水杨酸钠对百草枯所致大鼠肺损伤的干预研究
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摘要
百草枯(paraquat,PQ)是一种非选择性有机杂环类脱叶剂和除草剂,因其除草效能高,接触土壤后迅速灭活,环境中残留量少,在全球使用广泛。百草枯中毒多见于误服或自杀。大量研究表明,肺是百草枯中毒的主要靶器官,其发病机制相当复杂至今尚未完全明确,可能涉及百草枯及其代谢产物诱导肺组织产生各种细胞调节因子,诱发氧化应激损伤及细胞凋亡等,早期引起肺的氧化损伤,晚期导致肺成纤维细胞增殖及细胞外基质的沉积,发展为迁延性的纤维化。临床病例研究提示早期的肺损伤有可能是死亡的主要原因。水杨酸钠是临床上常用的抗炎药,近年来的研究提示高剂量的水杨酸钠对PQ所致的毒效应可能具有潜在的治疗效果。
因此,本研究采用整体动物模型,运用分子生物学技术研究百草枯致肺损伤的早期的可能机制,集中探讨氧化损伤,TGF-β1,TNF-α,NF-κB及caspase-3,Bcl-2,P53在百草枯毒性中的作用;并探究水杨酸钠(NaSAL)对百草枯所致肺损伤的干预和潜在的治疗作用;为寻找并确立百草枯中毒的肺损伤治疗提供理论依据。
PQ一次性灌胃80mg/kg建立大鼠中毒模型。72只雄性SD大鼠随机分为NaCl对照组、PQ染毒组和PQ+NaSAL干预组,每组24只。对照组给予0.9%NaCl一次性灌胃,2h后给予等量0.9%NaCl腹腔注射;PQ组给予80mg/kg PQ一次性灌胃,2h后给予等量0.9%NaCl腹腔注射;干预组给予80mg/kg PQ一次性灌胃,2h后给予120mg/kg NASAL一次性腹腔注射。成功建模后,在染毒的第1、3、7、14d分批处死动物。腹主动脉采血,37℃放置2h,取上清,常规方法取肺组织,分别测定血清和肺组织匀浆中总抗氧化能力(T-AOC)、过氧化氢酶(CAT)水平,超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活力、丙二醛(MDA)含量以及肺组织匀浆中羟脯氨酸(HYP)含量。利用凝胶阻滞迁移实验(EMSA)检测肺组织中NF-κB表达情况;肺组织TGF-β1,TNF-α蛋白含量采用rat TGF-β1,TNF-αkit检测。采用实时荧光定量PCR法(real-time PCR)检测凋亡基因caspase-3,Bcl-2,P53表达。
结果显示,80mg/kg PQ染毒后,PQ组SD大鼠血清GSH-Px活性在第1、3、7、14天均低于对照组,分别为对照组的82.69%、74.58%、78.91%和75.07%,差异均具有统计学意义(P＜0.05);SOD活力在第1、3、7、14天分别为对照组的85.27%、79.66%和74.45%,71.49%,差异具统计学意义(P＜0.05);T-AOC活力在第1、3、7、14天分别为对照组的71.87%(P＜0.05)、53.62%(P＜0.05)、62.19%(P＜0.05)和92.3%(P＞0.05);染毒组CAT活力在第1、3天下降,分别为对照组的42.5%(P＜0.05)及42.09%(P＜0.05),随后逐渐回升,与对照相比,差异无统计学意义;PQ染毒后MDA含量升高,分别是对照组的3.28、1.8l、2.16和2.67倍,且差异均有统计学意义(P＜0.05);120mg/kg水杨酸钠干预后血清中各项指标较染毒组有所改善,表现为GSH-Px在第1、3、7天较染毒组高,差异有统计学意义(P＜0.05);SOD活力在第1、3、7、14天分别为对照组的86.98%、93.26%、81.78%及78.96%,与对照相比差异均有统计学意义,第3、7天活力高于PQ组(P＜0.05);干预组的T-AOC,CAT活力在第1、3天分别为对照组的95.16%、64.73%、71.23%、87.3%,明显高于PQ组(P＜0.05);干预后MDA含量在第1、3、7、14天分别为对照组的2.11、0.98、1.72及1.46倍,与相应时点的PQ组相比,含量明显降低(P＜0.05)。肺组织匀浆中GSH-Px活力在染毒第1、3、7、14天均低于对照组(分别为对照的67.67%、44.54%、54.12%、33.87%);SOD活力在第1、3、7、14天低于对照组(分别为对照组的86.08%、80.85%、74.9%、71.26%);T-AOC、CAT活力在各个时点均低于相应时点的对照组,且差异具有统计学意义(P＜0.05);肺组织匀浆中HYP含量升高,在第7、14天分别为对照组的1.21倍和1.24倍(P＜0.05);120mg/kg水杨酸钠干预后肺组织所有时点上GSH-Px活力均较PQ组明显改善(P＜0.05);CAT活力在第1、3、7天较染毒组有所提高(P＜0.05)。80mg/kg PQ染毒后,大鼠肺组织中NF-κB含量上升,TGF-β1蛋白表达量分别为对照组的1.78、1.59、1.51和1.61倍(P＜0.05)、TNF-α蛋白表达量分别为相应时点对照组的1.38、1.41、1.73和1.67倍(P＜0.05);水杨酸钠干预后TGF-β1,TNF-α蛋白表达基本恢复至正常水平,与对照相比,差异无统计学意义(P＞0.05)。染毒后凋亡基因caspase-3、P53 mRNA表达上升,Bcl-2 mRNA降低(P＜0.05);NASAL干预组大鼠的caspase-3、P53mRNA表达较PQ组升高,Bcl-2 mRNA表达较PQ组下降(P＜0.05)。表明NASAL在一定程度上对抗了PQ造成的细胞凋亡。
另外,实验过程中单纯染毒组出现明显的肺损伤,病理特征为早期的肺出血、水肿、单核细胞浸润及炎症反应表现,中晚期表现为成纤维细胞增生,胶原纤维聚集。NASAL干预组动物肺脏也有充血,肿胀,出血等病理改变,但程度较PQ组轻微,质地较软,炎性细胞少,局部水肿轻微。由此可知,水杨酸钠能明显改善PQ所致大鼠的肺水肿。
