oral liquid (BOL). METHODS: The model was induced by subcutaneous injection of CCl(4). BOL was administered and the change of serum hyaluronic acid (HA) and laminin (LN) was observed and the degeneration of liver cells and the degree of fibre hyperplasia analyzed. Changes of ultra micro-structure in liver cells were observed in some samples. RESULTS: HA was reduced in both the groups with low and high dosage of BOL, which showed a remarkable difference as compared with that of the model group (low dosage group: 376.15 microg/L+/-35.48 microg/L vs 806.07 microg/L+/-98.49 microg/L P【0.05; high dosage group: 340.14 microg/L+/-30.18 microg/L vs 806.07 microg/L+/-98.49 microg/L P【0.05). The LN content of low and high dosage group of BOL was lower than that of model group (low dosage group: 71.99 microg/L+/-8.15 microg/L vs 133.94 microg/L+/-14.45 microg/L P 【0.01; high dosage group: 71.68 microg/L+/-11.62 microg/L vs 133.94 microg/L+/-14.45 microg/L P【0.01) and colchicine group (low dosage group: 71.99 microg/L+/-8.15 microg/L vs 118.28 microg/L+/-16.13 microg/L P 【 0.05; high dosage group: 71.68 microg/L+/-11.62 microg/L vs 118.28 microg/L+/-16.13 microg/L P 【0.05). Examined by Ridit, BOL could reduce the degeneration and necrosis of liver cells (chi(2)=11.99 P【0.05), the degree of fibre hyperplasia (chi(2)=13.24 P【0.05) and the pathological change of ultra micro-structure as well. CONCLUSION: The BOL has certain therapeutic effect on the experiment hepatofibrosis. Its mechanisms might include: protecting the function of liver cells, inhibiting excessive synthesis and secretion of extracellular matrix from hepatic stellate cells, relieving the capillarization of hepatic sinusoid, improving liver micro-circulation, and regulating immune function.展开更多
文摘That Ho cells in rat liver express desmin was confirmed by immunohistochemical technique. Consequently, changes of desmin-positive cells, lysozyme-positive cells and fibronectin were further studied in experimental cirrhosis of rat. It was found that desmln- positive cells, with the transitional feature between Ito cells and myofibroblasts or fibrobiasts under electron microscope, increased in number and expression of desmin in the necrotic areas as well as in the cellular fibrous septa, but decreased in number in the fibrous septa except those areas closed to the edges of the septa. These results suggested that Ito cells, myofibroblasts and fibroblasts might belong to the same cellular system and play an important role in the pathogenesis of cirrhosis. Meanwhile, it was also noted that changes of both fibronectin and lysozymepositive cells were correlated with those of desmin-positive cells. These provide evidence in vivo that flbronectin and Kupffer cells might exert certain effects on the migration and proliferation of Ito cells in liver cirrhosis.
基金Supported by Grant-in-Aid for Young Scientists,Ministry of Education,Culture,Sports,Science and Technology of Japan,No.24791434(to Hayashi H)and Takeda Science Foundation,Japan(to Hayashi H)
文摘Thrombocytopenia is a common complication in liver disease and can adversely affect the treatment of liver cirrhosis,limiting the ability to administer therapy and delaying planned surgical/diagnostic procedures because of an increased risk of bleeding.Multiple factors,including splenic sequestration,reduced activity of the hematopoietic growth factor thrombopoietin,bone marrow suppression by chronic hepatitis C virus infection and anti-cancer agents,and antiviral treatment with interferon-based therapy,can contribute to the development of thrombocytopenia in cirrhotic patients.Of these factors,the major mechanisms for thrombocytopenia in liver cirrhosis are(1)platelet sequestration in the spleen;and(2)decreased production of thrombopoietin in the liver.Several treatment options,including platelet transfusion,interventional partial splenic embolization,and surgical splenectomy,are now available for severe thrombocytopenia in cirrhotic patients.Although thrombopoietin agonists and targeted agents are alternative tools for noninvasively treating thrombocytopenia due to liver cirrhosis,their ability to improve thrombocytopenia in cirrhotic patients is under investigation in clinical trials.In this review,we propose a treatment approach to thrombocytopenia according to our novel concept of splenic volume,and we describe the current management of thrombocytopenia due to liver cirrhosis.
