慢加急性肝衰竭内毒素血症对清道夫受体CD163作用的研究
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摘要
【目的】
探讨局限表达在单核巨噬细胞系的清道夫受体CD163与血清中可溶性CD163(sCD163)在慢加急性肝衰竭(ACLF)中的临床表达和意义,肝衰竭内毒素血症对CD163调节免疫的影响以及糖皮质诱导CD163表达对肝衰竭大鼠的保护作用。
【方法】
1.收集ACLF患者的血清,新鲜血液标本,肝移植组织标本以及临床资料。
2. Elisa检测血清中sCD163,分析sCD163与临床资料的联系。
3.鲎试剂检测血清中LPS。
4.流式分析仪检测CD 163、HLA-DR分子在外周血单核细胞的表达。
5. Real-time PCR检测外周血单核细胞CD 163,TLR4转录。
6.LPS体外刺激ACLF患者外周血单核细胞,Elisa检测sCD163、TNF-α、IL-10等。
7.HE染色,免疫组化方法检测CD163阳性枯否细胞在ACLF肝组织上的表达。
8.HE染色,免疫组化观察糖皮质激素对正常大鼠肝组织内枯否细胞表达CD163分子的影响。
9.采用全自动生化分析仪器测定肝衰竭大鼠与糖皮质激素给药组大鼠血清谷丙转氨酶,总胆红素。
10.Elisa测定肝衰竭以及糖皮质激素给药组大鼠血清中sCD163。
11.采用HE染色观察肝衰竭大鼠与造模后予以糖皮质激素组大鼠肝组织的病理改变。
12.Western blotting分析肝衰竭模型组,造模后立即给药组(即0h给药组)、4h给药组、8h给药组的肝组织CD163、HO-1的表达。
【结果】
1.ACLF患者sCD163水平较肝硬化、慢性乙肝、急性肝炎组和正常组增高(P<0.05)。
2.经Pearson相关分析,ACLF患者入院时血清sCD163与临床生化指标总胆红素和反映凝血功能的国际标准化比值呈正相关,(P<0.05)。
3.ACLF患者合并感染或肝肾综合征或者肝性脑病等并发症时,血清中sCD163水平明显高于非感染组与无并发症组,(P<0.05)。
4.ACLF患者死亡组sCD163水平在入院时和出院时均高于存活组(P<0.05),死亡组病情加重时,sCD163有增高趋势；而存活组出院时sCD163较入院时有降低的趋势。
5.ACLF组内毒素血症发生率以及内毒素水平明显高于肝硬化组、慢性乙肝组、急性肝炎组和正常组,(P<0.05)。
6.绘制LPS与sCD163值的散点图,内毒素血症与血清中sCD163水平具有一定的相关性,r=0.56。
7.ACLF患者死亡组外周血单核细胞体外接受LPS刺激后上清液中TNF-α低于正常组与存活组,(P<0.05)：而IL-10和sCD163水平高于正常组和存活组,(P<0.05)。
8.ACLF患者死亡组CD 163 MFI低于存活组和正常组,(P<0.05)；死亡组中的外周血单核细胞表面HLA-DR分子表达最低、存活组次之、正常组(P<0.05)。
9.ACLF患者外周血单核细胞CD 163 mRNA表达上调高于慢性重度组、慢性乙肝轻中度组、正常组,(P<0.05)；外周血单核细胞TLR4 mRNA表达也上调,但低于慢性重度组,而高于正常组、慢性轻中度组(P<0.05)。
10.ACLF移植肝组织HE染色后可见：再生肝结节内肝细胞广泛气球样变,坏死出现空洞,肝窦内可见亮黄色胆栓,以及存在不同程度的肝小叶界面性坏死和纤维化增生,胆小管增生；汇管区内巨噬细胞多见。
11.ACLF肝组织标本免疫组化染色显示肝窦内多见三角形、细长型、形状不规则的染成棕黄色细胞,即为标记的CD163阳性枯否细胞,正常组织内偶可见染成棕色枯否细胞。
12.正常组与地塞米松诱导组的大鼠6h后比较：肝组织免疫组化染色显示地塞米松诱导组CD163阳性枯否细胞数量较正常组明显增多,而血清中sCD163水平无差异,肝组织结构均完整。
13.肝衰竭模型组大鼠血清中sCD163水平比给药组减少,造模后立即给药组sCD163水平高于4h给药组、8h给药组(P<0.05)；
14.造模后给药组CD163,HO-1表达较肝衰竭造模组升高,P<0.05；而造模后8h给药组的CD163,HO-1最高,4h组给药组次之,立即给药组CD163与HO-1表达最低,(P<0.05)。
【结论】
1.在ACLF患者中血清sCD163显著增多,明显高于肝硬化、慢性乙肝、急性肝炎和健康对照组,提示sCD163是ACLF的敏感血清标志蛋白；合并腹膜炎的患者sCD163水平增高,提示血清中sCD163的水平与感染相关,可能是临床反映感染的指标；sCD163与TBIL和INR相关,一定程度上可以反映ACLF患者的病情。
