大鼠肠缺血再灌注致急性肺损伤信号转导机制及白藜芦醇苷的保护作用
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摘要
目的:探讨小肠缺血再灌注(ischemia/reperfusion,I/R)所致的急性肺损伤(acute lung injury, ALI)信号转导机制和白藜芦醇苷(polydatin, PD)的保护机制。
方法:224只健康雄性Sprague-Dawley(SD)大鼠,随机分为假手术对照组(C组)、肠缺血再灌注I/R肺损伤组(I/R组),I/R + NS组和I/R + PD治疗组。将大鼠腹腔打开后用暂时性夹持肠系膜上动脉(superior mesenteric artery, SMA)45分钟再松开的方法建立急性I/R肺损伤模型。在SMA松夹同时给予腹腔注射10 mg/kg PD为I/R + PD治疗组,注射生理盐水为I/R + NS组。假手术对照组的操作除不阻断SMA外其余操作与I/R组相同。分别于损伤后0h、0.5h、2h、6h、12h、24h、48h七个不同时间点处死实验大鼠留取大鼠肺标本保存待检。用苏木素-伊红(hematoxylin and eosin,HE)染色肺组织观察其在光镜下的病理形态学变化;用烘干前后肺组织的湿、干重(W/D)称量法测量肺组织水肿情况;比色法检测肺组织髓过氧化物酶(myeloperoxidase,MPO)活性变化;免疫组织化学染色法检测肺组织NF-κBp65和ICAM-1 (CD54)蛋白的表达;RT- PCR法检测肺组织HMGB1mRNA表达。
结果:肺组织HE染色示假手术对照组仅有轻微的肺间质增宽改变,而I/R和I/R+NS组可见肺泡结构破坏,肺泡隔增宽且肺泡间隔炎性细胞浸润,肺泡腔内有渗出液、红细胞及渗出的炎性细胞,I/R+PD治疗组较I/R+NS组有明显改善。I/R组肺组织W/D值在0.5h、2h、6h、12h及24h升高与假手术对照组比较有显著统计学差异(P<0.01)。I/R组MPO活化表达升高,与假手术对照组在各时间点相比均有显著统计学差异(P<0.01)。I/R组ICAM-1(CD54)表达随肠I/R时间延长而增加,6h达峰值(160.67±21.62/HP),此后稍有下降,24h轻度升高(107.83±20.40/HP),与假手术对照组在各时间点相比均有明显升高(P<0.05)。I/R组MPO与ICAM-1之间存在较强的正相关(P<0.01)。I/R组NF-κBp65表达随肠I/R时间延长而增加,24h达峰值(169.00±22.65/HP),较假手术对照组在各时间点表达有统计学差异(P<0.05)。I/R组HMGB1mRNA随肠I/R时间延长表达升高,24h达峰值(1.81±0.22),较假手术对照组在2h、6h、12h、24h及48h表达有显著统计学差异(P<0.01)。I/R组NF-κBp6与HMGB1mRNA之间存在较强的正相关(P<0.01)。I/R+PD治疗组W/D值在0.5h、2h、6h及12h有显著降低,与I/R+NS组比较有显著统计学差异(P<0.01)。I/R+PD治疗组MPO活化表达较I/R+NS组在各时间点均有明显下降(P<0.05)。I/R+PD治疗组ICAM-1表达下降,在0.5h、2h、6h、12h及24h与I/R+NS组比较均有统计学差异(P<0.05)。I/R+PD治疗组NF-κBp65和HMGB1RNA表达均在2h后下降,与I/R+NS组比较有统计学差异(P<0.05)。
结论:
1.运用大鼠小肠缺血再灌注的方法成功建立了急性肺损伤动物模型。
2. PMNs和ICAM-1表达有相互介导关系,而HMGB1肺内表达升高可能与NF-κB的转录调控有关。
3. PD可能是通过减少PMNs和ICAM-1表达同时抑制NF-κB的激活,阻断其信号转导通路,下调HMGB1基因表达而实现对损伤肺组织的保护作用。
【Objective】To investigate the mechanism of signal transduction and the protective effect of polydatin (PD) in intestinal ischemia- reperfusion (I/R) induced acute lung injury in rats.