基金Akdeniz University Scientific Research Foundation, 2004. 04. 0103. 013
文摘AIM:To investigate the significance of Thrombospondin-1 (TSP-1) expression and its relationship with angiogenesis during experimental fibrosis. METHODS:Cirrhosis was induced in male Wistar rats by intraperitoneal administration of diethyl nitrosamine (DEN). The serial sections from liver tissues were stained with anti-CD34 and anti-TSP-1 antibodies before being quantitated by light microscopy. RESULTS:Our results showed that of TSP-1 expression gradually increases according to the severity of fibrosis (GroupⅠvs group Ⅱ, Group Ⅲ and Group Ⅳ;Group Ⅱ vs group Ⅲ and group Ⅳ;group Ⅲ vs group Ⅳ, P < 0.05). Moreover, TSP-1 expression was found to be correlated with angiogenesis (P < 0.05). CONCLUSION:The correlative evidence of the link between TSP-1 and fibrosis or angiogenesis provided by this study suggests that besides its role as a strong promoter of transforming growth factor-β1 (TGF-β1), TSP-1 might have an additional role in liver fibrogenesis by stimulating angiogenesis and this protein could be a potential target to prevent fibrogenesis in chronic inflammatory diseases of the liver.
基金the National Natural Science Foundation of China,No.39970934Scientific Researches by Science Coinmittee of Hangzhou+2 种基金State Administration of Traditional Chinese Medicine,No.97Z031Zhejiang Provincial Administration of Traditional Chinese Medicineexcellent young talented person by Chinese Ministry of Health and Analysis and Testing fundation of Zhejiang Province.
文摘AIM: To observe the regulatory effect of Chinese herbal medicine on peritoneal lymphatic stomata and its significance in treating ascites in liver fibrosis model mice. METHODS: Two Chinese herbal composite prescriptions were used separately to treat the carbon tetrachloride-induced mouse model of liver fibrosis. The histo-pathologic changes of the liver sections (HE and VG stainings) were observed. The peritoneal lymphatic stomata was detected by scanning electron microscopy and computer image processing. The changes of urinary volume and sodium ion concentration were measured. RESULTS: In the model group, lots of fibrous tissue formed in liver and extended into the hepatic lobules to separate them incompletely. In the treated and prevention groups, the histo-pathologic changes of liver was rather milder, only showed much less fibrous tissue proliferation in the hepatic lobules. The peritoneal lymphatic stomata enlarged with increased density in the experimental groups (diameter: PA, 3.07 +/- 0.69 microm; PB, 2.82 +/- 0.37 microm; TA, 3.25 +/- 0.82 microm and TB, 2.82 +/- 0.56 microm; density: PA, 7.11 +/- 1.90 stomata.1000 microm(-2); PB, 8.76 +/- 1.45 stomata.1000 microm(-2); TA, 6.55 +/- 1.44 stomata.1000 microm(-2)and TB, 8.76+/-1.79 stomata.1000 microm(-2)), as compared with the model group (diameter: 2.00+/-0.52 microm density: 4.45+/-1.05 stomata.1000 microm(-2)). After treatment, the urinary volume and sodium ion excretion increased in the experimental groups (PA, 231.28+/-41.09 mmol.L(-1); PB, 171.69 +/- 27.48 mmol.L(-1) and TA, 231.44 +/- 34.12 mmol.L(-1)), which were significantly different with those in the model group (129.33 +/- 36.75 mmol.L(-1)). CONCLUSION: Chinese herbal medicine has marked effects in alleviating liver fibrosis, regulating peritoneal lymphatic stomata, improving the drainage of ascites from peritoneal cavity and causing increase of urinary volume and sodium ion excretion to reduce the water and sodium retention, and thus have favorable therapeutic effect in treating ascites.
基金Supported by The Medical Research Council of Hungary, ETT 226/2003, 232/2003The Hungarian Scientific Research Fund, OTKA T038067, T038154
文摘AIM： To investigate the change of bone parameters in a new model of experimentally induced liver cirrhosis and hepatocellular carcinoma （HCC） in growing rats. METHODS： Fischer-344 rats （n = 55） were used. Carbon tetrachloride （CCh）, phenobarbital （PB）, and a single diethylnitrosamine （DEN） injection were used. Animals were killed at wk 8 and 16. Bone mineral content, femoral length, cortical index （quotient of cortical thickness and whole diameter） and ultimate bending load （Fmax） of the femora were determined. The results in animals treated with DEN＋PB＋CCh （DPC, n = 21） were com- pared to those in untreated animals （UNT, n = 14） and in control group treated only with DEN＋PB （DP, n = 20）. RESULTS： Fatty liver and cirrhosis developed in each DPC-treated rat at wk 8 and HCC was presented at wk 16. No skeletal changes were found in this group at wk 8, but each parameter was lower （P〈0.05 for each） at wk 16 in comparison to the control group. Neither fatty liver nor cirrhosis was observed in DP-treated animals at any time point. Femoral length and Fmax values were higher （P〈0.05 for both） in DP-treated animals at wk 8 compared to the UNT controls. However, no difference was found at wk 16. CONCLUSION： Experimental liver cirrhosis and HCC are accompanied with inhibited skeletal growth, reduced bone mass, and decreased mechanical resistance in growing rats. Our results are in concordance withthe data of other studies using different animal models. A novel finding is the transiently accelerated skeletal growth and bone strength after a 8-wk long phenobarbital treatment following diethylnitrosamine injection.