2.ACLF死亡组患者中,血清sCD163水平明显高于存活组,死亡组经治疗后sCD163仍处于较高的水平,存活组在经过治疗后sCD163呈下降的趋势,该研究提示sCD163的基础水平以及治疗过程中的变化趋势可以一定程度上反映ACLF患者的治疗效果及预后。
3.ACLF患者血清sCD163、LPS水平均增高,LPS识别受体TLR4表达也上调,Pearson检验显示sCD163与LPS水平呈正相关,相关系数r=0.56,结果提示ACLF患者sCD163增高与体内内毒素血症诱发的机体感染有关。
4. ACLF患者中外周血单核细胞CD163mRNA水平增高,单核细胞CD163表达减少,提示血清中sCD163可能一部分来自外周血单核细胞CD163蛋白水解。
5.体外用LPS继续刺激ACLF患者分离的外周血单核细胞,结果显示死亡组患者分泌TNF-α水平较正常组均减少,而sCD163、IL-10分泌增多；ACLF患者外周血单核细胞上HLA-DR表达水平明显下调,死亡组患者较存活组和正常组HLA-DR下调更加显著,血清中sCD163增高更加显著,提示在慢性肝病病理基础上内毒素血症长期刺激可造成ACLF对LPS耐受,患者体内存在炎症反应到抗炎反应的免疫紊乱,过高的sCD163标志着机体的免疫耐受,耐受的巨噬细胞使机体处于瘫痪状态,增加了后续感染的风险,因而过高的sCD163有更高的死亡风险,预后不良。
6.我们的结果证实糖皮质激素在体内可以诱导肝内表达CD163的枯否细胞增多,造模后立即给药组及4h给药组对急性肝衰竭大鼠有保护作用,而血清中sCD163明显增多,提示早期给予糖皮质激素可通过诱导抗炎的急性期反应蛋白CD163来保护肝细胞免受炎性因子的损伤,为糖皮质激素在控制内毒素血症中的临床应用提供了新的免疫学依据。
【Objective】
Investigated into clinical expression and significance of scavenger receptor CD163, which only expressed on monocyte-macrophage cell lines, and serum soluble CD 163 in acute-on-chronic liver failure (ACLF).Further, to investigate into the endotoxemia influencing on immune regulatory of CD 163 and into the protection mechanisms of increased CD 163 induced by cortex in rats with liver failure.
【Methods】
1.Samples from serum, from fresh blood, from tissue samples of liver transplantation and from clinical data in ACLF were collected.
2.Serum sCD163 was detected by Elisa and the correction was evaluated between sCD163 and clinical data.
3.Serum LPS was assayed by TAL.
4.FACS analyzed the expression of CD163 and HLA-DR in peripheral blood monocytes.
5.The transcription of CD 163 and TLR4 in peripheral blood monocyte was detected by real-time PCR.
6.LPS stimulated peripheral blood monocytes in patients with ACLF in vitro. sCD163, IL-10 and TNF-αwere detection by Elisa.
7.We detected CD163-positive Kupffer cells in patients liver tissue with ACLF by HE staining and immunohistochemistry.
8.Kupffer cells induced by glucocorticoid were observed in rat liver by HE staining and immunohistochemical staining.
