黄芩苷对脓毒症大鼠肾脏的保护作用和机制探讨
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摘要
[目的]
本研究旨在通过观察黄芩苷(Baicalin)对盲肠结扎和穿孔术(cecal ligation and puncture, CLP)诱导的脓毒症大鼠血清中性粒细胞明胶酶相关载脂蛋白(Neutrophil gelatinase associated lipocalin, NGAL)浓度、血清肌酐浓度,肾组织肿瘤坏死因子α(tumor necrosis factor-α, TNF-α)水平、肾组织核因子κB (nuclear factor-κB, NF-κB)水平,肾组织细胞凋亡率、肾组织内半胱氨酸天冬氨酸蛋白酶-3信使核糖核酸(casepase-3mRNA)相对含量以及肾组织病理变化的影响,探讨黄芩苷对脓毒症大鼠的肾脏保护作用及其可能的机制。
[方法]
清洁级雄性Sprague Dawley (SD)大鼠采用盲肠结扎和穿刺术制备大鼠脓毒症模型。实验大鼠随机分为假手术组、模型组、黄芩苷干预组(每组24只)假手术组(Sham组)：行剖腹术,术后立即腹腔注射0.9%氯化钠溶液2mL；模型组(CLP组)：行盲肠结扎和穿刺术,术后立即腹腔注射0.9%氯化钠溶液2mL;黄芩苷干预组(Baicalin+CLP组)：行盲肠结扎穿刺术造模后,黄芩苷按照120mg/kg剂量,用0.9%氯化钠溶液稀释至2mL,行腹腔注射。每组大鼠在CLP术后0h、3h、6h、24h分别采血标本和右肾组织标本。血清NGAL浓度由酶联免疫法(enzyme-linked immuno sorbent, ELISA)测得。血清肌酐浓度由自动生化分析仪测得。肾组织TNF-α和NF-κB水平由免疫组织化学法测得。肾组织细胞凋亡率由原位末端标记法(TdT-mediated dUTP nick end labeling, Tunel)测得。肾组织内相对casepase-3mRNA含量,由实时荧光定量多聚酶链反应法(real-time fluorescent quatitative reverse transcription polymerase chain reaction, FQ RT-PCR)测得。术后24h肾组织标本经HE染色观察病理变化。
[结果]
1、血清NGAL和肌酐浓度：CLP组大鼠自术后3h明显升高,分别为171.04±13.35 pg/mL和42.17±3.19umol/L,与Sham组相比(分别为57.93±13.77pg/mL和25.50±2.42μmol/L),CLP组明显高于Sham组,差别有统计学意义,P<0.05;黄芩苷干预组术后3h分别为112.77±17.32 pg/mL和37.83±4.54μmol/L,明显低于CLP组,差异有统计学意义,P<0.05。
2、大鼠肾组织TNF-α和NF-κB水平：CLP组大鼠术后3h即显著升高,TNF-α和NF-κB免疫组织化学指数(immunohistochemistry index)分别为53460.25±1936.97和30611.14±1682.88,明显高于Sham组(19103.82±1800.99和13752.87±1375.66),差别有统计学意义,P<0.05；黄芩苷干预组术后3h分别为28205.23±774.44和18907.09±1110.95明显低于CLP组,差异有统计学意义,P<0.05。
3、肾组织细胞凋亡率以及肾组织内相对casepase-3mRNA含量：CLP组大鼠术后3h肾组织细胞凋亡率和肾组织相对caspase-3mRNA含量均明显增高,分别为18.92±1.56%和3.323±0.240,明显高于Sham组(7.06±1.37%和1.310±0.130),差别有统计学意义,P<0.05；黄芩苷干预组术后3h分别为12.00±1.49%和1.900±0.171,明显低于CLP组,差异有统计学意义,P<0.05。
4、大鼠肾组织病理改变：术后24 h, CLP组大鼠肾脏病理可见部分肾小球系膜基质有所增加,系膜细胞增生,肾组织内大量炎性细胞浸润,部分肾小管细胞肿胀,空泡变性等改变；而黄芩苷+CLP组大鼠在术后24 h肾组织上述病理改变明显减轻。
[结论]
脓毒症早期应用黄芩苷对脓毒症大鼠急性肾脏损伤有保护作用。其机制可能与降低脓毒症大鼠肾组织TNF-α和NF-κB水平,减少casepase-3表达,从而减轻炎症反应以及减少脓毒症大鼠肾脏组织细胞凋亡有关。
Objective
Through observing the change of the serum NGAL and Creatinine concentration, the level of TNF-αand NF-κB in the kidney tissue, the apoptosis ratio and the casepase-3mRNA relative content in the septic rats' kidney tissue and the pathological alterations of the kidney with the treatment of Baicalin, we investigate the protective effects of Baicalin for Septic Rats' Kidneys and the possible mechanism.
