急性肠损伤大鼠体内Ghrelin及受体的表达和电针干预作用的关联
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摘要
目的探讨急性肠损伤大鼠体内Ghrelin及其受体的表达以及电针足三里穴的干预作用。
方法①建立大鼠急性肠损伤(ABI)动物模型通过盲肠结扎穿孔术导致的腹腔感染来诱发急性肠损伤。将32只Wistar雄性大鼠分为两个实验组：急性肠损伤组(CLP组)和假手术对照组(Sham组),各16只。CLP组采用盲肠结扎穿孔术(CLP)的方法建立,取正中切口开腹,暴露盲肠并结扎根部,用16号针贯通穿刺盲肠4次形成肠瘘,再逐层缝合腹壁切口;假手术对照组以相同的方式暴露盲肠后回纳并缝合腹壁切口,并不行盲肠结扎和穿孔。于术后12h麻醉下留取血样本后处死,留取肠组织,测定大鼠血清TNF-α、HMGB1和肠组织含水率、肠组织髓过氧化物酶(MPO)活性和二胺氧化酶(DAO)活性,肠组织的大体及镜下病理组织学变化来确定ABI的形成。②急性肠损伤大鼠体内ghrelin及其受体的表达和电针足三里穴干预作用的关联将48只Wistar大鼠随机分为：假手术对照组(Sham组)、急性肠损伤组(CLP组)、电针治疗组(CLP+EA组)及ghrelin受体阻断剂组(CLP+GHSRA+EA组),每组各12只。假手术对照组取腹正中切口、暴露盲肠后回纳、缝合腹腔切口,急性肠损伤组采用盲肠结扎穿孔术(CLP)的方法建立,电针治疗组于建立大鼠ABI模型后取双侧足三里穴电针仪持续针刺30min, ghrelin受体阻断剂组于建立大鼠ABI模型后在尾静脉注射ghrelin受体阻断剂[D-Arg1, D-Phe5, D-Trp7.9,Leu11] substance P、再行双侧足三里穴电针仪持续针刺30min。于术后12h麻醉下留取血样本后处死,留取肠组织。测定血清ghrelin、TNF-α、HMGB1和肠组织含水率、肠组织髓过氧化物酶(MPO)活性和二胺氧化酶(DAO)活性,并通过western blot测定肠组织ghrelin及其受体、HMGB1蛋白表达,免疫组化测定肠组织ghrelin及其受体阳性的细胞数。
结果①CLP组肠组织结构明显破坏,肠组织含水率和病理评分明显高于假手术对照组(P<0.05)。与Sham组相比,ABI模型组血清TNF-α、HMGB1两者均较对照组高,有统计学意义(P<0.05)。CLP组肠组织含水率和髓过氧化物酶(MPO)活性明显高于Sham组、而肠组织二胺氧化酶(DAO)活性则低于Sham组,两者有统计学意义(P<0.05)。②CLP组血清ghrelin水平、肠组织ghrelin阳性细胞数和蛋白表达量均低于Sham组(P<0.05),肠组织ghrelin受体蛋白表达量在CLP组明显低于假手术对照组,有统计学意义(P<0.05)。③CLP+EA组血清TNF-α、HMGB1水平以及肠组织MPO活性均较CLP组低,而肠组织DAO活性则高于CLP组,均有统计学意义(P<0.05),与CLP组相比,CLP+EA组肠组织含水率和病理评分均有下降(P<0.05)。④CLP+EA组血清ghrelin水平、肠组织ghrelin阳性细胞数和蛋白表达量均高于CLP组(P<0.05),与CLP组相比,CLP+EA组肠组织ghrelin受体蛋白表达量明显升高,有统计学意义(P<0.05)。⑤CLP+GHSRA+EA组血清TNF-α、HMGB1水平以及肠组织MPO活性均较CLP+EA组高,而肠组织DAO活性则低于CLP+EA组,均有统计学意义(P<0.05),与CLP+EA相比,CLP+GHSRA+EA组肠组织含水率和病理评分均升高(P<0.05)。⑥血液中Ghrelin水平和血清HMGB1水平呈负相关(r=-0.664,p<0.001),血液中Ghrelin水平和肠组织DAO活性呈负相关(r=-0.423,p=0.003,血液中Ghrelin水平和肠组织MPO活性呈负相关(r=-0.404,p=0.004)。
结论①盲肠结扎穿孔术能诱发大鼠急性肠损伤模型。②急性肠损伤大鼠体内Ghrelin及其受体的血清水平和肠组织蛋白表达是下降的。③电针足三里穴能抑制急性肠损伤大鼠体内促炎因子(TNF-α、HMGB1)产生和改善肠粘膜屏障功能。④电针足三里穴能促进急性肠损伤大鼠体内Ghrelin的分泌和肠组织Ghrelin受体的表达。⑤Ghrelin受体阻断后,电针足三里穴就失去对急性肠损伤的保护作用,说明电针足三里穴对急性肠损伤的影响与大鼠体内Ghrelin及其受体的作用有关。
Objective To study the levels of ghrelin and ghrelin receptor density in serum and intestinal tissue and the influence of electroacupuncture in the acute bowl injury (ABI) rats model.
