泻心汤有效组分对重症急性胰腺炎相关性肠/肺损伤的保护作用与机制研究
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摘要
目的
重症急性胰腺炎(severe acute pancreatitis, SAP)是常见的急腹症,常并发肠和肺等胰外器官损伤,目前尚缺乏特异有效的治疗手段。中西医结合的治疗效果远好于单纯西医常规治疗,大黄及含大黄的复方已成为SAP临床重要的辅助疗法之一。大黄游离蒽醌-黄芩总黄酮是本课题从已完成的国家自然科学基金课题中筛选出的泻心汤抗内毒素有效组分配伍,大黄游离蒽醌和黄芩总黄酮能否具有保护SAP相关性肠／肺功能损伤的作用?配伍后是否发挥协同增效作用?本研究拟通过逆行胰胆管注射牛磺胆酸钠建立SAP大鼠动物模型,在SAP诱导后3、6、12h动态观察血清淀粉酶(AMS)、肠／肺组织病理学、湿干重比、组织匀浆丙二醛(MDA)／一氧化氮(NO)／髓过氧化物酶(MPO)水平、肠／肺组织微血管通透性等多个肠／肺损伤指标的改变,以期了解SAP时肠和肺损伤之间的关系,为SAP临床治疗时肠肺同治提供理论依据,同时观察大黄游离蒽醌-黄芩总黄酮配伍对SAP相关性肠／肺损伤的干预效应,并从改善微循环障碍、抗炎抗氧化损伤、调节细胞因子水平、抑制核转录因子等多角度探讨大黄游离蒽醌-黄芩总黄酮配伍肺肠保护功能的作用机制。
方法
逆行胰胆管注射3.5%牛磺胆酸钠建立SAP大鼠动物模型；假手术对照组：用等剂量的无菌生理盐水替代牛磺胆酸钠逆行胰胆管注射；泻心汤有效组分干预组：在SAP大鼠模型诱导前8小时和2小时,以200mg/kg的剂量分别灌胃给予大黄总游离蒽醌、黄芩总黄酮和二者配伍溶液。按计划于3、6和12小时各时间点处死各组大鼠,收集血清、小肠和肺组织。H.E染色用于小肠和肺组织损伤的病理学评价；湿肠／肺组织称重后,置于烤箱中烘烤至恒重,测定组织湿／干重比；酶化学法测定肺和肠组织匀浆中MPO、MDA和NO含量；比色法测定肺和肠组织中EBD含量,以反映组织微血管通透性；放射免疫法测定血清TNF-a和IL-1β水平；PTAH染色显示肺和肠组织微血栓；免疫组织化学法测定肠和肺组织COX-2,NF-κB和ICAM-1的表达；RT-PCR检测肠和肺组织中COX-2mRNA,iNOS mRNA和TFmRNA的表达。
结果
第一部分：与假手术对照组比较,SAP诱导后各时相点肺和肠组织病理学评分、湿干重比、MDA,NO、MPO和EBD含量等均明显增加(p<0.01)。大黄游离蒽醌、黄芩总黄酮和二者恶配伍具有非常突出的肺／肠保护作用,各药物干预组均明显改善SAP大鼠的肺和肠病理学损伤程度,降低病理学评分；各药物干预组均明显降低了SAP大鼠肺和肠组织各时间段MPO活性、MDA及NO水平；同样,肺和肠组织EBD含量和组织湿干重比也明显降低。各药物干预组中尤以配伍组的作用更优。
第二部分：SAP诱导后各时相点大鼠血清TNF-a和IL-1β水平明显升高；PTAH染色显示SAP大鼠肺和肠组织可见较多的血栓形成,血栓多数分布于中小血管及末梢血管,部分主干血管也有血栓形成；免疫组织化学结果显示,牛磺胆酸钠诱导后,大鼠肺和肠组织NF-κB、ICAM-1和COX-2蛋白表达均明显上调；同样,肠和肺组织中COX-2mRNA,iNOS mRNA和TFmRNA的表达亦明显上调,以上各指标与假手术对照组比较差异具有显著性(p<0.01)。与SAP组比较,大黄游离蒽醌-黄芩总黄酮配伍除了对肠组织12小时COX-2表达的抑制作用不明显,对肺组织3和12小时、肠组织3和6小时ICAM-1表达的抑制作用不明显外,对其余指标均具有明显抑制效应。
结论
(1)SAP诱导后从3小时起即并发明显的肠和肺组织损伤,且肺和肠损伤之间具有显著相关性,本研究中尽管肺和肠损伤之间未显示出明显的因果关系,但SAP时同时存在肠和肺组织的损伤是一个基本事实,研究结果提示SAP治疗时,不管是西医还是中医,除了常规疗法外,还应考虑同时对肠和肺损伤进行治疗,研究结果不仅为SAP时肠肺同治提供了理论依据,也为SAP早期防治MODS提供了理论依据。
(2)大黄游离蒽醌、黄芩总黄酮和二者的配伍明显降低血清AMS水平；改善SAP大鼠肠和肺组织的病理性损伤程度；明显降低肺和肠组织中MPO和MDA含量,减少中性粒细胞的滞留程度,降低中性粒细胞对肺和肠组织的炎性损伤和氧化应激损伤程度；明显降低肺和肠组织湿干重比、NO和EBD含量,改善组织微血管通透性和微循环障碍,具有非常突出的肺／肠保护作用,其中尤以配伍组的作用更突出,两药配伍后协同增效。
(3)大黄游离蒽醌-黄芩总黄酮配伍可降低中性粒细胞对肺和肠组织的炎性损伤和氧化应激损伤程度,但其抗炎和抗氧化应激作用可能不是通过抑制ICAM-1途径实现的；该配伍抑制COX-2 mRNA的转录和蛋白的表达、抑制TF mRNA的转录,这可能是其改善肺和肠微循环障碍的重要机制；该配伍可通过抑制TNF-α、IL-1β和NO的产生,进而减轻其介导的炎症级联放大效应,减轻全身炎症反应和器官功能损伤程度：大黄游离蒽醌-黄芩总黄酮配伍明显下调了NF-κB蛋白的表达,由于NF-κB是调控TNF-α, COX-2、iNOS和ICAM-1等转录活化的主要核转录因子,由此,我们推测大黄游离蒽醌-黄芩总黄酮配伍降低肺和肠组织上述因子的表达可能是通过抑制NF-κB活性的途径实现的。
Objective