Methods
Sepsis model was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley (SD) rats. Rats were randomly divided into 3 groups, which were the sham group (n=24), the CLP group(n=24) and the Baicalin treatment group(n=24). We intraperitoneally administered Baicalin at the dose of 120 mg/kg, altogether 2ml liquid to the rats after the operation in the Baicalin group and the rats of the other two groups were treated with 2ml saline. The rats were separately sacrificed at Oh,3h,6h or 24h after the operation (n=6). The sample of blood and the right kidney tissues were harvested at each time point. The serum NGAL concentration was examined by enzyme-linked immuno sorbent (ELISA) assay. The serum Creatinine concentration was examined by auto analyzer. The level of TNF-αand NF-κB in the kidney tissue were examined by immunohistochemistry assay. The apoptosis ratio of the kidney tissues was examined by TdT-mediated dUTP nick end labeling (Tunel) assay. The casepase-3mRNA relative content in the septic rats' kidney was examined by real-time fluorescent quatitative reverse transcription polymerase chain reaction (FQ RT-PCR) assay. The kidney tissue's histological alterations were observed by HE staining.
Results
1、The serum concentrations of NGAL and Creatinine:Compared with the sham group, the serum concentrations of NGAL and Creatinine of the CLP group significantly increased at 3h after the operation were 171.04±13.35 pg/mL and 42.17±3.19μmol/L in the CLP group vs.57.93±13.77 pg/mL and 25.50±2.42 miu2 mol/L in the sham group, P<0.05. Compared with the CLP group, the serum concentrations of NGAL and Creatinine of the Baicalin+CLP group significantly decreased at each time point after the operation (the serum concentrations of NGAL and Creatinine at 3h after the operation were 112.77±17.32 pg/mL and 37.83±4.54μmol/L in the Baicalin+CLP group vs.171.04±13.35pg/mL and 42.17±3.19μmol/L in the CLP group, P<0.05).
2、The level of TNF-αand NF-κB in the kidney tissues:Compared with the sham group, the level of TNF-αand NF-κB in the kidney tissues of the CLP group significantly increased at 3h,6h, and 24h after the operation (the immunohistochemistry index of TNF-αand NF-κB in the kidney tissues at 3h after the operation were 53460.25±1936.97 and 30611.14±1682.88 in the CLP group vs.19103.82±1800.99 and 13752.87±1375.66 in the sham group, P<0.05). Compared with the CLP group, the level of TNF-αand NF-κB in the kidney tissues with the treatment of Baicaline significantly decreased at each time point after the operation (the immunohistochemistry index of TNF-αand NF-κB in the kidney tissues at 3h after the operation were 28205.23±774.44 and 18907.09±1110.95 in the Baicalin+CLP group vs. 53460.25±1936.97 and 30611.14±1682.88 in the CLP group, P<0.05).
3、The apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues:Compared with the sham group, the apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues of the CLP group significantly increased at 3h,6h, and 24h after the operation (the apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues at 3h after the operation were 18.92±1.56% and 3.323±0.240 in the CLP group vs.7.06±1.37% and 1.310±0.130 in the sham group, P<0.05). Compared with the CLP group, the apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues with the treatment of Baicaline significantly decreased at each time point after the operation (the apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues at 3h after the operation were 12.00±1.49% and 1.900±0.171 in the Baicalin+CLP group vs.18.92±1.56% and 3.323±0.240 in the CLP group, P<0.05).
4、Histological alterations:Obvious histological alterations were discovered in the kidney tissues at 24h after the operation in the CLP group, characterized by increased mesangial matrix, mesangial cell proliferation partly, inflammatory cell infiltration in tubular area and part of the tubular cell swelling, vacuolar degeneration. Such histological alterations in the Baicalin+CLP group at 24h after the operation were much milder than those in the CLP group.
Conclusion
These data revealed that Baicalin has protective effects on the kidney of rats with sepsis. These beneficial effects are partly due to decreasing the levels of TNF-αand NF-κB, the casepase-3 expression and the apoptosis ratio in the kidney tissues. Thus, treatment with Baicalin may be effective in the clinical setting.
