肺纤灵Ⅱ号对博莱霉素致肺纤维化动物模型的干预作用及其机制研究
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摘要
目的:观察肺纤灵Ⅱ号(FXL-Ⅱ)对博莱霉素(BLM)致肺纤维化动物模型的干预作用,并探讨其抗肺纤维化作用机制。
方法:昆明种小鼠及SD大鼠分别随机分为正常对照组、模型组、醋酸泼尼松组与肺纤灵Ⅱ号大、中、小剂量组。通过气管内滴注博莱霉素(5mg/kg)复制肺纤维化动物模型。造模第2 d起,各治疗组给予相应药物灌服治疗,正常对照组及模型组给予相应体积的5%羧甲基纤维素钠(CMC-Na)。各实验组动物于给药后28 d处死,取肺组织称取肺湿重,计算肺系数:肺湿重(mg)/体重(g);进行HE、Masson染色及透射电镜,观察其病理形态,并参照Szaopiel[1]等方法对肺泡炎和肺纤维化程度进行评分;应用免疫组织化学技术,检测转化生长因子β1(TGF-β1 )、Smad2/3、Ⅲ型胶原蛋白(Col-Ⅲ)、核因子κB(NF-κB)、α平滑肌动蛋白(α-SMA)、小窝蛋白-1(Cav-1)、骨桥蛋白(OPN)在肺组织中的表达;测定肺组织及血清中羟脯氨酸(HYP)、超氧化物歧化酶(SOD)、丙二醛(MDA)、总抗氧化能力(T-AOC)、一氧化氮合酶(NOS)、琥珀酸脱氢酶(SDH)、抑制羟自由基(OH-·)能力的水平。
结果:(1) FXL-Ⅱ可不同程度抵抗BLM所致小鼠、大鼠的体重减轻和降低肺系数;(2)光镜及透射电镜观察结果显示,各治疗组小鼠、大鼠肺组织肺泡炎、肺纤维化程度及超微结构的改变均明显减轻(P<0.05,P<0.01);(3)免疫组化结果显示,FXL-Ⅱ可明显抑制肺组织中TGF-β1、Smad2/3、Col-Ⅲ、NF-κB、α-SMA、OPN蛋白的表达,上调Cav-1蛋白的表达(P<0.05,P<0.01);(4)FXL-Ⅱ可显著降低肺纤维化动物模型肺组织HYP的含量(P<0.05,P<0.01, P<0.001);(5)肺组织及血清生化指标测定结果显示,FXL-Ⅱ可显著增强SOD,SDH活性(P<0.05,P<0.01, P<0.001),降低MDA含量(P<0.05,P<0.01),提高T-AOC和抑制OH-·能力(P<0.05,P<0.01),减弱NOS活性(P<0.05,P<0.01, P<0.001)。
结论:肺纤灵Ⅱ号对博莱霉素所致小鼠、大鼠肺纤维化有一定的干预作用,其机制可能为抗炎、抗氧化、清除自由基、保护线粒体功能、抗成纤维细胞增殖、抑制TGF-β/Smads信号转导通路、抑制肺组织Col-Ⅲ沉积、抑制肺纤维化正相关蛋白NF-κB、α-SMA、OPN的表达及上调肺纤维化负相关蛋白Cav-1的表达有关。
Objective:To investigate the effects of Fei-Xian-LingⅡon pulmonary fibrosis with animal model induced by bleomycin and its mechanisms.
Methods: Kunming strian mice and Sprague-Dawley rats were randomly divided into control group,model group,prednisolone group and FXL-Ⅱhigh-dose,middle- dose,low-dose group.Models were reproduced by intratracheal injection of bleomycin. On the second day,the animals in each curing group were orally administrated corresponding dose of FXL-Ⅱ,control group and model group were orally administra -ted corresponding dose of CMC-Na. After continully administrated of 28 d, models in each group were sacrificed,and lungs were havested for investigating of pathomorphological changes by HE staining,Masson staining and electron microscope.The extent of plumonary alveolitis and fibrosis were evaluated by Szaopiel’s method; the level of SOD,MDA,T-AOC,NOS,SDH,OH-·,HYP in serum and lung tissue were determinated by biochemical analysis,expression of TGF-β1,Smad2/3, Col-Ⅲ,NF-κB,α-SMA, Cav-1,OPN protein in lung tissue were detected by immunohistochemical methods.
