吲哚美辛对COPD营养不良模型大鼠骨骼肌蛋白质分解代谢的影响
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摘要
目的:观察吲哚美辛(IND)对COPD营养不良模型大鼠骨骼肌蛋白质分解代谢的影响以及大鼠体内TNF-α的变化。
方法:100只健康Wistar大鼠随机分为模型组80只,对照组20只。采用气道内滴猪胰弹性蛋白酶加烟熏方法建立COPD大鼠模型。造模第68天以低于正常对照组大鼠平均体重的90%作为判断营养不良的标准,把模型大鼠分为营养不良组(n=40)和营养正常组(n=37)。营养不良组按随机区组设计分为A、B、C、D四组。A组、对照组和COPD营养正常组每天予等量生理盐水灌胃,B、C、D组每天予不同剂量IND灌胃(B组:IND 0.5mg/kg.d,C组:IND 1mg/kg.d,D组:IND 2mg/kg.d),干预14天后,饲养14天。称大鼠体重,采用双抗体夹心ABC-ELISA法测定血清、膈肌和伸趾长肌匀浆中肿瘤坏死因子-α的浓度;采用高效液相色谱技术检测膈肌、伸趾长肌匀浆中3-甲基组氨酸和酪氨酸的含量。
结果:(1)干预C组大鼠体重增长速度显著高于干预B、D组和干预A组(P=0.001,P=0.002,P=0.00),与正常对照组、COPD营养正常组相比均无显著性差异(P均＞0.05)。干预B组与D组之间无明显差异(P＞0.05)。干预B、D组大鼠体重增长速度比干预A组稍有增高,无统计学差异(P＞0.05),低于COPD营养正常组和对照组,有统计学差异(P＜0.05,P＜0.01)。
(2)干预前,干预A、B、C、D组大鼠血清、骨骼肌匀浆中TNF-α浓度均明显高于COPD营养正常组(P＜0.01)及对照组(P＜0.01),COPD营养正常组明显高于对照组(P＜0.01)。干预后,干预B、C、D组大鼠血清TNF-α浓度较干预前均明显降低(P＜0.01),并明显低于干预A组(P＜0.01),其中以干预C组最明显。
(3)模型组大鼠血清TNF-α浓度与体重呈显著负相关(R=-0.846,P＜0.01);与膈肌、伸趾长肌重量均呈显著负相关(R=-0.778,P＜0.01:R=-0.772,P＜0.01)。
(4)干预A组膈肌、伸趾长肌3-甲基组氨酸、酪氨酸含量均明显高于对照组(P＜0.01)、COPD营养正常组(P＜0.01)、干预B、C、D组(P＜0.01),干预C组明显低于COPD营养正常组(P＜0.01),低于干预B、D组(P＜0.05),干预B、D组之间无显著性差异(P＞0.05)。
结论:(1)TNF-α参与了COPD营养不良、骨骼肌萎缩的发生。(2)1mg/kg剂量的吲哚美辛可以降低COPD营养不良大鼠血清、骨骼肌匀浆中TNF-α的水平,同时也可降低COPD营养不良大鼠骨骼肌蛋白分解代谢率,可部分改善COPD营养不良大鼠骨骼肌萎缩。(3)0.5mg/kg、2mg/kg剂量的吲哚美辛并不具有更显著的作用。
Objective:To observe the influence of indomethacin on skeletal muscle protein catabolism and the changes of tumor necrosis factor(TNF) -alpha in COPD malnutrition rats.
Methods:100 healthy male adult Wistar rats were randomly divided into two groups:model group(n=80) and normal control group(n=20). Model group was performed with intratracheal instillation of porcine pancreatic elastase and exposed to cigarette smoke to establish COPD models.On the 68th day of modeling,malnutrition was defined if the body weights of the rats in the model group were lower than 90%of the mean body weight of the control group.Model rats were divided into two groups:the non-malnutrition COPD group(n=37) and the malnutrition COPD group(n=40).The malnutrition group rats were divided by randomized block design into four groups(group A,B,C,D).Isotonic physiologic saline was administered to group A,the control group and the non-malnutrition COPD group,and different doses of oral indomethacin were administered to groups B,C,and D daily(group B:IND 0.5mg/kg.d,C:IND 1mg/kg.d,D:IND 2mg/kg.d).After 14 days of intervention,they were changed to normal feeding for 14 days,and then the weights of each rat body were scaled.The concentrations of TNF-αlpha in the serum,the diaphragm and extensor digitorum longus muscle homogenates from these rats were measured by double-antibody sandwiched ABC-ELISA method.The contents of 3-methyl-histidine and tyrosine in the diaphragm and extensor digitorum longus muscle homogenates were detected by high-performance liquid chromatography.