本研究旨在通过观察黄芩苷(Baicalin)对盲肠结扎和穿孔术(cecal ligation and puncture, CLP)诱导的脓毒症大鼠血清中性粒细胞明胶酶相关载脂蛋白(Neutrophil gelatinase associated lipocalin, NGAL)浓度、血清肌酐浓度,肾组织肿瘤坏死因子α(tumor necrosis factor-α, TNF-α)水平、肾组织核因子κB (nuclear factor-κB, NF-κB)水平,肾组织细胞凋亡率、肾组织内半胱氨酸天冬氨酸蛋白酶-3信使核糖核酸(casepase-3mRNA)相对含量以及肾组织病理变化的影响,探讨黄芩苷对脓毒症大鼠的肾脏保护作用及其可能的机制。
[方法]
清洁级雄性Sprague Dawley (SD)大鼠采用盲肠结扎和穿刺术制备大鼠脓毒症模型。实验大鼠随机分为假手术组、模型组、黄芩苷干预组(每组24只)假手术组(Sham组)：行剖腹术,术后立即腹腔注射0.9%氯化钠溶液2mL；模型组(CLP组)：行盲肠结扎和穿刺术,术后立即腹腔注射0.9%氯化钠溶液2mL;黄芩苷干预组(Baicalin+CLP组)：行盲肠结扎穿刺术造模后,黄芩苷按照120mg/kg剂量,用0.9%氯化钠溶液稀释至2mL,行腹腔注射。每组大鼠在CLP术后0h、3h、6h、24h分别采血标本和右肾组织标本。血清NGAL浓度由酶联免疫法(enzyme-linked immuno sorbent, ELISA)测得。血清肌酐浓度由自动生化分析仪测得。肾组织TNF-α和NF-κB水平由免疫组织化学法测得。肾组织细胞凋亡率由原位末端标记法(TdT-mediated dUTP nick end labeling, Tunel)测得。肾组织内相对casepase-3mRNA含量,由实时荧光定量多聚酶链反应法(real-time fluorescent quatitative reverse transcription polymerase chain reaction, FQ RT-PCR)测得。术后24h肾组织标本经HE染色观察病理变化。
[结果]
1、血清NGAL和肌酐浓度：CLP组大鼠自术后3h明显升高,分别为171.04±13.35 pg/mL和42.17±3.19umol/L,与Sham组相比(分别为57.93±13.77pg/mL和25.50±2.42μmol/L),CLP组明显高于Sham组,差别有统计学意义,P<0.05;黄芩苷干预组术后3h分别为112.77±17.32 pg/mL和37.83±4.54μmol/L,明显低于CLP组,差异有统计学意义,P<0.05。
2、大鼠肾组织TNF-α和NF-κB水平：CLP组大鼠术后3h即显著升高,TNF-α和NF-κB免疫组织化学指数(immunohistochemistry index)分别为53460.25±1936.97和30611.14±1682.88,明显高于Sham组(19103.82±1800.99和13752.87±1375.66),差别有统计学意义,P<0.05；黄芩苷干预组术后3h分别为28205.23±774.44和18907.09±1110.95明显低于CLP组,差异有统计学意义,P<0.05。
3、肾组织细胞凋亡率以及肾组织内相对casepase-3mRNA含量：CLP组大鼠术后3h肾组织细胞凋亡率和肾组织相对caspase-3mRNA含量均明显增高,分别为18.92±1.56%和3.323±0.240,明显高于Sham组(7.06±1.37%和1.310±0.130),差别有统计学意义,P<0.05；黄芩苷干预组术后3h分别为12.00±1.49%和1.900±0.171,明显低于CLP组,差异有统计学意义,P<0.05。
4、大鼠肾组织病理改变：术后24 h, CLP组大鼠肾脏病理可见部分肾小球系膜基质有所增加,系膜细胞增生,肾组织内大量炎性细胞浸润,部分肾小管细胞肿胀,空泡变性等改变；而黄芩苷+CLP组大鼠在术后24 h肾组织上述病理改变明显减轻。
[结论]
脓毒症早期应用黄芩苷对脓毒症大鼠急性肾脏损伤有保护作用。其机制可能与降低脓毒症大鼠肾组织TNF-α和NF-κB水平,减少casepase-3表达,从而减轻炎症反应以及减少脓毒症大鼠肾脏组织细胞凋亡有关。
Objective
Through observing the change of the serum NGAL and Creatinine concentration, the level of TNF-αand NF-κB in the kidney tissue, the apoptosis ratio and the casepase-3mRNA relative content in the septic rats' kidney tissue and the pathological alterations of the kidney with the treatment of Baicalin, we investigate the protective effects of Baicalin for Septic Rats' Kidneys and the possible mechanism.