Severe acute pancreatitis (SAP) is a frequent acute abdomen in clinic, intestinal and lung injury is frequent complications, which still lack of effective therapy. Treatment effectiveness of integrated TCM-WM is better than conventional therapy of west medicine.Now, TCM is become one of important complementary therapies of SAP. Compatibility of free anthraquinone of rhubarb and total flavonoids of Scutellaria baicalensis Georgi is anti-endotoxic effective components from Xiexin Decoction. In this study, we arm to evaluate the potent effect of this compatibility on the the lung injury and intestinal injury of SAP, and more attention was payed to the underlying molecular mechanisms of this compatibility.
Methods
The SAP model was induced by standard retrograde infusion of bilio-pancreatic duct with 3.5% sterile sodium taurocholate solution at lml/kg in Sprague-Dawley rats, the same dose of saline solution, replacement of sodium taurocholate,were administrated in sham operation control group. Free anthraquinone of rhubarb, total flavonoios of Scutellaria baicalensis Georgi and their compatibility were administrated affusedly down alimentary canal from mouth to stomach at 200mg/kg within 8 and 2 hours before the inducement of SAP, rats were killed on scheme over a time course(3,6,12hours).The blood serum, small intestine and lung tissue of rats were harvested, H.E Dyeing of small intestine and lung tissue were employed for pathological assessment;the severity of tissue edema was determined by the ratio of the weight of wet tissue to that of dry tissue(ww/wd);the level of MPO,MDA and NO of small intestine and lung tissue homogenate were determined by method of zymochemistry;the content of EBD in small intestine and lung tissue,reflecting the microvascular permeability of tissue,was determined by Colorimetry, according to a standard curve of EBD;the level of serum TNF-a and IL-1βwere determined by radioimmunoassay(RIA);PTAH Dyeing of small intestine and lung tissue for microthrombus;the expression of COX-2, NF-κB and intercellular adherension molecule-1 (ICAM-1)protein were determined immunohistochemistrically,and expression of COX-2mRNA,iNOS mRNA,and TFmRNA in lung tissues were determined by RT-PCR.
Results
PART I
The SAP group, pathological assessment,ww/wd, level of MPO, MDA and NO,content of EBD were all significant increase, comparing with sham operation group(P<0.01).Free anthraquinone of rhubarb, total flavonoids of Scutellaria baicalensis Georgi and their compatibility had very excellent protective effect on lung and intestinal injury, they ameliorated the degree of pathological injuries about lung and intestine, decreased pathological score;they decreased the level of MPO, MDA and NO of small intestine and lung tissue homogenate significantly; the content of EBD and ww/wd were also decreased.The compatibility group had more excellent protective effect than other groups.