综上所述,本研究条件下,120mg/kg NASAL对PQ所致的急性肺损伤的干预能不同程度的改善各项氧化酶指标,平衡凋亡基因的启动,减少炎性因子的释放,在一定程度上减轻了PQ引起的肺损伤。表明PQ可能通过上述途径引起肺损伤,但PQ的毒作用机制及干预药物的药理作用还有待进一步的研究。
Paraquat(PQ) is a non-selective contact herbicide,which is used word-widely for its high efficiency and characteristics of no residues detectable in the crops. Paraquat poisoning was particularly prevalent in the accidental or suicide.
It has been extensively demonstrated that the target organ of PQ is lung. However,the exact mechanism of its toxicity still remains unclear and there are no known pharmacological antagonists for its poisoning at present.The mechanism may be involved as follows:a variety of regulatory factors,oxidative stress and apoptosis induced by paraquat and/or its metabolites,after which becomes oxidative damage of lungs at the early stage and the persistent fibrosis with fibroblast proliferation and extracellular matrix.Previous studies have shown that the pulmonary damage at early stage may be the main cause for death.Sodium salicylate is an anti-inflammatory drug widely used in the clinical,however,studies in recent years suggested that high doses of the therapeutic effect of sodium salicylate may have potential therapeutic effects on PQ-induced toxic effects.Therefore,we determined the expression of TGF-β1,TNF-α,NF-κB,caspase-3,Bcl-2,P53 and some oxidative index in the rat model of paraquat-induced pulmonary damage and evaluated their roles in this specific process.Moreover,we aimed to investigate effects of sodium salicylate(NaSAL) on the pulmonary damage induced by paraquat and to observe its potential therapeutic effects so as to provide evidence for the treatment strategy of paraquat-induced lung damage.
We established rat poisoning model by intragastric administration of 80mg/kg PQ.72 male SD rats were randomly divided into 0.9%NaCl control group,PQ exposure group,PQ+NaSAL intervention group,24 rats in each group.
Control group were made orally in an injection volume of 0.5 mL/100 g of body weight,after 2h an injection of equivalent 0.9%NaCl were made intraperitoneally; PQ group were made 80mg/kg PQ orally,after 2h an injection of equivalent 0.9% NaCl were made intraperitoneally;PQ+NaSAL group were given an intraperitoneal injection of 120mg/kg NASAL after an orally administrating of 80mg/kg PQ.After exposure,animals were sacrificed in batches on days 1,3,7,14.After dislodged from abdominal aorta,the blood was placed in 37℃waterbath for 2h and the supernatant was taken away and retained in eppendorf tubes.Lung tissues were obtained with routine method.