Methods①To establish the rats model of acute bowl injury Intra-abdominal infection leads to acute intestinal injury induced by cecal ligation and puncture (CLP).The study was performed on32Wistar male rats.Two experimental groups composed12rats were established:acute bowl injury(ABI)group(CLP group) was established by using cecal ligation and puncture (CLP):a2-cm ventral midline abdominal incision was performed, the cecum was then exposed, ligated just distal to the ileocecal valve,punctured four times with an16-gauge needle, and returned to the abdominal cavity,the incisionwas then closed in layers. Sham-operated group (Sham group) underwent the same procedure with the exception that the cecum was neither ligated nor punctured. Twele animals in each group were sacrificed after taking the blood sample,the intestines at the time of12h after CLP surgery.To detect the level of serum TNF-α and high mobility group box1(HMGB1),take intestinal tissue to detect the rate of water content、the activity of myeloperoxidase (MPO) and diamine oxidase (DAO), and to evaluate the existence of pathological changes of intestines to evaluate the existence of acute bowl injury.②To study on changes of ghrelin and ghrelin receptor density in serum and intestinal tissue and the influence of electroacupuncture in the ABI rats model to investigate the it's mechanism of treatment on acute bowl injury whether is associated with ghrelin Forty-eight Wister male rats were randomly divided into four groups:Sham operation group(Sham group),acute bowl injury group(CLP group), electroacupuncture treatment group (CLP+EA group)and ghrelin receptor antagonist group(CLP+GHSRA+EA group),twele rats were in each group. CLP group was established by using cecal ligation and puncture (CLP):a2-cm ventral midline abdominal incision was performed, the cecum was then exposed, ligated just distal to the ileocecal valve,punctured four times with an16-gauge needle, and returned to the abdominal cavity,the incisionwas then closed in layers. Sham group underwent the same procedure with the exception that the cecum was neither ligated nor punctured. An electroacupuncture at Zusanli point (ST36) was performed at constant voltage immediately for30minutes after CLP surgery in CLP+EA group.In CLP+GHSRA+EA group,ghrelin receptor antagonist([D-Arg1,D-Phe5,D-Trp7.9,Leu11]substance P) was injected tail vein,and then electr-oacupuncture at Zusanli point (ST36) was performed at constant voltage immediately for30minutes, each group was taken the blood from the heart at the time of12h after operation,the-n,was killed and intestines was taken from the body.So,we can detect the level of TNF-α、 HMGB1and ghrelin in serum, and detect the rate of water content、the activity of myeloperoxidase (MPO) and diamine oxidase (DAO), and using western blot to detect the expression of ghrelin and ghrelin receptor protein, using immunohistochemistry to detect the positive cells of ghrelin and ghrelin receptor.