9.Serum alanine aminotransferase and bilirubin were measured by automatic biochemical analysis instrument in rats with liver failure and in rats with the intervention after liver failure.
10.Serum sCD163 by Elisa was determined in rats with liver failure and with glucocorticoid administration.
11.The pathological changes were observed by HE staining in rats liver tissue with liver failure and with the intervention group.
12.Western blotting analysis the expression of CD163,HO-1 in the model group with liver failure, administration group after modeling at the same time,4h administration group, 8h administration group.
【Results】
1.sCD163 levels in ACLF patients were increased compared with liver cirrhosis, chronic hepatitis B, acute hepatitis group and the control group (P<0.05).
2.The Pearson correlation analysis, serum sCD163 in ACLF patients in admission were positively related to the clinical total bilirubin and international normalized ratio, (P <0.05).
3.In ACLF patients with infection or complications such as hepatic encephalopathy, or hepatorenal syndrome, serum sCD163 was significantly higher than non-infected group and that no complication group, (P<0.05).
4.In the dead group of ACLF patients, sCD163 levels were higher than that in the survival group both on admission and at discharge (P<0.05),when the death group exacerbations, sCD163 tended to increase in the death at discharge compared to on admission,whereas, sCD163 tended to decrease in the survival group.
5.In ACLF group the incidence of endotoxemia and endotoxin levels were significantly higher than liver cirrhosis group, chronic hepatitis B group, acute hepatitis group and normal group, (P<0.05).
6.Endotoxemia was correlation with serum sCD163 in ACLF group, r=0.56.
7.In ACLF death group, TNF-αfrom supernatant was significantly less than that in survival group when peripheral blood monocytes cells were stimulated by LPS in vitro (P <0.05).Intetestingly, IL-10 and sCD163 levels were significantly higher than that in both the normal group and the survival group (P<0.05).
8.In ACLF patients who died, CD 163 MFI was less than that both in the survival group and in the normal group, (P<0.05);Expression of HLA-DR molecules of peripheral blood monocytes in the death group was the lowest, that was second in the survival group, at last the normal group (P<0.05).
9.In ACLF patients,CD 163 mRNA of peripheral blood monocytes was up-regulation and was higher than that in chronic severe group and in the normal group, (P<0.05);TLR4 mRNA of peripheral blood monocytes was also up-regulation in ACLF patients. But the levels were less than that in chronic severe group and higher than that in the normal group and in mild to moderate chronic group (P<0.05).
10.Liver tissues from transplantation in ACLF by HE staining showed that hepatocytes in regeneration nodules were extensively ballooning degeneration and necrosis, bile thrombus with bright yellow can be seen in sinusoidal. Necrosis with different degrees from the interface hyperplasia and fibrosis in lobular bile duct proliferation were also observed; the macrophages were more common.
11.In ACLF liver tissue by immunohistochemical staining, triangular, slender, or irregularly shaped cells which were brown were more common in hepatic sinusoid, that is labeled CD163-positive Kupffer cells, but, in normal tissues Kupffer cells dyed brown were less.
12.Normal rats group induced by dexamethasone compared with that were not induced after 6h:immunohistochemical staining of liver tissue showed that in the group induced by dexamethasone, CD 163-positive Kupffer cells were significantly higher than that in the normal group.
13.In liver failure model,serum sCD163 levels was less than that in the treatment group, sCD163 in the immediate administration group after modeling was higher than that in administration group at 4h and at 8h administration (P<0.05).
14.For administration group after modeling, the expression of CD163 and HO-1 in liver failure was higher than that in the model, (P<0.05);for the immediate administration group after modeling, the expression of CD 163,HO-1 were the lowest, was the second for the group at 4h administration, was at last for the group at 8h administration, (P<0.05).
【Conclusion】
1.Serum sCD163 in ACLF patients was significantly higher than liver cirrhosis group, chronic hepatitis B group, acute hepatitis group and healthy controls, suggesting that sCD163 is sensitive serum marker proteins;the level of sCD163 increased in patients with peritonitis, suggesting that the level of serum sCD163 were response to inflammation and were the clinical indicators of infection; To a certain extent, sCD163 was related to TBIL and INR, suggesting that the severity of patients with ACLF.