【Methods】Two hundred and twenty-four Male Sprague-Dawley (SD) rats were randomly divided into four groups, the sham-operation control group (group C), the intestinal I/R induced lung injury group (I/R group), I/R + NS group and I/R + PD treatment group. The I/R induced ALI model was established by temporally clamping the superior mesenteric artery (SMA) for 45 minutes. Either 10 mg/kg PD (I/R + PD treatment group) or normal saline (I/R + NS group) was intraperitoneally administered immediately before the clamp released. The operative procedures of the sham-operation control group were the same as those of I/R group except not clamping the SMA. The rates were sacrificed and the lung tissues were separated at different time points of 0h, 0.5h, 2h, 6h, 12h, 24h or 48h after I/R injury. The pathological changes of lung tissues were examined under the light microscope with hematoxylin and eosin (HE) stain. The lung tissue Wet/dry weight ratio (W/D) were examined. The levels of lung tissue myeloperoxidase (MPO), the neutrophil sequestration indicator, were detected by colorimetric method. Formalin-fixed and paraffin embedded lung tissues were stained with immunohistochemistry technique for nuclear factor-κB(NF-κB) and intercellular adhesion molecule-1 (ICAM-1) detection. The lung tissue High mobility group box 1(HMGB1mRNA) expressions were determined by RT-PCR.
【Results】Histological changes of the lung tissues showed slight thickening of the alveolar walls in sham-operation control group. There were massive inflammatory cell infiltrations, byperemia and of interstitial lung tissue edema, diffusate, akaryocyte, inflame-cellule in alveolar intracavitary, alveolar wall thickening in I/R group and I/R + NS group. The above lung pathological changes were not so severe in I/R + PD treatment group. The lung tissue wet-to-dry weight ratios markedly rose in I/R group compared with those in sham-operation control group at any corresponding time point of 0.5h, 2h, 6h, 12h and 24h, with statistical significance(P<0.01). The expressions of lung tissue MPO markedly rose in I/R group compared with those in sham-operation control group at any corresponding time point, with statistical significance(P < 0.01). The expressions of lung tissue ICAM-1 increased with time after intestinal I/R, peaked at 6h (160.67±21.62/HP), then decreased, and slightly increase at 24h(170.83±20.40/HP)in I/R group. The expressions of lung tissue ICAM-1 were higher than those in sham-operation control group at any corresponding time point (P < 0.05). There exists a strong positive correlation between MPO and ICAM-1, with statistical significance (P<0.01). The expressions of lung tissue NF-κBp65 in I/R group increased with time after intestinal I/R, peaked at 24h (169.00±22.65/HP). The expressions of lung tissue NF-κBp65 in I/R group was lower than those in sham-operation control group at any corresponding time point (P<0.05). The expressions of lung tissue HMGB1mRNA in I/R group increased with time after intestinal I/R, peaked at 24h (1.81±0.22), The expressions of lung tissue HMGB1mRNA markedly rose in I/R group compared with those in sham-operation control group at any corresponding time point of 2h, 6h, 12h, 24h and 48h, with statistical significance(P<0.01). There exists a strong positive correlation between NF-κBp65 and HMGB1 mRNA, with statistical significance (P<0.01). Lung tissue wet-to-dry weight ratios markedly decreased in I/R + PD treatment group compared with those in I/R + NS group at any corresponding time point of 0.5h, 2h, 6h and 12h,with statistical significance(P<0.01). The expressions of lung tissue MPO in I/R + PD treatment group was lower than those in the I/R + NS group at any corresponding time point (P<0.05). The expressions of lung tissue ICAM-1in I/R + PD treatment group was lower than those in the I/R + NS group at any corresponding time point of 0.5h, 2h, 6h, 12h and 24h (P < 0.05). The expressions of lung tissue NF-κBp65 and HMGB1mRNA in I/R + PD treatment group was lower than those in the I/R + NS group at any corresponding time point of 2h, 6h, 12h, 24h and 48h (P<0.05).
【Conclusion】
1. Acute lung injury model was successfully induced by intestinal ischemia/reperfusion injury in rats.
2. The expressions of PMNs and ICAM-1 inter-mediated each other. The increased lung tissue HMGB1 expressions may be regulated by NF-κB through transcriptional control in intestinal I/R induced ALI.