PART II
The SAP group, serum TNF-a and IL-1βwere significant increase; microthrombus determined by PTAH could be observed in tissue;significant overexpression of NF-κB, COX-2 and ICAM-1 were demonstrated in lung and intestinal tissue of rat with SAP by IHC; COX-2mRNA, iNOS mRNA and TFmRNA were also overexpression in lung and intestinal tissue of rat with SAP by RT-PCR. The compatibility obviously decreased the level of serum TNF-a and IL-1β,decreased the density of microthrombus;it inhibited the expression of NF-κB, ICAM-1,and COX-2 protein in lung and intestinal tissue over the time course, except the expression of COX-2 in intestinal tissue at 12hour and the expression of ICAM-1 in lung tissue at 3 and 12hour, in intestinal tissue at 3 and 6hour;it dramatically down-regulated the expression of COX-2mRNA,iNOS mRNA and TFmRNA in lung and intestinal tissue.
Conclusions
(1)Our results showed that obvious intestinal and lung injury were observed after SAP model was induced 3h, it had significant correlation between intestinal injury and lung injury. The studies suggested that additional attention should be paided to treatment of intestinal and lung injury,except for conventional therapy.
(2)Our results clearly suggested that free anthraquinone of rhubarb,total flavonoids of Scutellaria baicalensis Georgi and their compatibility reduced the degree of serum AMS, ameliorated the degree of pathological injury of intestinal and lung,reduced the content of MPO, NO, MDA and EBD of intestinal and lung tissue.The compatibility group had more excellent protective effect on lung and intestinal injury than other groups, the result of compatibility was increase efficiency
(3)The compatibility reduced degree.of injury of.inflammationary and oxidative stress by decreasing stagnation of polymorphonuclear leukocytes in lung and intestinaltissue of SAP rats,but the effect might not by inhibiting the expression of ICAM-1 to attain.The compatibility ameliorated microvascular permeability and microcirculation disturbance of lung and intestinal tissue of SAP rats, the effect was close relevant to suppression of COX-2 and TF activation, which might be important mechanism about ameliorating microcirculation disturbance of tissue.The compatibility alleviated drgree of systemic inflammatory reaction and organ function impairment by inhibiting TNF-α、IL-1βand NO. The compatibility significantly down-regulated the expression of NF-κB,which was a main nuclear factor about regulating the transcription of TNF-α,COX-2,iNOS and ICAM-1,and so on.Thereby, we presumed that the compatibility depressed the expression of factors above mentioned via suppression of NF-κB activation.