Results①CLP led to the development of acute bowl injury.The model rats intestines structure was destroyed.The pathological scores of the CLP groups were significantly higher than the Sham groups(P<0.05).The levels of TNF-a and HMGB1of serum in CLP groups markedly higher than the Sham groups(P<0.05).The rates of water content and the activity of MPO in intestines in CLP groups were significantly higher than those in the Sham groups,while the activity of DAO in CLP groups was markedly lower than that in Sham groups(all P<0.05).②The ghrelin density of serum in CLP group is abviously lower than that in Sham group (P<0.05).The ghrelin and ghrelin receptor poteins are expressed in intestinal tissue,the expression quantity of them in CLP group were significantly lower than those in sham group(P<0.05).Ghrelin immunopositive cells and ghrelin receptor immunopositive cells are found in intestinal tissue,the numbers of them in CLP group were significantly lower than those in Sham group(P<0.05).③The levels of TNF-a and HMGB1of serum in CLP+EA group markedly lower than t CLP group (P<0.05).The rates of water content and the activity of MPO in intestines in CLP+EA group were significantly lower than those in CLP group,while the activity of DAO in CLP+EA group was markedly higher than that in in CLP group(all P<0.05). The model rats intestines structure was destroyed.The pathological scores of CLP+EA group were significantly lower than that of CLP group (P<0.05).④The ghrelin density of serum,the expressions quantity of ghrelin and ghrelin receptor poteins, and the numbers of ghrelin and ghrelin receptor immunopositive cells in intestinal tissue in the CLP+EA group were significantly higher than those in CLP group (all P<0.05).⑤The levels of TNF-α and HMGB1of serum, the rates of water content and the activity of MPO in intestines,and The pathological scores in CLP+GHSRA+EA group were significantly higher than those in CLP+EA group,while the activity of DAO in CLP+GHSRA+EA group was markedly lower than that in CLP+EA group (all P<0.05).⑥The level of HMGB1was in serum negatively correlated with ghrelin (r=-0.664, p<0.001) in serum.the activity of MPO in intestines was negatively correlated with ghrelin (r=-0.404, p=0.004) in serum, the activity of DAO in intestines was negatively correlated with ghrelin (r=-0.423, p=0.003) in serum.
Conclusion①The acute intestinal injury model of rats can be induced by cecal ligation and puncture.②The level of ghrelin of serum in ABI was decrease, the expressions quantity of ghrelin and ghrelin receptor poteins,and the numbers of ghrelin and ghrelin receptor immunopositive cells in intestinal tissue were very low in ABI.③Electroacupuncture at Zusanli point (ST36) can inhibit the production of proinflammatory cytokines(TNF-α, HMGB1) in acute bowl injury in rats,and can ameliorate the intestinal mucosal barrier.④Ele-ctroacupuncture at Zusanli point (ST36) can increase the level of serum ghrelin and promote the expression of ghrelin and ghrelin receptor in intestinal in acute intestinal injury.⑤When the ghrelin receptor is blocked, Electroacupuncture at Zusanli point (ST36) can't ameliorate the intestinal mucosal barrier.So the effect of electroacupuncture at Zusanli point (ST36) on acute bowl injury is realized by promoting the expression of ghrelin and ghrelin receptor in intestinal.
方法①建立大鼠急性肠损伤(ABI)动物模型通过盲肠结扎穿孔术导致的腹腔感染来诱发急性肠损伤。将32只Wistar雄性大鼠分为两个实验组：急性肠损伤组(CLP组)和假手术对照组(Sham组),各16只。CLP组采用盲肠结扎穿孔术(CLP)的方法建立,取正中切口开腹,暴露盲肠并结扎根部,用16号针贯通穿刺盲肠4次形成肠瘘,再逐层缝合腹壁切口;假手术对照组以相同的方式暴露盲肠后回纳并缝合腹壁切口,并不行盲肠结扎和穿孔。于术后12h麻醉下留取血样本后处死,留取肠组织,测定大鼠血清TNF-α、HMGB1和肠组织含水率、肠组织髓过氧化物酶(MPO)活性和二胺氧化酶(DAO)活性,肠组织的大体及镜下病理组织学变化来确定ABI的形成。②急性肠损伤大鼠体内ghrelin及其受体的表达和电针足三里穴干预作用的关联将48只Wistar大鼠随机分为：假手术对照组(Sham组)、急性肠损伤组(CLP组)、电针治疗组(CLP+EA组)及ghrelin受体阻断剂组(CLP+GHSRA+EA组),每组各12只。假手术对照组取腹正中切口、暴露盲肠后回纳、缝合腹腔切口,急性肠损伤组采用盲肠结扎穿孔术(CLP)的方法建立,电针治疗组于建立大鼠ABI模型后取双侧足三里穴电针仪持续针刺30min, ghrelin受体阻断剂组于建立大鼠ABI模型后在尾静脉注射ghrelin受体阻断剂[D-Arg1, D-Phe5, D-Trp7.9,Leu11] substance P、再行双侧足三里穴电针仪持续针刺30min。于术后12h麻醉下留取血样本后处死,留取肠组织。测定血清ghrelin、TNF-α、HMGB1和肠组织含水率、肠组织髓过氧化物酶(MPO)活性和二胺氧化酶(DAO)活性,并通过western blot测定肠组织ghrelin及其受体、HMGB1蛋白表达,免疫组化测定肠组织ghrelin及其受体阳性的细胞数。