Results: (1)FXL-Ⅱcould inhibit body weight loss in the animal models induced by bleomycin and reduce lung index in some extent;(2) FXL-Ⅱcould decrease the extent of alveolitis, fibrosis and ultrastructural injury(P<0.05,P<0.01);(3) FXL-Ⅱcould obviously down-regulate the expression of TGF-β1,Smad2/3,NF-κB,Col-Ⅲ,α-SMA,OPN protein in lung tissue(P<0.05,P<0.01),but up-regulate the expression of Caveolin-1;(4) FXL-Ⅱcould dramatically decrease the content of HYP in the lung tissue(P<0.05,P<0.01, P<0.001);(5) Biochemical indicator results displayed that FXL-Ⅱcould significantly enhance the activity of SOD and SDH(P<0.05,P<0.01, P<0.001),reduce the content of MDA(P<0.05,P<0.01), improve the capacity of T-AOC and inhibiting hydroxy radical(P<0.05,P<0.01), attenuate the activity of NOS(P<0.05,P<0.01, P<0.001).
Conclusion:FXL-Ⅱmight have some disturbing effects on pulmonary fibrosis induced by bleomycin,and the mechanisms might be associated with its effects of anti-inflammatory, anti-oxidation, scavenging free radical, mitochondrial protection, anti-fibroblastic proliferation, inhibiting TGF-β/ Smads signaling pathway, inhibiting depositing of Col-Ⅲin lung tissue,down-regulating the expression of NF-κB, Col-Ⅲ,α-SMA,OPN protein and up- regulating the expression of Caveolin-1 protein in lung tissue.
方法:昆明种小鼠及SD大鼠分别随机分为正常对照组、模型组、醋酸泼尼松组与肺纤灵Ⅱ号大、中、小剂量组。通过气管内滴注博莱霉素(5mg/kg)复制肺纤维化动物模型。造模第2 d起,各治疗组给予相应药物灌服治疗,正常对照组及模型组给予相应体积的5%羧甲基纤维素钠(CMC-Na)。各实验组动物于给药后28 d处死,取肺组织称取肺湿重,计算肺系数:肺湿重(mg)/体重(g);进行HE、Masson染色及透射电镜,观察其病理形态,并参照Szaopiel[1]等方法对肺泡炎和肺纤维化程度进行评分;应用免疫组织化学技术,检测转化生长因子β1(TGF-β1 )、Smad2/3、Ⅲ型胶原蛋白(Col-Ⅲ)、核因子κB(NF-κB)、α平滑肌动蛋白(α-SMA)、小窝蛋白-1(Cav-1)、骨桥蛋白(OPN)在肺组织中的表达;测定肺组织及血清中羟脯氨酸(HYP)、超氧化物歧化酶(SOD)、丙二醛(MDA)、总抗氧化能力(T-AOC)、一氧化氮合酶(NOS)、琥珀酸脱氢酶(SDH)、抑制羟自由基(OH-·)能力的水平。
结果:(1) FXL-Ⅱ可不同程度抵抗BLM所致小鼠、大鼠的体重减轻和降低肺系数;(2)光镜及透射电镜观察结果显示,各治疗组小鼠、大鼠肺组织肺泡炎、肺纤维化程度及超微结构的改变均明显减轻(P<0.05,P<0.01);(3)免疫组化结果显示,FXL-Ⅱ可明显抑制肺组织中TGF-β1、Smad2/3、Col-Ⅲ、NF-κB、α-SMA、OPN蛋白的表达,上调Cav-1蛋白的表达(P<0.05,P<0.01);(4)FXL-Ⅱ可显著降低肺纤维化动物模型肺组织HYP的含量(P<0.05,P<0.01, P<0.001);(5)肺组织及血清生化指标测定结果显示,FXL-Ⅱ可显著增强SOD,SDH活性(P<0.05,P<0.01, P<0.001),降低MDA含量(P<0.05,P<0.01),提高T-AOC和抑制OH-·能力(P<0.05,P<0.01),减弱NOS活性(P<0.05,P<0.01, P<0.001)。
结论:肺纤灵Ⅱ号对博莱霉素所致小鼠、大鼠肺纤维化有一定的干预作用,其机制可能为抗炎、抗氧化、清除自由基、保护线粒体功能、抗成纤维细胞增殖、抑制TGF-β/Smads信号转导通路、抑制肺组织Col-Ⅲ沉积、抑制肺纤维化正相关蛋白NF-κB、α-SMA、OPN的表达及上调肺纤维化负相关蛋白Cav-1的表达有关。
Objective:To investigate the effects of Fei-Xian-LingⅡon pulmonary fibrosis with animal model induced by bleomycin and its mechanisms.