重症急性胰腺炎(severe acute pancreatitis, SAP)是常见的急腹症,常并发肠和肺等胰外器官损伤,目前尚缺乏特异有效的治疗手段。中西医结合的治疗效果远好于单纯西医常规治疗,大黄及含大黄的复方已成为SAP临床重要的辅助疗法之一。大黄游离蒽醌-黄芩总黄酮是本课题从已完成的国家自然科学基金课题中筛选出的泻心汤抗内毒素有效组分配伍,大黄游离蒽醌和黄芩总黄酮能否具有保护SAP相关性肠／肺功能损伤的作用?配伍后是否发挥协同增效作用?本研究拟通过逆行胰胆管注射牛磺胆酸钠建立SAP大鼠动物模型,在SAP诱导后3、6、12h动态观察血清淀粉酶(AMS)、肠／肺组织病理学、湿干重比、组织匀浆丙二醛(MDA)／一氧化氮(NO)／髓过氧化物酶(MPO)水平、肠／肺组织微血管通透性等多个肠／肺损伤指标的改变,以期了解SAP时肠和肺损伤之间的关系,为SAP临床治疗时肠肺同治提供理论依据,同时观察大黄游离蒽醌-黄芩总黄酮配伍对SAP相关性肠／肺损伤的干预效应,并从改善微循环障碍、抗炎抗氧化损伤、调节细胞因子水平、抑制核转录因子等多角度探讨大黄游离蒽醌-黄芩总黄酮配伍肺肠保护功能的作用机制。
方法
逆行胰胆管注射3.5%牛磺胆酸钠建立SAP大鼠动物模型；假手术对照组：用等剂量的无菌生理盐水替代牛磺胆酸钠逆行胰胆管注射；泻心汤有效组分干预组：在SAP大鼠模型诱导前8小时和2小时,以200mg/kg的剂量分别灌胃给予大黄总游离蒽醌、黄芩总黄酮和二者配伍溶液。按计划于3、6和12小时各时间点处死各组大鼠,收集血清、小肠和肺组织。H.E染色用于小肠和肺组织损伤的病理学评价；湿肠／肺组织称重后,置于烤箱中烘烤至恒重,测定组织湿／干重比；酶化学法测定肺和肠组织匀浆中MPO、MDA和NO含量；比色法测定肺和肠组织中EBD含量,以反映组织微血管通透性；放射免疫法测定血清TNF-a和IL-1β水平；PTAH染色显示肺和肠组织微血栓；免疫组织化学法测定肠和肺组织COX-2,NF-κB和ICAM-1的表达；RT-PCR检测肠和肺组织中COX-2mRNA,iNOS mRNA和TFmRNA的表达。
结果
第一部分：与假手术对照组比较,SAP诱导后各时相点肺和肠组织病理学评分、湿干重比、MDA,NO、MPO和EBD含量等均明显增加(p<0.01)。大黄游离蒽醌、黄芩总黄酮和二者恶配伍具有非常突出的肺／肠保护作用,各药物干预组均明显改善SAP大鼠的肺和肠病理学损伤程度,降低病理学评分；各药物干预组均明显降低了SAP大鼠肺和肠组织各时间段MPO活性、MDA及NO水平；同样,肺和肠组织EBD含量和组织湿干重比也明显降低。各药物干预组中尤以配伍组的作用更优。
第二部分：SAP诱导后各时相点大鼠血清TNF-a和IL-1β水平明显升高；PTAH染色显示SAP大鼠肺和肠组织可见较多的血栓形成,血栓多数分布于中小血管及末梢血管,部分主干血管也有血栓形成；免疫组织化学结果显示,牛磺胆酸钠诱导后,大鼠肺和肠组织NF-κB、ICAM-1和COX-2蛋白表达均明显上调；同样,肠和肺组织中COX-2mRNA,iNOS mRNA和TFmRNA的表达亦明显上调,以上各指标与假手术对照组比较差异具有显著性(p<0.01)。与SAP组比较,大黄游离蒽醌-黄芩总黄酮配伍除了对肠组织12小时COX-2表达的抑制作用不明显,对肺组织3和12小时、肠组织3和6小时ICAM-1表达的抑制作用不明显外,对其余指标均具有明显抑制效应。
结论
(1)SAP诱导后从3小时起即并发明显的肠和肺组织损伤,且肺和肠损伤之间具有显著相关性,本研究中尽管肺和肠损伤之间未显示出明显的因果关系,但SAP时同时存在肠和肺组织的损伤是一个基本事实,研究结果提示SAP治疗时,不管是西医还是中医,除了常规疗法外,还应考虑同时对肠和肺损伤进行治疗,研究结果不仅为SAP时肠肺同治提供了理论依据,也为SAP早期防治MODS提供了理论依据。
(2)大黄游离蒽醌、黄芩总黄酮和二者的配伍明显降低血清AMS水平；改善SAP大鼠肠和肺组织的病理性损伤程度；明显降低肺和肠组织中MPO和MDA含量,减少中性粒细胞的滞留程度,降低中性粒细胞对肺和肠组织的炎性损伤和氧化应激损伤程度；明显降低肺和肠组织湿干重比、NO和EBD含量,改善组织微血管通透性和微循环障碍,具有非常突出的肺／肠保护作用,其中尤以配伍组的作用更突出,两药配伍后协同增效。
(3)大黄游离蒽醌-黄芩总黄酮配伍可降低中性粒细胞对肺和肠组织的炎性损伤和氧化应激损伤程度,但其抗炎和抗氧化应激作用可能不是通过抑制ICAM-1途径实现的；该配伍抑制COX-2 mRNA的转录和蛋白的表达、抑制TF mRNA的转录,这可能是其改善肺和肠微循环障碍的重要机制；该配伍可通过抑制TNF-α、IL-1β和NO的产生,进而减轻其介导的炎症级联放大效应,减轻全身炎症反应和器官功能损伤程度：大黄游离蒽醌-黄芩总黄酮配伍明显下调了NF-κB蛋白的表达,由于NF-κB是调控TNF-α, COX-2、iNOS和ICAM-1等转录活化的主要核转录因子,由此,我们推测大黄游离蒽醌-黄芩总黄酮配伍降低肺和肠组织上述因子的表达可能是通过抑制NF-κB活性的途径实现的。
Objective
Severe acute pancreatitis (SAP) is a frequent acute abdomen in clinic, intestinal and lung injury is frequent complications, which still lack of effective therapy. Treatment effectiveness of integrated TCM-WM is better than conventional therapy of west medicine.Now, TCM is become one of important complementary therapies of SAP. Compatibility of free anthraquinone of rhubarb and total flavonoids of Scutellaria baicalensis Georgi is anti-endotoxic effective components from Xiexin Decoction. In this study, we arm to evaluate the potent effect of this compatibility on the the lung injury and intestinal injury of SAP, and more attention was payed to the underlying molecular mechanisms of this compatibility.
