褪黑素对慢性阻塞性肺疾病大鼠肺部炎症和气道氧化应激的抑制作用
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摘要
目的:慢性阻塞性肺疾病(COPD)是一种具有气流受限特征的可预防和治疗的慢性疾病,发病机制复杂,治疗棘手,本研究旨在探讨褪黑素(MLT)对COPD大鼠模型肺部炎症和气道氧化应激的影响,以为其在COPD防治方面提供理论依据。
方法: 36只雄性Wistar大鼠随机分成对照组、COPD组、MLT组,采用熏烟加气管注入脂多糖(LPS)复制COPD大鼠模型,MLT组在造模前30min腹腔注入MLT。28d后气管切开测定肺功能,检测肺泡灌洗液(BALF)中白细胞计数及分类, BALF中一氧化氮(NO)、丙二醛(MDA)、总超氧化物歧化酶(T-SOD)、谷光甘肽过氧化物酶(GSH-PX), BALF和肺匀浆的髓过氧化物酶(MPO)、肿瘤坏死因子(TNF-α)、白细胞介素8(IL-8) ,光镜下观察病理形态。
结果:⑴MLT组BALF中白细胞总数、中性粒细胞比例较COPD组明显减低(分别为P < 0.01,P < 0.05),单核-巨噬细胞绝对计数下降,均与对照组无显著差异。⑵MLT组大鼠BALF中NO、MDA较COPD组明显减低(P < 0.05), T-SOD、GSH-PX较COPD组明显增高(P < 0.05)。⑶MLT组大鼠BALF和肺匀浆的MPO、TNF-α、IL-8含量均较COPD组显著降低(P < 0.05或P < 0.01)。⑷MLT组0.3s用力呼气容积(FEV0.3)、0.3s用力呼气容积/用力肺活量(FEV0.3/FVC)、峰流速(PEF)较COPD组均有增加,但两者之间无显著性差异(P > 0.05),同时仍较对照组减低(P < 0.05)。⑸COPD组支气管、肺实质病理改变具有特征性,MLT组病理损害减轻,但仍然与对照组有明显差异。
结论:对造模成功的COPD动物模型,同予MLT进行干预后大鼠比较发现,后者可以明显减少炎症细胞、炎症介质以及减轻氧化应激、增加抗氧化酶类的活性。提示MLT早期干预能够部分阻止COPD的进程。
Objective: Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. The pathogenesis of COPD is complex and it is difficult to treat. To investigate the effect of melatonin (MLT) on lung inflammation and airway oxidative stress in rats with COPD, we could find the theoretical evidence to prevent and manage COPD by MLT.
Methods: 36 male wistar rats were randomly divided into 3 groups as follows: control group, COPD group and MLT group. The COPD model was established by intratracheal lipopolysaccharide (LPS) and exposure to cigarette smoking for 28 days, the MLT group was given intraperitoneal injection of 10 mg/kg MLT 30 minutes before each cigarette challenge. After incision of trachea, the lung function was measured. Then the rats were lavaged, the total and different white blood cell counts of bronchial alveolar lavage fluid (BALF) were determined, nitric oxide (NO), malondialdehyde(MDA), total superoxide dismutase(T-SOD), glutathione superoxide (GSH-PX) in BALF were carry out respectively. Then, after the lung homogenates were obtained, we analyzed the content of myeloperoxidase (MPO), tumor necrosis factor (TNF-α), interleukin -8(IL-8) in BALF and homogenates. The pathological changes were observed with light microscope.
Results :(1) Significant decrease in total white blood cells and neutrophils in BALF was found in MLT group than these in COPD group (P<0.01, P<0.05, respectively), and the ratio of monocyt-macrophage was lower in MLT group. (2) NO and MDA in BALF of MLT group significantly decreased (P<0.05), T-SOD and GSH-PX in BALF of MLT group significantly increased (P<0.05), compared with those of COPD group. (3)The content of MPO, TNF-α, IL-8 in BALF and lung homogenates of MLT group remarkably decreased compared with those of COPD group (P<0.01 or P<0.05). (4) Forced expiratory volume in 0.3 second (FEV0.3), forced expiratory volume in 0.3 second /forced vital capacity (FEV0.3/FVC) and peak expiratory flow (PEF) in MLT group were higher than those in COPD group, but there were no obvious differences between these groups. (5) The model rats shared specific pathological features in bronchial walls and lung tissues, the pathological damages in MLT group were lessened but still abnormal.
Conclusions: We successfully replicated the COPD experimental models .Early intervention with MLT can partly inhibit proceeding of COPD by decreasing the cells and mediators of inflammation, airway oxidative stress and increasing activity of antioxidant.