结果①CLP组肠组织结构明显破坏,肠组织含水率和病理评分明显高于假手术对照组(P<0.05)。与Sham组相比,ABI模型组血清TNF-α、HMGB1两者均较对照组高,有统计学意义(P<0.05)。CLP组肠组织含水率和髓过氧化物酶(MPO)活性明显高于Sham组、而肠组织二胺氧化酶(DAO)活性则低于Sham组,两者有统计学意义(P<0.05)。②CLP组血清ghrelin水平、肠组织ghrelin阳性细胞数和蛋白表达量均低于Sham组(P<0.05),肠组织ghrelin受体蛋白表达量在CLP组明显低于假手术对照组,有统计学意义(P<0.05)。③CLP+EA组血清TNF-α、HMGB1水平以及肠组织MPO活性均较CLP组低,而肠组织DAO活性则高于CLP组,均有统计学意义(P<0.05),与CLP组相比,CLP+EA组肠组织含水率和病理评分均有下降(P<0.05)。④CLP+EA组血清ghrelin水平、肠组织ghrelin阳性细胞数和蛋白表达量均高于CLP组(P<0.05),与CLP组相比,CLP+EA组肠组织ghrelin受体蛋白表达量明显升高,有统计学意义(P<0.05)。⑤CLP+GHSRA+EA组血清TNF-α、HMGB1水平以及肠组织MPO活性均较CLP+EA组高,而肠组织DAO活性则低于CLP+EA组,均有统计学意义(P<0.05),与CLP+EA相比,CLP+GHSRA+EA组肠组织含水率和病理评分均升高(P<0.05)。⑥血液中Ghrelin水平和血清HMGB1水平呈负相关(r=-0.664,p<0.001),血液中Ghrelin水平和肠组织DAO活性呈负相关(r=-0.423,p=0.003,血液中Ghrelin水平和肠组织MPO活性呈负相关(r=-0.404,p=0.004)。
结论①盲肠结扎穿孔术能诱发大鼠急性肠损伤模型。②急性肠损伤大鼠体内Ghrelin及其受体的血清水平和肠组织蛋白表达是下降的。③电针足三里穴能抑制急性肠损伤大鼠体内促炎因子(TNF-α、HMGB1)产生和改善肠粘膜屏障功能。④电针足三里穴能促进急性肠损伤大鼠体内Ghrelin的分泌和肠组织Ghrelin受体的表达。⑤Ghrelin受体阻断后,电针足三里穴就失去对急性肠损伤的保护作用,说明电针足三里穴对急性肠损伤的影响与大鼠体内Ghrelin及其受体的作用有关。
Objective To study the levels of ghrelin and ghrelin receptor density in serum and intestinal tissue and the influence of electroacupuncture in the acute bowl injury (ABI) rats model.
Methods①To establish the rats model of acute bowl injury Intra-abdominal infection leads to acute intestinal injury induced by cecal ligation and puncture (CLP).The study was performed on32Wistar male rats.Two experimental groups composed12rats were established:acute bowl injury(ABI)group(CLP group) was established by using cecal ligation and puncture (CLP):a2-cm ventral midline abdominal incision was performed, the cecum was then exposed, ligated just distal to the ileocecal valve,punctured four times with an16-gauge needle, and returned to the abdominal cavity,the incisionwas then closed in layers. Sham-operated group (Sham group) underwent the same procedure with the exception that the cecum was neither ligated nor punctured. Twele animals in each group were sacrificed after taking the blood sample,the intestines at the time of12h after CLP surgery.To detect the level of serum TNF-α and high mobility group box1(HMGB1),take intestinal tissue to detect the rate of water content、the activity of myeloperoxidase (MPO) and diamine oxidase (DAO), and to evaluate the existence of pathological changes of intestines to evaluate the existence of acute bowl injury.②To study on changes of ghrelin and ghrelin receptor density in serum and intestinal tissue and the influence of electroacupuncture in the ABI rats model to investigate the it's mechanism of treatment on acute bowl injury whether is associated with ghrelin Forty-eight Wister male rats were randomly divided into four groups:Sham operation group(Sham group),acute bowl injury group(CLP group), electroacupuncture treatment group (CLP+EA group)and ghrelin receptor antagonist group(CLP+GHSRA+EA group),twele rats were in each group. CLP group was established by using cecal ligation and puncture (CLP):a2-cm ventral midline abdominal incision was performed, the cecum was then exposed, ligated just distal to the ileocecal valve,punctured four times with an16-gauge needle, and returned to the abdominal cavity,the incisionwas then closed in layers. Sham group underwent the same procedure with the exception that the cecum was neither ligated nor punctured. An electroacupuncture at Zusanli point (ST36) was performed at constant voltage immediately for30minutes after CLP surgery in CLP+EA group.In CLP+GHSRA+EA group,ghrelin receptor antagonist([D-Arg1,D-Phe5,D-Trp7.9,Leu11]substance P) was injected tail vein,and then electr-oacupuncture at Zusanli point (ST36) was performed at constant voltage immediately for30minutes, each group was taken the blood from the heart at the time of12h after operation,the-n,was killed and intestines was taken from the body.So,we can detect the level of TNF-α、 HMGB1and ghrelin in serum, and detect the rate of water content、the activity of myeloperoxidase (MPO) and diamine oxidase (DAO), and using western blot to detect the expression of ghrelin and ghrelin receptor protein, using immunohistochemistry to detect the positive cells of ghrelin and ghrelin receptor.