3. The protective effect of polydatin may be through decreasing the lung tissue PMNs and ICAM-1 expressions, inhibiting the NF-κB activiation, blocking the signal transduction and down-regulating the expressions of HMGB1 during intestinal I/R induced lung injury.
方法:224只健康雄性Sprague-Dawley(SD)大鼠,随机分为假手术对照组(C组)、肠缺血再灌注I/R肺损伤组(I/R组),I/R + NS组和I/R + PD治疗组。将大鼠腹腔打开后用暂时性夹持肠系膜上动脉(superior mesenteric artery, SMA)45分钟再松开的方法建立急性I/R肺损伤模型。在SMA松夹同时给予腹腔注射10 mg/kg PD为I/R + PD治疗组,注射生理盐水为I/R + NS组。假手术对照组的操作除不阻断SMA外其余操作与I/R组相同。分别于损伤后0h、0.5h、2h、6h、12h、24h、48h七个不同时间点处死实验大鼠留取大鼠肺标本保存待检。用苏木素-伊红(hematoxylin and eosin,HE)染色肺组织观察其在光镜下的病理形态学变化;用烘干前后肺组织的湿、干重(W/D)称量法测量肺组织水肿情况;比色法检测肺组织髓过氧化物酶(myeloperoxidase,MPO)活性变化;免疫组织化学染色法检测肺组织NF-κBp65和ICAM-1 (CD54)蛋白的表达;RT- PCR法检测肺组织HMGB1mRNA表达。
结果:肺组织HE染色示假手术对照组仅有轻微的肺间质增宽改变,而I/R和I/R+NS组可见肺泡结构破坏,肺泡隔增宽且肺泡间隔炎性细胞浸润,肺泡腔内有渗出液、红细胞及渗出的炎性细胞,I/R+PD治疗组较I/R+NS组有明显改善。I/R组肺组织W/D值在0.5h、2h、6h、12h及24h升高与假手术对照组比较有显著统计学差异(P<0.01)。I/R组MPO活化表达升高,与假手术对照组在各时间点相比均有显著统计学差异(P<0.01)。I/R组ICAM-1(CD54)表达随肠I/R时间延长而增加,6h达峰值(160.67±21.62/HP),此后稍有下降,24h轻度升高(107.83±20.40/HP),与假手术对照组在各时间点相比均有明显升高(P<0.05)。I/R组MPO与ICAM-1之间存在较强的正相关(P<0.01)。I/R组NF-κBp65表达随肠I/R时间延长而增加,24h达峰值(169.00±22.65/HP),较假手术对照组在各时间点表达有统计学差异(P<0.05)。I/R组HMGB1mRNA随肠I/R时间延长表达升高,24h达峰值(1.81±0.22),较假手术对照组在2h、6h、12h、24h及48h表达有显著统计学差异(P<0.01)。I/R组NF-κBp6与HMGB1mRNA之间存在较强的正相关(P<0.01)。I/R+PD治疗组W/D值在0.5h、2h、6h及12h有显著降低,与I/R+NS组比较有显著统计学差异(P<0.01)。I/R+PD治疗组MPO活化表达较I/R+NS组在各时间点均有明显下降(P<0.05)。I/R+PD治疗组ICAM-1表达下降,在0.5h、2h、6h、12h及24h与I/R+NS组比较均有统计学差异(P<0.05)。I/R+PD治疗组NF-κBp65和HMGB1RNA表达均在2h后下降,与I/R+NS组比较有统计学差异(P<0.05)。
结论:
1.运用大鼠小肠缺血再灌注的方法成功建立了急性肺损伤动物模型。
2. PMNs和ICAM-1表达有相互介导关系,而HMGB1肺内表达升高可能与NF-κB的转录调控有关。
3. PD可能是通过减少PMNs和ICAM-1表达同时抑制NF-κB的激活,阻断其信号转导通路,下调HMGB1基因表达而实现对损伤肺组织的保护作用。
【Objective】To investigate the mechanism of signal transduction and the protective effect of polydatin (PD) in intestinal ischemia- reperfusion (I/R) induced acute lung injury in rats.