方法: 36只雄性Wistar大鼠随机分成对照组、COPD组、MLT组,采用熏烟加气管注入脂多糖(LPS)复制COPD大鼠模型,MLT组在造模前30min腹腔注入MLT。28d后气管切开测定肺功能,检测肺泡灌洗液(BALF)中白细胞计数及分类, BALF中一氧化氮(NO)、丙二醛(MDA)、总超氧化物歧化酶(T-SOD)、谷光甘肽过氧化物酶(GSH-PX), BALF和肺匀浆的髓过氧化物酶(MPO)、肿瘤坏死因子(TNF-α)、白细胞介素8(IL-8) ,光镜下观察病理形态。
结果:⑴MLT组BALF中白细胞总数、中性粒细胞比例较COPD组明显减低(分别为P < 0.01,P < 0.05),单核-巨噬细胞绝对计数下降,均与对照组无显著差异。⑵MLT组大鼠BALF中NO、MDA较COPD组明显减低(P < 0.05), T-SOD、GSH-PX较COPD组明显增高(P < 0.05)。⑶MLT组大鼠BALF和肺匀浆的MPO、TNF-α、IL-8含量均较COPD组显著降低(P < 0.05或P < 0.01)。⑷MLT组0.3s用力呼气容积(FEV0.3)、0.3s用力呼气容积/用力肺活量(FEV0.3/FVC)、峰流速(PEF)较COPD组均有增加,但两者之间无显著性差异(P > 0.05),同时仍较对照组减低(P < 0.05)。⑸COPD组支气管、肺实质病理改变具有特征性,MLT组病理损害减轻,但仍然与对照组有明显差异。
结论:对造模成功的COPD动物模型,同予MLT进行干预后大鼠比较发现,后者可以明显减少炎症细胞、炎症介质以及减轻氧化应激、增加抗氧化酶类的活性。提示MLT早期干预能够部分阻止COPD的进程。
Objective: Chronic obstructive pulmonary disease (COPD) is a disease state characterized by airflow limitation that is not fully reversible. The pathogenesis of COPD is complex and it is difficult to treat. To investigate the effect of melatonin (MLT) on lung inflammation and airway oxidative stress in rats with COPD, we could find the theoretical evidence to prevent and manage COPD by MLT.
Methods: 36 male wistar rats were randomly divided into 3 groups as follows: control group, COPD group and MLT group. The COPD model was established by intratracheal lipopolysaccharide (LPS) and exposure to cigarette smoking for 28 days, the MLT group was given intraperitoneal injection of 10 mg/kg MLT 30 minutes before each cigarette challenge. After incision of trachea, the lung function was measured. Then the rats were lavaged, the total and different white blood cell counts of bronchial alveolar lavage fluid (BALF) were determined, nitric oxide (NO), malondialdehyde(MDA), total superoxide dismutase(T-SOD), glutathione superoxide (GSH-PX) in BALF were carry out respectively. Then, after the lung homogenates were obtained, we analyzed the content of myeloperoxidase (MPO), tumor necrosis factor (TNF-α), interleukin -8(IL-8) in BALF and homogenates. The pathological changes were observed with light microscope.
Results :(1) Significant decrease in total white blood cells and neutrophils in BALF was found in MLT group than these in COPD group (P<0.01, P<0.05, respectively), and the ratio of monocyt-macrophage was lower in MLT group. (2) NO and MDA in BALF of MLT group significantly decreased (P<0.05), T-SOD and GSH-PX in BALF of MLT group significantly increased (P<0.05), compared with those of COPD group. (3)The content of MPO, TNF-α, IL-8 in BALF and lung homogenates of MLT group remarkably decreased compared with those of COPD group (P<0.01 or P<0.05). (4) Forced expiratory volume in 0.3 second (FEV0.3), forced expiratory volume in 0.3 second /forced vital capacity (FEV0.3/FVC) and peak expiratory flow (PEF) in MLT group were higher than those in COPD group, but there were no obvious differences between these groups. (5) The model rats shared specific pathological features in bronchial walls and lung tissues, the pathological damages in MLT group were lessened but still abnormal.
Conclusions: We successfully replicated the COPD experimental models .Early intervention with MLT can partly inhibit proceeding of COPD by decreasing the cells and mediators of inflammation, airway oxidative stress and increasing activity of antioxidant.
引文
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[5] 宋一平,崔德健,茅培英.COPD 大鼠模型的建立及药物干预的影响[J].中华内科杂志,2000,39(8):556-557.
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[7] Fehrenbach H.Animal models of chronic obstructive pulmonary disease: some critical remarkes [J].Pathobiology,2002-2003,70(3):277-283.
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[13] Calikoglu M,Unlu A,Tamer L,et a1.The levels of serum vitamin C,malonyldialdehyde and erythrocyte reduced glutathione in chronic obstructive pulmonary disease and in healthy smokers[J].Clin Chem Lab Med,2002,40 (10):126-130.
[14] Macnee W .Oxidants/ antioxidants and chronic obstructive pulmonary disease :pathogenesis to therapy.Novartis Found Syru p,2001,234(3):169-188.
[15] Macnee W ,Donaldson K.Exacerbations of COPD :environmental mechanisms. Chest,2000,117(5 Suppl 2):390s-397s.