Results①CLP led to the development of acute bowl injury.The model rats intestines structure was destroyed.The pathological scores of the CLP groups were significantly higher than the Sham groups(P<0.05).The levels of TNF-a and HMGB1of serum in CLP groups markedly higher than the Sham groups(P<0.05).The rates of water content and the activity of MPO in intestines in CLP groups were significantly higher than those in the Sham groups,while the activity of DAO in CLP groups was markedly lower than that in Sham groups(all P<0.05).②The ghrelin density of serum in CLP group is abviously lower than that in Sham group (P<0.05).The ghrelin and ghrelin receptor poteins are expressed in intestinal tissue,the expression quantity of them in CLP group were significantly lower than those in sham group(P<0.05).Ghrelin immunopositive cells and ghrelin receptor immunopositive cells are found in intestinal tissue,the numbers of them in CLP group were significantly lower than those in Sham group(P<0.05).③The levels of TNF-a and HMGB1of serum in CLP+EA group markedly lower than t CLP group (P<0.05).The rates of water content and the activity of MPO in intestines in CLP+EA group were significantly lower than those in CLP group,while the activity of DAO in CLP+EA group was markedly higher than that in in CLP group(all P<0.05). The model rats intestines structure was destroyed.The pathological scores of CLP+EA group were significantly lower than that of CLP group (P<0.05).④The ghrelin density of serum,the expressions quantity of ghrelin and ghrelin receptor poteins, and the numbers of ghrelin and ghrelin receptor immunopositive cells in intestinal tissue in the CLP+EA group were significantly higher than those in CLP group (all P<0.05).⑤The levels of TNF-α and HMGB1of serum, the rates of water content and the activity of MPO in intestines,and The pathological scores in CLP+GHSRA+EA group were significantly higher than those in CLP+EA group,while the activity of DAO in CLP+GHSRA+EA group was markedly lower than that in CLP+EA group (all P<0.05).⑥The level of HMGB1was in serum negatively correlated with ghrelin (r=-0.664, p<0.001) in serum.the activity of MPO in intestines was negatively correlated with ghrelin (r=-0.404, p=0.004) in serum, the activity of DAO in intestines was negatively correlated with ghrelin (r=-0.423, p=0.003) in serum.
Conclusion①The acute intestinal injury model of rats can be induced by cecal ligation and puncture.②The level of ghrelin of serum in ABI was decrease, the expressions quantity of ghrelin and ghrelin receptor poteins,and the numbers of ghrelin and ghrelin receptor immunopositive cells in intestinal tissue were very low in ABI.③Electroacupuncture at Zusanli point (ST36) can inhibit the production of proinflammatory cytokines(TNF-α, HMGB1) in acute bowl injury in rats,and can ameliorate the intestinal mucosal barrier.④Ele-ctroacupuncture at Zusanli point (ST36) can increase the level of serum ghrelin and promote the expression of ghrelin and ghrelin receptor in intestinal in acute intestinal injury.⑤When the ghrelin receptor is blocked, Electroacupuncture at Zusanli point (ST36) can't ameliorate the intestinal mucosal barrier.So the effect of electroacupuncture at Zusanli point (ST36) on acute bowl injury is realized by promoting the expression of ghrelin and ghrelin receptor in intestinal.
引文
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