2.In ACLF death patients, serum sCD163 levels were significantly higher than that in the survival group. In death group after treatment sCD163 remained at a high level, but, in the survival group after treatment sCD163 showed a decline, which suggested that sCD163 levels and change trends after treatment were related to treatment and prognosis, to some extent.
3.In ACLF patients, sCD163 and LPS levels increased, accordingly, the expression also increases of TLR4 which was knowned as LPS recognition receptors. Pearson test showed the levels of sCD163 correlated with LPS,the correlation coefficient r=0.56, suggesting that increased sCD163 in ACLF patients were induced by endotoxemia in vivo.
4.In ACLF patients, CD 163 mRNA in peripheral blood monocytes increased, however, the expression of CD 163 was decreased, which suggesting that serum sCD163 may be partly from CD 163 protein hydrolysis in the peripheral blood monocytes.
5.LPS stimulating peripheral blood momocytes in vitro isolated from ACLF patients showed that the secretion of TNF-αin patients died was less than that in the normal group. However, secretion levels of sCD163,IL-10 increased; HLA-DR expression in peripheral blood monocytes from ACLF patients was reduced. Compared with the survival group and the normal group, down-regulation of HLA-DR in the death group were more significant, while, up-regulation of serum sCD163 were more significant, suggesting that on the basis of chronic liver disease, pathologically long-term stimulation by endotoxin can result in LPS tolerance in ACLF, which indicated immune disorders from inflammation reaction to anti-inflammatory response in patients. Very high sCD163 marked immune tolerance, after tolerance of macrophages the immune paralyzed, and increased risk of subsequent infection, and therefore high sCD163 had higher risk of death and poor prognosis.
6.Our results confirmed that corticosteroids can induce the expression of CD 163 in Kupffer cells in vivo,immediate administration after modeling and that at 4h in treatment group has a protective effect on rats with acute liver failure, however, significantly increased serum sCD163,suggesting that glucocorticoid in the early can induce acute anti-inflammatory protein CD 163 to protect liver cells against inflammatory factor damage. The study provided with the new immunological basis for the clinical application with glucocorticoid to control endotoxemia.
探讨局限表达在单核巨噬细胞系的清道夫受体CD163与血清中可溶性CD163(sCD163)在慢加急性肝衰竭(ACLF)中的临床表达和意义,肝衰竭内毒素血症对CD163调节免疫的影响以及糖皮质诱导CD163表达对肝衰竭大鼠的保护作用。
【方法】
1.收集ACLF患者的血清,新鲜血液标本,肝移植组织标本以及临床资料。
2. Elisa检测血清中sCD163,分析sCD163与临床资料的联系。
3.鲎试剂检测血清中LPS。
4.流式分析仪检测CD 163、HLA-DR分子在外周血单核细胞的表达。
5. Real-time PCR检测外周血单核细胞CD 163,TLR4转录。
6.LPS体外刺激ACLF患者外周血单核细胞,Elisa检测sCD163、TNF-α、IL-10等。