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[24] Silva SO,Rodrigues MR,Ximenes VF,et a1.Neutrophils as a specific target for melatonin and kynuramines:effects on cytokine release [J].J Neuroimmunol,2004,156(1-2):146-152.
[25] Li JH,Yu JP,Yu HG,Xu XM,et a1.Melatonin reduces inflammatory injury through inhibiting NF-kappa B activation in rats with colitis[J].Mediators lnflamm,2005,31(4):l85-193.
[26] ]周莉,钱朝霞,李锋,等. 褪黑素对支气管哮喘小鼠胶原沉积及基质金属蛋白酶9 和基质金属蛋白酶组织抑制剂 1mRNA 与蛋白表达的动态调节[J].中华结核和呼吸杂志,2007,30(7):527-532.
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[2] 中华医学会呼吸病学分会慢性阻塞性肺疾病学组.慢性阻塞性肺疾病诊治指南(2007 年修订版)[J].中华内科杂志,2007,46(1):254-261.
[3] Kühlwein E, Irwin M.Melatonin modulation of lymphocyte proliferation and Th1/Th2 cytokine expression [J] .Neuroimmunol,2001,117(1-2):51-57.
[4] 王亚亭,陈胜利,徐叔云.褪黑素对哮喘大鼠核因子出表达的影响及抗炎作用[J].中华儿科杂志,2004,42(2):94-97.
[5] 宋一平,崔德健,茅培英.COPD 大鼠模型的建立及药物干预的影响[J].中华内科杂志,2000,39(8):556-557.
[6] 郑鸿翱.建立慢性阻塞性肺疾病动物模型方法的研究进展.中国实验动物学报,2003,11(4):249-252.
[7] Fehrenbach H.Animal models of chronic obstructive pulmonary disease: some critical remarkes [J].Pathobiology,2002-2003,70(3):277-283.
[8] Barnes PJ,Shapiro SD,Pauwels RA.Chronic obstructive pulmonary disease;molecular and cellular mechanisms[J].Eur Respir J,2003,22 (4):672-681.
[9] Wymann MP.The onset of the respiratory burst in human neutrophils.Real-time studies of H20Z formation revealarapidagonist- induced transduction process[J].J BiolChem,1987,262(25):12048-12053.
[10] Christman JW, Sadikot RT, Blackwell TS. The role of nuclear factor-kappaB in pulmonary diseases [J].Chest, 2000, 17(5):1482-1487.
[11] Wang T, Zhang X, Li JJ. The role of NF-kappaB in the regulation of cell stress responses [J].Int Immunopharmacol, 2002, 2(11):1509-1520.
[12] Agarwal S, Long P, Seyedain A, et al.Acentral role for the nuclear factor-kappaB pathway in anti-inflammatory and proinflammatory actions of mechanical strain [J]. FASEBJ, 2003, 17(8):899-901.
[13] Calikoglu M,Unlu A,Tamer L,et a1.The levels of serum vitamin C,malonyldialdehyde and erythrocyte reduced glutathione in chronic obstructive pulmonary disease and in healthy smokers[J].Clin Chem Lab Med,2002,40 (10):126-130.
[14] Macnee W .Oxidants/ antioxidants and chronic obstructive pulmonary disease :pathogenesis to therapy.Novartis Found Syru p,2001,234(3):169-188.
[15] Macnee W ,Donaldson K.Exacerbations of COPD :environmental mechanisms. Chest,2000,117(5 Suppl 2):390s-397s.
[16] Rahman I,Mulier B,Gilmour PS,et a1.Oxidant-mediated lung epithelial cell tolerance:the role of intracellular glutathione and nuclear factor-kappaB.Biochem pharma,2001.62(6):787-794.
[17] Barnes PJ. Chronic obstructive pulmonary disease [J] .N Engl J Med, 2000, 343(4):269-280.
[18] Daga MK, Chhabra R, Sharma B, et al. Effects of exogenous vitamin E supplementation on the levels of oxidants and antioxidants in chronic obstructive pulmonary disease [J] .J-Biosci, 2003 , 28(1): 7-11.
[19] Hanta I, Kocabas A, Canacankatan. Oxidant-antioxidant balance in patients with COPD [J]. Lung, 2006, 184(2): 51-55.
[20] Tan DX,Chen LD,Poeggeler B,et al. Melatonin: a potent,endogenous hydroxyl radical scavenger [J] . Endocrinol J,1993, 1(1):57-60.
[21] Melchiorri D,Reiter RJ, Attia AM, et al.Potent protective effect of melatonin On in vivo paraquat-induced oxidative damage [J] .Life sci, 1994,56(1):83-89.
[22] Reiter RJ,Calvo JR。Karbownik M,et a1.Melatonin and its relation to the immune system and inflammation.Ann N Y Acad Sci.2000,32(2):56-61
[23] Seyithan T,Harun U,Mahfuz E,et a1.Effect of melatoninon lipid peroxidation,glutathione and glutathione-dependent enzyme activities in experimental otitis media with effusion in guinea pigs [J].Journal of Pineal Research,2005,39(3):283-286.
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