Then the activities of total antioxidative capacity(T-AOC),catalase(CAT), superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),malondialdehyde (MDA) both in serum and lung homogenate of rats and the contents of hypertrophy (HYP) in lung homogenate were measured using qualified kits provided by Nanjing Institute of Bio-engineering.The level of NF-κB was assayed by electrophoresis mobility shift assay(EMSA),while the protein level of TGF-β1,TNF-αwere determined with Rat TGF-β1,TNF-αkits.And the mRNA of caspase-3,Bcl-2, P-53 was determined using real-time reverse transcription polymerase chain reaction (real-time RT PCR).
It has been found that the activities of SOD,GSH-Px,T-AOC,CAT in serum and lung homogenate were decreased with positive significance(P＜0.05) and MDA level was increased in both PQ group and PQ+NaSAL group compared with the control group.So was the HYP level(P＜0.05).However,the activities of SOD, GSH-Px,T-AOC,CAT in PQ+NaSAL group were markedly higher than that of PQ treated group,and still lower than that of the control group.MDA content was lower than that of the PQ group(P＜0.05),but still higher than that of the control group(P＜0.05).HYP in PQ+NaSAL group was lower than that of the PQ group but higher than that of the control group.After 80mg/kg PQ exposure,the rat lung tissue NF-κB content,TGF-β1 and TNF-αprotein expression increased remarkebly than that of the control group(P＜0.05);apoptosis-related gene such as caspase-3,P53 mRNA increased and Bcl-2 mRNA reduced evidently compared with the control group(P＜0.05).NF-κB content,TGF-β1 and TNF-αprotein showed a low expression than that of the PQ group(P＜0.05),however,There was no significant difference compared with the control one.Meanwhile,NaSAL withstand increasing of PQ-induced caspase-3,P53 mRNA and decreasing of Bcl-2 mRNA expression to a certain extent(P＜0.05).
In addition,the histological examination showed ultra-morphological changes such as alveolar edema,hemorrhage and inflammatory cell infiltration in the PQ group.Similar changes such as hyperemia,edema and hemorrhage were also found in the PQ+NaSAL group,but it was slighter than that of the PQ group.So,it can be seen that sodium salicylate can improve the PQ-induced pulmonary edema in rats evidently.
In summary,we found that NaSAL significantly improved PQ-induced pulmonary damage.These findings suggested that NaSAL may exert its therapeutic effects on paraquat-induced pulmonary damage via counteracting paraquat-induced oxidative stress in rat lung and by regulating the mRNA expression of apoptosis gene and decreasing inflammatory factor releasing.However,further studies are still needed to investigate and clarify the underlying mechanisms involved in this complicated process.