7.HE染色,免疫组化方法检测CD163阳性枯否细胞在ACLF肝组织上的表达。
8.HE染色,免疫组化观察糖皮质激素对正常大鼠肝组织内枯否细胞表达CD163分子的影响。
9.采用全自动生化分析仪器测定肝衰竭大鼠与糖皮质激素给药组大鼠血清谷丙转氨酶,总胆红素。
10.Elisa测定肝衰竭以及糖皮质激素给药组大鼠血清中sCD163。
11.采用HE染色观察肝衰竭大鼠与造模后予以糖皮质激素组大鼠肝组织的病理改变。
12.Western blotting分析肝衰竭模型组,造模后立即给药组(即0h给药组)、4h给药组、8h给药组的肝组织CD163、HO-1的表达。
【结果】
1.ACLF患者sCD163水平较肝硬化、慢性乙肝、急性肝炎组和正常组增高(P<0.05)。
2.经Pearson相关分析,ACLF患者入院时血清sCD163与临床生化指标总胆红素和反映凝血功能的国际标准化比值呈正相关,(P<0.05)。
3.ACLF患者合并感染或肝肾综合征或者肝性脑病等并发症时,血清中sCD163水平明显高于非感染组与无并发症组,(P<0.05)。
4.ACLF患者死亡组sCD163水平在入院时和出院时均高于存活组(P<0.05),死亡组病情加重时,sCD163有增高趋势；而存活组出院时sCD163较入院时有降低的趋势。
5.ACLF组内毒素血症发生率以及内毒素水平明显高于肝硬化组、慢性乙肝组、急性肝炎组和正常组,(P<0.05)。
6.绘制LPS与sCD163值的散点图,内毒素血症与血清中sCD163水平具有一定的相关性,r=0.56。
7.ACLF患者死亡组外周血单核细胞体外接受LPS刺激后上清液中TNF-α低于正常组与存活组,(P<0.05)：而IL-10和sCD163水平高于正常组和存活组,(P<0.05)。
8.ACLF患者死亡组CD 163 MFI低于存活组和正常组,(P<0.05)；死亡组中的外周血单核细胞表面HLA-DR分子表达最低、存活组次之、正常组(P<0.05)。
9.ACLF患者外周血单核细胞CD 163 mRNA表达上调高于慢性重度组、慢性乙肝轻中度组、正常组,(P<0.05)；外周血单核细胞TLR4 mRNA表达也上调,但低于慢性重度组,而高于正常组、慢性轻中度组(P<0.05)。
10.ACLF移植肝组织HE染色后可见：再生肝结节内肝细胞广泛气球样变,坏死出现空洞,肝窦内可见亮黄色胆栓,以及存在不同程度的肝小叶界面性坏死和纤维化增生,胆小管增生；汇管区内巨噬细胞多见。
11.ACLF肝组织标本免疫组化染色显示肝窦内多见三角形、细长型、形状不规则的染成棕黄色细胞,即为标记的CD163阳性枯否细胞,正常组织内偶可见染成棕色枯否细胞。
12.正常组与地塞米松诱导组的大鼠6h后比较：肝组织免疫组化染色显示地塞米松诱导组CD163阳性枯否细胞数量较正常组明显增多,而血清中sCD163水平无差异,肝组织结构均完整。
13.肝衰竭模型组大鼠血清中sCD163水平比给药组减少,造模后立即给药组sCD163水平高于4h给药组、8h给药组(P<0.05)；
14.造模后给药组CD163,HO-1表达较肝衰竭造模组升高,P<0.05；而造模后8h给药组的CD163,HO-1最高,4h组给药组次之,立即给药组CD163与HO-1表达最低,(P<0.05)。
【结论】
1.在ACLF患者中血清sCD163显著增多,明显高于肝硬化、慢性乙肝、急性肝炎和健康对照组,提示sCD163是ACLF的敏感血清标志蛋白；合并腹膜炎的患者sCD163水平增高,提示血清中sCD163的水平与感染相关,可能是临床反映感染的指标；sCD163与TBIL和INR相关,一定程度上可以反映ACLF患者的病情。
2.ACLF死亡组患者中,血清sCD163水平明显高于存活组,死亡组经治疗后sCD163仍处于较高的水平,存活组在经过治疗后sCD163呈下降的趋势,该研究提示sCD163的基础水平以及治疗过程中的变化趋势可以一定程度上反映ACLF患者的治疗效果及预后。
3.ACLF患者血清sCD163、LPS水平均增高,LPS识别受体TLR4表达也上调,Pearson检验显示sCD163与LPS水平呈正相关,相关系数r=0.56,结果提示ACLF患者sCD163增高与体内内毒素血症诱发的机体感染有关。
4. ACLF患者中外周血单核细胞CD163mRNA水平增高,单核细胞CD163表达减少,提示血清中sCD163可能一部分来自外周血单核细胞CD163蛋白水解。
5.体外用LPS继续刺激ACLF患者分离的外周血单核细胞,结果显示死亡组患者分泌TNF-α水平较正常组均减少,而sCD163、IL-10分泌增多；ACLF患者外周血单核细胞上HLA-DR表达水平明显下调,死亡组患者较存活组和正常组HLA-DR下调更加显著,血清中sCD163增高更加显著,提示在慢性肝病病理基础上内毒素血症长期刺激可造成ACLF对LPS耐受,患者体内存在炎症反应到抗炎反应的免疫紊乱,过高的sCD163标志着机体的免疫耐受,耐受的巨噬细胞使机体处于瘫痪状态,增加了后续感染的风险,因而过高的sCD163有更高的死亡风险,预后不良。
6.我们的结果证实糖皮质激素在体内可以诱导肝内表达CD163的枯否细胞增多,造模后立即给药组及4h给药组对急性肝衰竭大鼠有保护作用,而血清中sCD163明显增多,提示早期给予糖皮质激素可通过诱导抗炎的急性期反应蛋白CD163来保护肝细胞免受炎性因子的损伤,为糖皮质激素在控制内毒素血症中的临床应用提供了新的免疫学依据。
【Objective】
Investigated into clinical expression and significance of scavenger receptor CD163, which only expressed on monocyte-macrophage cell lines, and serum soluble CD 163 in acute-on-chronic liver failure (ACLF).Further, to investigate into the endotoxemia influencing on immune regulatory of CD 163 and into the protection mechanisms of increased CD 163 induced by cortex in rats with liver failure.