Methods
The SAP model was induced by standard retrograde infusion of bilio-pancreatic duct with 3.5% sterile sodium taurocholate solution at lml/kg in Sprague-Dawley rats, the same dose of saline solution, replacement of sodium taurocholate,were administrated in sham operation control group. Free anthraquinone of rhubarb, total flavonoios of Scutellaria baicalensis Georgi and their compatibility were administrated affusedly down alimentary canal from mouth to stomach at 200mg/kg within 8 and 2 hours before the inducement of SAP, rats were killed on scheme over a time course(3,6,12hours).The blood serum, small intestine and lung tissue of rats were harvested, H.E Dyeing of small intestine and lung tissue were employed for pathological assessment;the severity of tissue edema was determined by the ratio of the weight of wet tissue to that of dry tissue(ww/wd);the level of MPO,MDA and NO of small intestine and lung tissue homogenate were determined by method of zymochemistry;the content of EBD in small intestine and lung tissue,reflecting the microvascular permeability of tissue,was determined by Colorimetry, according to a standard curve of EBD;the level of serum TNF-a and IL-1βwere determined by radioimmunoassay(RIA);PTAH Dyeing of small intestine and lung tissue for microthrombus;the expression of COX-2, NF-κB and intercellular adherension molecule-1 (ICAM-1)protein were determined immunohistochemistrically,and expression of COX-2mRNA,iNOS mRNA,and TFmRNA in lung tissues were determined by RT-PCR.
Results
PART I
The SAP group, pathological assessment,ww/wd, level of MPO, MDA and NO,content of EBD were all significant increase, comparing with sham operation group(P<0.01).Free anthraquinone of rhubarb, total flavonoids of Scutellaria baicalensis Georgi and their compatibility had very excellent protective effect on lung and intestinal injury, they ameliorated the degree of pathological injuries about lung and intestine, decreased pathological score;they decreased the level of MPO, MDA and NO of small intestine and lung tissue homogenate significantly; the content of EBD and ww/wd were also decreased.The compatibility group had more excellent protective effect than other groups.
PART II
The SAP group, serum TNF-a and IL-1βwere significant increase; microthrombus determined by PTAH could be observed in tissue;significant overexpression of NF-κB, COX-2 and ICAM-1 were demonstrated in lung and intestinal tissue of rat with SAP by IHC; COX-2mRNA, iNOS mRNA and TFmRNA were also overexpression in lung and intestinal tissue of rat with SAP by RT-PCR. The compatibility obviously decreased the level of serum TNF-a and IL-1β,decreased the density of microthrombus;it inhibited the expression of NF-κB, ICAM-1,and COX-2 protein in lung and intestinal tissue over the time course, except the expression of COX-2 in intestinal tissue at 12hour and the expression of ICAM-1 in lung tissue at 3 and 12hour, in intestinal tissue at 3 and 6hour;it dramatically down-regulated the expression of COX-2mRNA,iNOS mRNA and TFmRNA in lung and intestinal tissue.
Conclusions
(1)Our results showed that obvious intestinal and lung injury were observed after SAP model was induced 3h, it had significant correlation between intestinal injury and lung injury. The studies suggested that additional attention should be paided to treatment of intestinal and lung injury,except for conventional therapy.
(2)Our results clearly suggested that free anthraquinone of rhubarb,total flavonoids of Scutellaria baicalensis Georgi and their compatibility reduced the degree of serum AMS, ameliorated the degree of pathological injury of intestinal and lung,reduced the content of MPO, NO, MDA and EBD of intestinal and lung tissue.The compatibility group had more excellent protective effect on lung and intestinal injury than other groups, the result of compatibility was increase efficiency
(3)The compatibility reduced degree.of injury of.inflammationary and oxidative stress by decreasing stagnation of polymorphonuclear leukocytes in lung and intestinaltissue of SAP rats,but the effect might not by inhibiting the expression of ICAM-1 to attain.The compatibility ameliorated microvascular permeability and microcirculation disturbance of lung and intestinal tissue of SAP rats, the effect was close relevant to suppression of COX-2 and TF activation, which might be important mechanism about ameliorating microcirculation disturbance of tissue.The compatibility alleviated drgree of systemic inflammatory reaction and organ function impairment by inhibiting TNF-α、IL-1βand NO. The compatibility significantly down-regulated the expression of NF-κB,which was a main nuclear factor about regulating the transcription of TNF-α,COX-2,iNOS and ICAM-1,and so on.Thereby, we presumed that the compatibility depressed the expression of factors above mentioned via suppression of NF-κB activation.
引文
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