基金This Work was supported by the grant from the Science and Technology Committee of Zhejiang Province,No.971103132
文摘AIM: To evaluate the effects of varying ischemic durations on cirrhotic liver and to determine the safe upper limit of repeated intermittent hepatic inflow occlusion. METHODS: Hepatic ischemia in cirrhotic rats was induced by clamping the common pedicle of left and median lobes after non-ischemic lobes resection. The cirrhotic rats were divided into six groups according to the duration and form of vascular clamping: sham occlusion (SO), intermittent occlusion for 10 (IO-10), 15(IO-15), 20(IO-20) and 30(IO-30) minutes with 5 minutes of reflow and continuous occlusion for 60 minutes (CO-60). All animals received a total duration of 60 minutes of hepatic inflow occlusion. Liver viability was investigated in relation of hepatic adenylate energy charge (EC). Triphenyltetrazollum chloride (TTC) reduction activities were assayed to qualitatively evaluate the degree of irreversible hepatocellular injury. The biochemical and morphological changes were also assessed and a 7-day mortality was observed. RESULTS: At 60 minutes after reperfusion following a total of 60 minutes of hepatic inflow occlusion, EC values in IO-10 (0.749 +/- 0.012) and IO-15 (0.699 +/- 0.002) groups were rapidly restored to that in SO group (0.748 +/- 0.016), TTC reduction activities remained in high levels (0.144 +/- 0.002 mg/mg protein, 0.139 +/- 0.003 mg/mg protein and 0.121 +/- 0.003 mg/mg protein in SO, IO-10 and IO-15 groups, respectively). But in IO-20 and IO-30 groups, EC levels were partly restored (0.457 +/- 0.023 and 0.534 +/- 0.027) accompanying with a significantly decreased TTC reduction activities (0.070 +/- 0.005 mg/mg protein and 0.061 +/- 0.003 mg/mg protein). No recovery in EC values (0.228 +/- 0.004) and a progressive decrease in TTC reduction activities (0.033 +/- 0.002 mg/mg protein) were shown in CO-60 group. Although not significantly different, the activities of the serum aspartate aminotransferase (AST) on the third postoperative day (POD(3)) and POD(7) and of the serum alanine aminotransferase (ALT) on POD(3) in CO-60 group remained higher than that in intermittent occlusion groups. Moreover, a 60% animal mortality rate and more severe morphological alterations were also shown in CO-60 group. CONCLUSION: Hepatic inflow occlusion during 60 minutes for liver resection in cirrhotic rats resulted in less hepatocellular injury when occlusion was intermittent rather than continuous. Each period of 15 minutes was the safe upper limit of repeated intermittent vascular occlusion that the cirrhotic liver could tolerate without undergoing irreversible hepatocellular injury.
基金Supported by the Natural Science Foundation of Zhejiang Province,No.398402
文摘AIM: To study the anti-hepatofibrosis mechanism of Bie Jia Jian oral liquid (BOL). METHODS: The model was induced by subcutaneous injection of CCl(4). BOL was administered and the change of serum hyaluronic acid (HA) and laminin (LN) was observed and the degeneration of liver cells and the degree of fibre hyperplasia analyzed. Changes of ultra micro-structure in liver cells were observed in some samples. RESULTS: HA was reduced in both the groups with low and high dosage of BOL, which showed a remarkable difference as compared with that of the model group (low dosage group: 376.15 microg/L+/-35.48 microg/L vs 806.07 microg/L+/-98.49 microg/L P【0.05; high dosage group: 340.14 microg/L+/-30.18 microg/L vs 806.07 microg/L+/-98.49 microg/L P【0.05). The LN content of low and high dosage group of BOL was lower than that of model group (low dosage group: 71.99 microg/L+/-8.15 microg/L vs 133.94 microg/L+/-14.45 microg/L P 【0.01; high dosage group: 71.68 microg/L+/-11.62 microg/L vs 133.94 microg/L+/-14.45 microg/L P【0.01) and colchicine group (low dosage group: 71.99 microg/L+/-8.15 microg/L vs 118.28 microg/L+/-16.13 microg/L P 【 0.05; high dosage group: 71.68 microg/L+/-11.62 microg/L vs 118.28 microg/L+/-16.13 microg/L P 【0.05). Examined by Ridit, BOL could reduce the degeneration and necrosis of liver cells (chi(2)=11.99 P【0.05), the degree of fibre hyperplasia (chi(2)=13.24 P【0.05) and the pathological change of ultra micro-structure as well. CONCLUSION: The BOL has certain therapeutic effect on the experiment hepatofibrosis. Its mechanisms might include: protecting the function of liver cells, inhibiting excessive synthesis and secretion of extracellular matrix from hepatic stellate cells, relieving the capillarization of hepatic sinusoid, improving liver micro-circulation, and regulating immune function.