Results:(1) The body weight growth rate of the intervention group C rats was significantly higher than the intervention groupB,D and A (P=0.001,P=0.002,P=0.00),and compared with the normal control group and the non-malnutrition COPD group respectively,the difference is not significant(P＞0.05).There was no significant difference between the intervention groups B and D(P＞0.05).The body weight growth rates of the intervention groups B and D rats were slightly higher than the intervention group A,with no significant difference(P＞0.05);they were lower than the non-malnutrition COPD group and the control group with significant difference(P＜0.05,P＜0.01).
(2) Before the intervention,the TNF-αlpha concentrations of the serum and the skeletal muscle homogenate of rats of the intervention groups A,B,C and D were significantly higher than those of normal nutrition COPD group(P＜0.01) and the control group(P＜0.01).The COPD normal nutrition group was obviously higher than the control group(P＜0.01).The TNF-αconcentrations of the serum and the skeletal muscle homogenate of rats of the intervention groups B,C andD after the intervention were significantly lower than before the intervention (P＜0.01),and were significantly lower than the intervention group A(P＜0.01),the most significant is the intervention group C.
(3) The serum TNF-αlpha concentration and body weight of model group rats were negatively correlated(R=-0.846,P＜0.01),as well as the diaphragm and extensor digitorum longus muscle weights(R=-0.778, P＜0.01;R=-0.772,P＜0.01).
(4) The 3-methyl-histidine and tyrosine levels of the diaphragm and extensor digitorum longus muscles of the intervention group A rats were significantly higher the control group(P＜0.01),the normal nutrition COPD group(P＜0.01),and the intervention groups B,C and D(P＜0.01). The COPD normal nutrition group was higher than the control group obviously(P＜0.01).The intervention group C was lower than the COPD normal nutrition group obviously(P＜0.05),as well as the intervention groups B and D.There was no significant difference between the intervention groups B and D(P＞0.05).
Conclusion:(1) TNF-αlpha is involved in the occurrence of COPD malnutrition and skeletal muscle amyotrophy.(2) Dose of 1mg/kg indomethacin can reduce the TNF-αlpha levels in the serum and the skeletal muscle homogenate in malnutrition COPD rats,and reduce the catabolic rate of the skeletal muscle proteins in malnutrition COPD rats, which can improve partly the malnutrition COPD rats nutrition and reverse the skeletal muscle atrophy.(3) Dose of 0.5mg/kg or 2mg/kg indomethacin does not have a more remarkable function.
方法:100只健康Wistar大鼠随机分为模型组80只,对照组20只。采用气道内滴猪胰弹性蛋白酶加烟熏方法建立COPD大鼠模型。造模第68天以低于正常对照组大鼠平均体重的90%作为判断营养不良的标准,把模型大鼠分为营养不良组(n=40)和营养正常组(n=37)。营养不良组按随机区组设计分为A、B、C、D四组。A组、对照组和COPD营养正常组每天予等量生理盐水灌胃,B、C、D组每天予不同剂量IND灌胃(B组:IND 0.5mg/kg.d,C组:IND 1mg/kg.d,D组:IND 2mg/kg.d),干预14天后,饲养14天。称大鼠体重,采用双抗体夹心ABC-ELISA法测定血清、膈肌和伸趾长肌匀浆中肿瘤坏死因子-α的浓度;采用高效液相色谱技术检测膈肌、伸趾长肌匀浆中3-甲基组氨酸和酪氨酸的含量。
结果:(1)干预C组大鼠体重增长速度显著高于干预B、D组和干预A组(P=0.001,P=0.002,P=0.00),与正常对照组、COPD营养正常组相比均无显著性差异(P均＞0.05)。干预B组与D组之间无明显差异(P＞0.05)。干预B、D组大鼠体重增长速度比干预A组稍有增高,无统计学差异(P＞0.05),低于COPD营养正常组和对照组,有统计学差异(P＜0.05,P＜0.01)。
(2)干预前,干预A、B、C、D组大鼠血清、骨骼肌匀浆中TNF-α浓度均明显高于COPD营养正常组(P＜0.01)及对照组(P＜0.01),COPD营养正常组明显高于对照组(P＜0.01)。干预后,干预B、C、D组大鼠血清TNF-α浓度较干预前均明显降低(P＜0.01),并明显低于干预A组(P＜0.01),其中以干预C组最明显。
(3)模型组大鼠血清TNF-α浓度与体重呈显著负相关(R=-0.846,P＜0.01);与膈肌、伸趾长肌重量均呈显著负相关(R=-0.778,P＜0.01:R=-0.772,P＜0.01)。
(4)干预A组膈肌、伸趾长肌3-甲基组氨酸、酪氨酸含量均明显高于对照组(P＜0.01)、COPD营养正常组(P＜0.01)、干预B、C、D组(P＜0.01),干预C组明显低于COPD营养正常组(P＜0.01),低于干预B、D组(P＜0.05),干预B、D组之间无显著性差异(P＞0.05)。
结论:(1)TNF-α参与了COPD营养不良、骨骼肌萎缩的发生。(2)1mg/kg剂量的吲哚美辛可以降低COPD营养不良大鼠血清、骨骼肌匀浆中TNF-α的水平,同时也可降低COPD营养不良大鼠骨骼肌蛋白分解代谢率,可部分改善COPD营养不良大鼠骨骼肌萎缩。(3)0.5mg/kg、2mg/kg剂量的吲哚美辛并不具有更显著的作用。
Objective:To observe the influence of indomethacin on skeletal muscle protein catabolism and the changes of tumor necrosis factor(TNF) -alpha in COPD malnutrition rats.