因此,本研究采用整体动物模型,运用分子生物学技术研究百草枯致肺损伤的早期的可能机制,集中探讨氧化损伤,TGF-β1,TNF-α,NF-κB及caspase-3,Bcl-2,P53在百草枯毒性中的作用;并探究水杨酸钠(NaSAL)对百草枯所致肺损伤的干预和潜在的治疗作用;为寻找并确立百草枯中毒的肺损伤治疗提供理论依据。
PQ一次性灌胃80mg/kg建立大鼠中毒模型。72只雄性SD大鼠随机分为NaCl对照组、PQ染毒组和PQ+NaSAL干预组,每组24只。对照组给予0.9%NaCl一次性灌胃,2h后给予等量0.9%NaCl腹腔注射;PQ组给予80mg/kg PQ一次性灌胃,2h后给予等量0.9%NaCl腹腔注射;干预组给予80mg/kg PQ一次性灌胃,2h后给予120mg/kg NASAL一次性腹腔注射。成功建模后,在染毒的第1、3、7、14d分批处死动物。腹主动脉采血,37℃放置2h,取上清,常规方法取肺组织,分别测定血清和肺组织匀浆中总抗氧化能力(T-AOC)、过氧化氢酶(CAT)水平,超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活力、丙二醛(MDA)含量以及肺组织匀浆中羟脯氨酸(HYP)含量。利用凝胶阻滞迁移实验(EMSA)检测肺组织中NF-κB表达情况;肺组织TGF-β1,TNF-α蛋白含量采用rat TGF-β1,TNF-αkit检测。采用实时荧光定量PCR法(real-time PCR)检测凋亡基因caspase-3,Bcl-2,P53表达。
结果显示,80mg/kg PQ染毒后,PQ组SD大鼠血清GSH-Px活性在第1、3、7、14天均低于对照组,分别为对照组的82.69%、74.58%、78.91%和75.07%,差异均具有统计学意义(P＜0.05);SOD活力在第1、3、7、14天分别为对照组的85.27%、79.66%和74.45%,71.49%,差异具统计学意义(P＜0.05);T-AOC活力在第1、3、7、14天分别为对照组的71.87%(P＜0.05)、53.62%(P＜0.05)、62.19%(P＜0.05)和92.3%(P＞0.05);染毒组CAT活力在第1、3天下降,分别为对照组的42.5%(P＜0.05)及42.09%(P＜0.05),随后逐渐回升,与对照相比,差异无统计学意义;PQ染毒后MDA含量升高,分别是对照组的3.28、1.8l、2.16和2.67倍,且差异均有统计学意义(P＜0.05);120mg/kg水杨酸钠干预后血清中各项指标较染毒组有所改善,表现为GSH-Px在第1、3、7天较染毒组高,差异有统计学意义(P＜0.05);SOD活力在第1、3、7、14天分别为对照组的86.98%、93.26%、81.78%及78.96%,与对照相比差异均有统计学意义,第3、7天活力高于PQ组(P＜0.05);干预组的T-AOC,CAT活力在第1、3天分别为对照组的95.16%、64.73%、71.23%、87.3%,明显高于PQ组(P＜0.05);干预后MDA含量在第1、3、7、14天分别为对照组的2.11、0.98、1.72及1.46倍,与相应时点的PQ组相比,含量明显降低(P＜0.05)。肺组织匀浆中GSH-Px活力在染毒第1、3、7、14天均低于对照组(分别为对照的67.67%、44.54%、54.12%、33.87%);SOD活力在第1、3、7、14天低于对照组(分别为对照组的86.08%、80.85%、74.9%、71.26%);T-AOC、CAT活力在各个时点均低于相应时点的对照组,且差异具有统计学意义(P＜0.05);肺组织匀浆中HYP含量升高,在第7、14天分别为对照组的1.21倍和1.24倍(P＜0.05);120mg/kg水杨酸钠干预后肺组织所有时点上GSH-Px活力均较PQ组明显改善(P＜0.05);CAT活力在第1、3、7天较染毒组有所提高(P＜0.05)。80mg/kg PQ染毒后,大鼠肺组织中NF-κB含量上升,TGF-β1蛋白表达量分别为对照组的1.78、1.59、1.51和1.61倍(P＜0.05)、TNF-α蛋白表达量分别为相应时点对照组的1.38、1.41、1.73和1.67倍(P＜0.05);水杨酸钠干预后TGF-β1,TNF-α蛋白表达基本恢复至正常水平,与对照相比,差异无统计学意义(P＞0.05)。染毒后凋亡基因caspase-3、P53 mRNA表达上升,Bcl-2 mRNA降低(P＜0.05);NASAL干预组大鼠的caspase-3、P53mRNA表达较PQ组升高,Bcl-2 mRNA表达较PQ组下降(P＜0.05)。表明NASAL在一定程度上对抗了PQ造成的细胞凋亡。
另外,实验过程中单纯染毒组出现明显的肺损伤,病理特征为早期的肺出血、水肿、单核细胞浸润及炎症反应表现,中晚期表现为成纤维细胞增生,胶原纤维聚集。NASAL干预组动物肺脏也有充血,肿胀,出血等病理改变,但程度较PQ组轻微,质地较软,炎性细胞少,局部水肿轻微。由此可知,水杨酸钠能明显改善PQ所致大鼠的肺水肿。
综上所述,本研究条件下,120mg/kg NASAL对PQ所致的急性肺损伤的干预能不同程度的改善各项氧化酶指标,平衡凋亡基因的启动,减少炎性因子的释放,在一定程度上减轻了PQ引起的肺损伤。表明PQ可能通过上述途径引起肺损伤,但PQ的毒作用机制及干预药物的药理作用还有待进一步的研究。
Paraquat(PQ) is a non-selective contact herbicide,which is used word-widely for its high efficiency and characteristics of no residues detectable in the crops. Paraquat poisoning was particularly prevalent in the accidental or suicide.