【Methods】
1.Samples from serum, from fresh blood, from tissue samples of liver transplantation and from clinical data in ACLF were collected.
2.Serum sCD163 was detected by Elisa and the correction was evaluated between sCD163 and clinical data.
3.Serum LPS was assayed by TAL.
4.FACS analyzed the expression of CD163 and HLA-DR in peripheral blood monocytes.
5.The transcription of CD 163 and TLR4 in peripheral blood monocyte was detected by real-time PCR.
6.LPS stimulated peripheral blood monocytes in patients with ACLF in vitro. sCD163, IL-10 and TNF-αwere detection by Elisa.
7.We detected CD163-positive Kupffer cells in patients liver tissue with ACLF by HE staining and immunohistochemistry.
8.Kupffer cells induced by glucocorticoid were observed in rat liver by HE staining and immunohistochemical staining.
9.Serum alanine aminotransferase and bilirubin were measured by automatic biochemical analysis instrument in rats with liver failure and in rats with the intervention after liver failure.
10.Serum sCD163 by Elisa was determined in rats with liver failure and with glucocorticoid administration.
11.The pathological changes were observed by HE staining in rats liver tissue with liver failure and with the intervention group.
12.Western blotting analysis the expression of CD163,HO-1 in the model group with liver failure, administration group after modeling at the same time,4h administration group, 8h administration group.
【Results】
1.sCD163 levels in ACLF patients were increased compared with liver cirrhosis, chronic hepatitis B, acute hepatitis group and the control group (P<0.05).
2.The Pearson correlation analysis, serum sCD163 in ACLF patients in admission were positively related to the clinical total bilirubin and international normalized ratio, (P <0.05).
3.In ACLF patients with infection or complications such as hepatic encephalopathy, or hepatorenal syndrome, serum sCD163 was significantly higher than non-infected group and that no complication group, (P<0.05).
4.In the dead group of ACLF patients, sCD163 levels were higher than that in the survival group both on admission and at discharge (P<0.05),when the death group exacerbations, sCD163 tended to increase in the death at discharge compared to on admission,whereas, sCD163 tended to decrease in the survival group.
5.In ACLF group the incidence of endotoxemia and endotoxin levels were significantly higher than liver cirrhosis group, chronic hepatitis B group, acute hepatitis group and normal group, (P<0.05).
6.Endotoxemia was correlation with serum sCD163 in ACLF group, r=0.56.
7.In ACLF death group, TNF-αfrom supernatant was significantly less than that in survival group when peripheral blood monocytes cells were stimulated by LPS in vitro (P <0.05).Intetestingly, IL-10 and sCD163 levels were significantly higher than that in both the normal group and the survival group (P<0.05).
8.In ACLF patients who died, CD 163 MFI was less than that both in the survival group and in the normal group, (P<0.05);Expression of HLA-DR molecules of peripheral blood monocytes in the death group was the lowest, that was second in the survival group, at last the normal group (P<0.05).