Methods:100 healthy male adult Wistar rats were randomly divided into two groups:model group(n=80) and normal control group(n=20). Model group was performed with intratracheal instillation of porcine pancreatic elastase and exposed to cigarette smoke to establish COPD models.On the 68th day of modeling,malnutrition was defined if the body weights of the rats in the model group were lower than 90%of the mean body weight of the control group.Model rats were divided into two groups:the non-malnutrition COPD group(n=37) and the malnutrition COPD group(n=40).The malnutrition group rats were divided by randomized block design into four groups(group A,B,C,D).Isotonic physiologic saline was administered to group A,the control group and the non-malnutrition COPD group,and different doses of oral indomethacin were administered to groups B,C,and D daily(group B:IND 0.5mg/kg.d,C:IND 1mg/kg.d,D:IND 2mg/kg.d).After 14 days of intervention,they were changed to normal feeding for 14 days,and then the weights of each rat body were scaled.The concentrations of TNF-αlpha in the serum,the diaphragm and extensor digitorum longus muscle homogenates from these rats were measured by double-antibody sandwiched ABC-ELISA method.The contents of 3-methyl-histidine and tyrosine in the diaphragm and extensor digitorum longus muscle homogenates were detected by high-performance liquid chromatography.
Results:(1) The body weight growth rate of the intervention group C rats was significantly higher than the intervention groupB,D and A (P=0.001,P=0.002,P=0.00),and compared with the normal control group and the non-malnutrition COPD group respectively,the difference is not significant(P＞0.05).There was no significant difference between the intervention groups B and D(P＞0.05).The body weight growth rates of the intervention groups B and D rats were slightly higher than the intervention group A,with no significant difference(P＞0.05);they were lower than the non-malnutrition COPD group and the control group with significant difference(P＜0.05,P＜0.01).
(2) Before the intervention,the TNF-αlpha concentrations of the serum and the skeletal muscle homogenate of rats of the intervention groups A,B,C and D were significantly higher than those of normal nutrition COPD group(P＜0.01) and the control group(P＜0.01).The COPD normal nutrition group was obviously higher than the control group(P＜0.01).The TNF-αconcentrations of the serum and the skeletal muscle homogenate of rats of the intervention groups B,C andD after the intervention were significantly lower than before the intervention (P＜0.01),and were significantly lower than the intervention group A(P＜0.01),the most significant is the intervention group C.
(3) The serum TNF-αlpha concentration and body weight of model group rats were negatively correlated(R=-0.846,P＜0.01),as well as the diaphragm and extensor digitorum longus muscle weights(R=-0.778, P＜0.01;R=-0.772,P＜0.01).
(4) The 3-methyl-histidine and tyrosine levels of the diaphragm and extensor digitorum longus muscles of the intervention group A rats were significantly higher the control group(P＜0.01),the normal nutrition COPD group(P＜0.01),and the intervention groups B,C and D(P＜0.01). The COPD normal nutrition group was higher than the control group obviously(P＜0.01).The intervention group C was lower than the COPD normal nutrition group obviously(P＜0.05),as well as the intervention groups B and D.There was no significant difference between the intervention groups B and D(P＞0.05).
Conclusion:(1) TNF-αlpha is involved in the occurrence of COPD malnutrition and skeletal muscle amyotrophy.(2) Dose of 1mg/kg indomethacin can reduce the TNF-αlpha levels in the serum and the skeletal muscle homogenate in malnutrition COPD rats,and reduce the catabolic rate of the skeletal muscle proteins in malnutrition COPD rats, which can improve partly the malnutrition COPD rats nutrition and reverse the skeletal muscle atrophy.(3) Dose of 0.5mg/kg or 2mg/kg indomethacin does not have a more remarkable function.
引文
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