【Methods】Two hundred and twenty-four Male Sprague-Dawley (SD) rats were randomly divided into four groups, the sham-operation control group (group C), the intestinal I/R induced lung injury group (I/R group), I/R + NS group and I/R + PD treatment group. The I/R induced ALI model was established by temporally clamping the superior mesenteric artery (SMA) for 45 minutes. Either 10 mg/kg PD (I/R + PD treatment group) or normal saline (I/R + NS group) was intraperitoneally administered immediately before the clamp released. The operative procedures of the sham-operation control group were the same as those of I/R group except not clamping the SMA. The rates were sacrificed and the lung tissues were separated at different time points of 0h, 0.5h, 2h, 6h, 12h, 24h or 48h after I/R injury. The pathological changes of lung tissues were examined under the light microscope with hematoxylin and eosin (HE) stain. The lung tissue Wet/dry weight ratio (W/D) were examined. The levels of lung tissue myeloperoxidase (MPO), the neutrophil sequestration indicator, were detected by colorimetric method. Formalin-fixed and paraffin embedded lung tissues were stained with immunohistochemistry technique for nuclear factor-κB(NF-κB) and intercellular adhesion molecule-1 (ICAM-1) detection. The lung tissue High mobility group box 1(HMGB1mRNA) expressions were determined by RT-PCR.
【Results】Histological changes of the lung tissues showed slight thickening of the alveolar walls in sham-operation control group. There were massive inflammatory cell infiltrations, byperemia and of interstitial lung tissue edema, diffusate, akaryocyte, inflame-cellule in alveolar intracavitary, alveolar wall thickening in I/R group and I/R + NS group. The above lung pathological changes were not so severe in I/R + PD treatment group. The lung tissue wet-to-dry weight ratios markedly rose in I/R group compared with those in sham-operation control group at any corresponding time point of 0.5h, 2h, 6h, 12h and 24h, with statistical significance(P<0.01). The expressions of lung tissue MPO markedly rose in I/R group compared with those in sham-operation control group at any corresponding time point, with statistical significance(P < 0.01). The expressions of lung tissue ICAM-1 increased with time after intestinal I/R, peaked at 6h (160.67±21.62/HP), then decreased, and slightly increase at 24h(170.83±20.40/HP)in I/R group. The expressions of lung tissue ICAM-1 were higher than those in sham-operation control group at any corresponding time point (P < 0.05). There exists a strong positive correlation between MPO and ICAM-1, with statistical significance (P<0.01). The expressions of lung tissue NF-κBp65 in I/R group increased with time after intestinal I/R, peaked at 24h (169.00±22.65/HP). The expressions of lung tissue NF-κBp65 in I/R group was lower than those in sham-operation control group at any corresponding time point (P<0.05). The expressions of lung tissue HMGB1mRNA in I/R group increased with time after intestinal I/R, peaked at 24h (1.81±0.22), The expressions of lung tissue HMGB1mRNA markedly rose in I/R group compared with those in sham-operation control group at any corresponding time point of 2h, 6h, 12h, 24h and 48h, with statistical significance(P<0.01). There exists a strong positive correlation between NF-κBp65 and HMGB1 mRNA, with statistical significance (P<0.01). Lung tissue wet-to-dry weight ratios markedly decreased in I/R + PD treatment group compared with those in I/R + NS group at any corresponding time point of 0.5h, 2h, 6h and 12h,with statistical significance(P<0.01). The expressions of lung tissue MPO in I/R + PD treatment group was lower than those in the I/R + NS group at any corresponding time point (P<0.05). The expressions of lung tissue ICAM-1in I/R + PD treatment group was lower than those in the I/R + NS group at any corresponding time point of 0.5h, 2h, 6h, 12h and 24h (P < 0.05). The expressions of lung tissue NF-κBp65 and HMGB1mRNA in I/R + PD treatment group was lower than those in the I/R + NS group at any corresponding time point of 2h, 6h, 12h, 24h and 48h (P<0.05).
【Conclusion】
1. Acute lung injury model was successfully induced by intestinal ischemia/reperfusion injury in rats.
2. The expressions of PMNs and ICAM-1 inter-mediated each other. The increased lung tissue HMGB1 expressions may be regulated by NF-κB through transcriptional control in intestinal I/R induced ALI.
3. The protective effect of polydatin may be through decreasing the lung tissue PMNs and ICAM-1 expressions, inhibiting the NF-κB activiation, blocking the signal transduction and down-regulating the expressions of HMGB1 during intestinal I/R induced lung injury.
引文
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