It has been extensively demonstrated that the target organ of PQ is lung. However,the exact mechanism of its toxicity still remains unclear and there are no known pharmacological antagonists for its poisoning at present.The mechanism may be involved as follows:a variety of regulatory factors,oxidative stress and apoptosis induced by paraquat and/or its metabolites,after which becomes oxidative damage of lungs at the early stage and the persistent fibrosis with fibroblast proliferation and extracellular matrix.Previous studies have shown that the pulmonary damage at early stage may be the main cause for death.Sodium salicylate is an anti-inflammatory drug widely used in the clinical,however,studies in recent years suggested that high doses of the therapeutic effect of sodium salicylate may have potential therapeutic effects on PQ-induced toxic effects.Therefore,we determined the expression of TGF-β1,TNF-α,NF-κB,caspase-3,Bcl-2,P53 and some oxidative index in the rat model of paraquat-induced pulmonary damage and evaluated their roles in this specific process.Moreover,we aimed to investigate effects of sodium salicylate(NaSAL) on the pulmonary damage induced by paraquat and to observe its potential therapeutic effects so as to provide evidence for the treatment strategy of paraquat-induced lung damage.
We established rat poisoning model by intragastric administration of 80mg/kg PQ.72 male SD rats were randomly divided into 0.9%NaCl control group,PQ exposure group,PQ+NaSAL intervention group,24 rats in each group.
Control group were made orally in an injection volume of 0.5 mL/100 g of body weight,after 2h an injection of equivalent 0.9%NaCl were made intraperitoneally; PQ group were made 80mg/kg PQ orally,after 2h an injection of equivalent 0.9% NaCl were made intraperitoneally;PQ+NaSAL group were given an intraperitoneal injection of 120mg/kg NASAL after an orally administrating of 80mg/kg PQ.After exposure,animals were sacrificed in batches on days 1,3,7,14.After dislodged from abdominal aorta,the blood was placed in 37℃waterbath for 2h and the supernatant was taken away and retained in eppendorf tubes.Lung tissues were obtained with routine method.
Then the activities of total antioxidative capacity(T-AOC),catalase(CAT), superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),malondialdehyde (MDA) both in serum and lung homogenate of rats and the contents of hypertrophy (HYP) in lung homogenate were measured using qualified kits provided by Nanjing Institute of Bio-engineering.The level of NF-κB was assayed by electrophoresis mobility shift assay(EMSA),while the protein level of TGF-β1,TNF-αwere determined with Rat TGF-β1,TNF-αkits.And the mRNA of caspase-3,Bcl-2, P-53 was determined using real-time reverse transcription polymerase chain reaction (real-time RT PCR).
It has been found that the activities of SOD,GSH-Px,T-AOC,CAT in serum and lung homogenate were decreased with positive significance(P＜0.05) and MDA level was increased in both PQ group and PQ+NaSAL group compared with the control group.So was the HYP level(P＜0.05).However,the activities of SOD, GSH-Px,T-AOC,CAT in PQ+NaSAL group were markedly higher than that of PQ treated group,and still lower than that of the control group.MDA content was lower than that of the PQ group(P＜0.05),but still higher than that of the control group(P＜0.05).HYP in PQ+NaSAL group was lower than that of the PQ group but higher than that of the control group.After 80mg/kg PQ exposure,the rat lung tissue NF-κB content,TGF-β1 and TNF-αprotein expression increased remarkebly than that of the control group(P＜0.05);apoptosis-related gene such as caspase-3,P53 mRNA increased and Bcl-2 mRNA reduced evidently compared with the control group(P＜0.05).NF-κB content,TGF-β1 and TNF-αprotein showed a low expression than that of the PQ group(P＜0.05),however,There was no significant difference compared with the control one.Meanwhile,NaSAL withstand increasing of PQ-induced caspase-3,P53 mRNA and decreasing of Bcl-2 mRNA expression to a certain extent(P＜0.05).
In addition,the histological examination showed ultra-morphological changes such as alveolar edema,hemorrhage and inflammatory cell infiltration in the PQ group.Similar changes such as hyperemia,edema and hemorrhage were also found in the PQ+NaSAL group,but it was slighter than that of the PQ group.So,it can be seen that sodium salicylate can improve the PQ-induced pulmonary edema in rats evidently.
In summary,we found that NaSAL significantly improved PQ-induced pulmonary damage.These findings suggested that NaSAL may exert its therapeutic effects on paraquat-induced pulmonary damage via counteracting paraquat-induced oxidative stress in rat lung and by regulating the mRNA expression of apoptosis gene and decreasing inflammatory factor releasing.However,further studies are still needed to investigate and clarify the underlying mechanisms involved in this complicated process.
引文
[1]Haddad LM,Winchester JF.Clinical management of poisoning and drug overdose[J].New England Journal of Medicine,1983,309(14):864.
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