Methods
Sepsis model was induced by cecal ligation and puncture (CLP) in male Sprague-Dawley (SD) rats. Rats were randomly divided into 3 groups, which were the sham group (n=24), the CLP group(n=24) and the Baicalin treatment group(n=24). We intraperitoneally administered Baicalin at the dose of 120 mg/kg, altogether 2ml liquid to the rats after the operation in the Baicalin group and the rats of the other two groups were treated with 2ml saline. The rats were separately sacrificed at Oh,3h,6h or 24h after the operation (n=6). The sample of blood and the right kidney tissues were harvested at each time point. The serum NGAL concentration was examined by enzyme-linked immuno sorbent (ELISA) assay. The serum Creatinine concentration was examined by auto analyzer. The level of TNF-αand NF-κB in the kidney tissue were examined by immunohistochemistry assay. The apoptosis ratio of the kidney tissues was examined by TdT-mediated dUTP nick end labeling (Tunel) assay. The casepase-3mRNA relative content in the septic rats' kidney was examined by real-time fluorescent quatitative reverse transcription polymerase chain reaction (FQ RT-PCR) assay. The kidney tissue's histological alterations were observed by HE staining.
Results
1、The serum concentrations of NGAL and Creatinine:Compared with the sham group, the serum concentrations of NGAL and Creatinine of the CLP group significantly increased at 3h after the operation were 171.04±13.35 pg/mL and 42.17±3.19μmol/L in the CLP group vs.57.93±13.77 pg/mL and 25.50±2.42 miu2 mol/L in the sham group, P<0.05. Compared with the CLP group, the serum concentrations of NGAL and Creatinine of the Baicalin+CLP group significantly decreased at each time point after the operation (the serum concentrations of NGAL and Creatinine at 3h after the operation were 112.77±17.32 pg/mL and 37.83±4.54μmol/L in the Baicalin+CLP group vs.171.04±13.35pg/mL and 42.17±3.19μmol/L in the CLP group, P<0.05).
2、The level of TNF-αand NF-κB in the kidney tissues:Compared with the sham group, the level of TNF-αand NF-κB in the kidney tissues of the CLP group significantly increased at 3h,6h, and 24h after the operation (the immunohistochemistry index of TNF-αand NF-κB in the kidney tissues at 3h after the operation were 53460.25±1936.97 and 30611.14±1682.88 in the CLP group vs.19103.82±1800.99 and 13752.87±1375.66 in the sham group, P<0.05). Compared with the CLP group, the level of TNF-αand NF-κB in the kidney tissues with the treatment of Baicaline significantly decreased at each time point after the operation (the immunohistochemistry index of TNF-αand NF-κB in the kidney tissues at 3h after the operation were 28205.23±774.44 and 18907.09±1110.95 in the Baicalin+CLP group vs. 53460.25±1936.97 and 30611.14±1682.88 in the CLP group, P<0.05).
3、The apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues:Compared with the sham group, the apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues of the CLP group significantly increased at 3h,6h, and 24h after the operation (the apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues at 3h after the operation were 18.92±1.56% and 3.323±0.240 in the CLP group vs.7.06±1.37% and 1.310±0.130 in the sham group, P<0.05). Compared with the CLP group, the apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues with the treatment of Baicaline significantly decreased at each time point after the operation (the apoptosis ratio and the casepase-3mRNA relative content in the kidney tissues at 3h after the operation were 12.00±1.49% and 1.900±0.171 in the Baicalin+CLP group vs.18.92±1.56% and 3.323±0.240 in the CLP group, P<0.05).
4、Histological alterations:Obvious histological alterations were discovered in the kidney tissues at 24h after the operation in the CLP group, characterized by increased mesangial matrix, mesangial cell proliferation partly, inflammatory cell infiltration in tubular area and part of the tubular cell swelling, vacuolar degeneration. Such histological alterations in the Baicalin+CLP group at 24h after the operation were much milder than those in the CLP group.
Conclusion
These data revealed that Baicalin has protective effects on the kidney of rats with sepsis. These beneficial effects are partly due to decreasing the levels of TNF-αand NF-κB, the casepase-3 expression and the apoptosis ratio in the kidney tissues. Thus, treatment with Baicalin may be effective in the clinical setting.
引文
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