9.In ACLF patients,CD 163 mRNA of peripheral blood monocytes was up-regulation and was higher than that in chronic severe group and in the normal group, (P<0.05);TLR4 mRNA of peripheral blood monocytes was also up-regulation in ACLF patients. But the levels were less than that in chronic severe group and higher than that in the normal group and in mild to moderate chronic group (P<0.05).
10.Liver tissues from transplantation in ACLF by HE staining showed that hepatocytes in regeneration nodules were extensively ballooning degeneration and necrosis, bile thrombus with bright yellow can be seen in sinusoidal. Necrosis with different degrees from the interface hyperplasia and fibrosis in lobular bile duct proliferation were also observed; the macrophages were more common.
11.In ACLF liver tissue by immunohistochemical staining, triangular, slender, or irregularly shaped cells which were brown were more common in hepatic sinusoid, that is labeled CD163-positive Kupffer cells, but, in normal tissues Kupffer cells dyed brown were less.
12.Normal rats group induced by dexamethasone compared with that were not induced after 6h:immunohistochemical staining of liver tissue showed that in the group induced by dexamethasone, CD 163-positive Kupffer cells were significantly higher than that in the normal group.
13.In liver failure model,serum sCD163 levels was less than that in the treatment group, sCD163 in the immediate administration group after modeling was higher than that in administration group at 4h and at 8h administration (P<0.05).
14.For administration group after modeling, the expression of CD163 and HO-1 in liver failure was higher than that in the model, (P<0.05);for the immediate administration group after modeling, the expression of CD 163,HO-1 were the lowest, was the second for the group at 4h administration, was at last for the group at 8h administration, (P<0.05).
【Conclusion】
1.Serum sCD163 in ACLF patients was significantly higher than liver cirrhosis group, chronic hepatitis B group, acute hepatitis group and healthy controls, suggesting that sCD163 is sensitive serum marker proteins;the level of sCD163 increased in patients with peritonitis, suggesting that the level of serum sCD163 were response to inflammation and were the clinical indicators of infection; To a certain extent, sCD163 was related to TBIL and INR, suggesting that the severity of patients with ACLF.
2.In ACLF death patients, serum sCD163 levels were significantly higher than that in the survival group. In death group after treatment sCD163 remained at a high level, but, in the survival group after treatment sCD163 showed a decline, which suggested that sCD163 levels and change trends after treatment were related to treatment and prognosis, to some extent.
3.In ACLF patients, sCD163 and LPS levels increased, accordingly, the expression also increases of TLR4 which was knowned as LPS recognition receptors. Pearson test showed the levels of sCD163 correlated with LPS,the correlation coefficient r=0.56, suggesting that increased sCD163 in ACLF patients were induced by endotoxemia in vivo.
4.In ACLF patients, CD 163 mRNA in peripheral blood monocytes increased, however, the expression of CD 163 was decreased, which suggesting that serum sCD163 may be partly from CD 163 protein hydrolysis in the peripheral blood monocytes.
5.LPS stimulating peripheral blood momocytes in vitro isolated from ACLF patients showed that the secretion of TNF-αin patients died was less than that in the normal group. However, secretion levels of sCD163,IL-10 increased; HLA-DR expression in peripheral blood monocytes from ACLF patients was reduced. Compared with the survival group and the normal group, down-regulation of HLA-DR in the death group were more significant, while, up-regulation of serum sCD163 were more significant, suggesting that on the basis of chronic liver disease, pathologically long-term stimulation by endotoxin can result in LPS tolerance in ACLF, which indicated immune disorders from inflammation reaction to anti-inflammatory response in patients. Very high sCD163 marked immune tolerance, after tolerance of macrophages the immune paralyzed, and increased risk of subsequent infection, and therefore high sCD163 had higher risk of death and poor prognosis.
6.Our results confirmed that corticosteroids can induce the expression of CD 163 in Kupffer cells in vivo,immediate administration after modeling and that at 4h in treatment group has a protective effect on rats with acute liver failure, however, significantly increased serum sCD163,suggesting that glucocorticoid in the early can induce acute anti-inflammatory protein CD 163 to protect liver cells against inflammatory factor damage. The study provided with the new immunological basis for the clinical application with glucocorticoid to control endotoxemia.
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