Methods: Kunming strian mice and Sprague-Dawley rats were randomly divided into control group,model group,prednisolone group and FXL-Ⅱhigh-dose,middle- dose,low-dose group.Models were reproduced by intratracheal injection of bleomycin. On the second day,the animals in each curing group were orally administrated corresponding dose of FXL-Ⅱ,control group and model group were orally administra -ted corresponding dose of CMC-Na. After continully administrated of 28 d, models in each group were sacrificed,and lungs were havested for investigating of pathomorphological changes by HE staining,Masson staining and electron microscope.The extent of plumonary alveolitis and fibrosis were evaluated by Szaopiel’s method; the level of SOD,MDA,T-AOC,NOS,SDH,OH-·,HYP in serum and lung tissue were determinated by biochemical analysis,expression of TGF-β1,Smad2/3, Col-Ⅲ,NF-κB,α-SMA, Cav-1,OPN protein in lung tissue were detected by immunohistochemical methods.
Results: (1)FXL-Ⅱcould inhibit body weight loss in the animal models induced by bleomycin and reduce lung index in some extent;(2) FXL-Ⅱcould decrease the extent of alveolitis, fibrosis and ultrastructural injury(P<0.05,P<0.01);(3) FXL-Ⅱcould obviously down-regulate the expression of TGF-β1,Smad2/3,NF-κB,Col-Ⅲ,α-SMA,OPN protein in lung tissue(P<0.05,P<0.01),but up-regulate the expression of Caveolin-1;(4) FXL-Ⅱcould dramatically decrease the content of HYP in the lung tissue(P<0.05,P<0.01, P<0.001);(5) Biochemical indicator results displayed that FXL-Ⅱcould significantly enhance the activity of SOD and SDH(P<0.05,P<0.01, P<0.001),reduce the content of MDA(P<0.05,P<0.01), improve the capacity of T-AOC and inhibiting hydroxy radical(P<0.05,P<0.01), attenuate the activity of NOS(P<0.05,P<0.01, P<0.001).
Conclusion:FXL-Ⅱmight have some disturbing effects on pulmonary fibrosis induced by bleomycin,and the mechanisms might be associated with its effects of anti-inflammatory, anti-oxidation, scavenging free radical, mitochondrial protection, anti-fibroblastic proliferation, inhibiting TGF-β/ Smads signaling pathway, inhibiting depositing of Col-Ⅲin lung tissue,down-regulating the expression of NF-κB, Col-Ⅲ,α-SMA,OPN protein and up- regulating the expression of Caveolin-1 protein in lung tissue.
引文
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[1] Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus[J]. Chest, 2007 ,132(4):1311-21.
[2] Pardo A, Selman M, Kaminski N. Approaching the degradome in idiopathic pulmonary fibrosis[J]. Int J Biochem Cell Biol. 2008,40(6-7):1141-55.
[3] Oikonomou N, Thanasopoulou A, Tzouvelekis A, et al.Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis[J]. Thorax, 2009 ,64(6):467-75.
[4] Khurana S, George SP. Regulation of cell structure and function by actin-binding proteins: villin's perspective[J]. FEBS Lett, 2008, 582(14):2128-39.
[5] Kwiatkowski DJ. Functions of gelsolin: motility, signaling, apoptosis, cancer[J]. Curr Opin Cell Biol,1999,11(1):103-8.
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[1] Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus[J]. Chest, 2007 ,132(4):1311-21.
[2] Pardo A, Selman M, Kaminski N. Approaching the degradome in idiopathic pulmonary fibrosis[J]. Int J Biochem Cell Biol. 2008,40(6-7):1141-55.
[3] Oikonomou N, Thanasopoulou A, Tzouvelekis A, et al.Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis[J]. Thorax, 2009 ,64(6):467-75.
[4] Khurana S, George SP. Regulation of cell structure and function by actin-binding proteins: villin's perspective[J]. FEBS Lett, 2008, 582(14):2128-39.
[5] Kwiatkowski DJ. Functions of gelsolin: motility, signaling, apoptosis, cancer[J]. Curr Opin Cell Biol,1999,11(1):103-8.
[6] Lueck A, Brown D, Kwiatkowski DJ. The actin-binding proteins·adseverin and gelsolin are both highly expressed but differentiallylocalized in kidney and intestine[J]. J Cell Sci, 1998,111 ( Pt 24):3633-43.
[7] Hubert T, Van Impe K, Vandekerckhove J, et al.The F-actin filament capping protein CapG is a bona fide nucleolar protein[J]. Biochem Biophys Res Commun. 2008,377(2):699-704.
[8] Marks PW, Arai M, Bandura JL, et al.Advillin (p92): a new member of the gelsolin/villin family of actin regulatory proteins[J]. J Cell Sci,1998,111(Pt 15):2129-36.
[9] Wang XZ, Kuroda M, Sok J,et al. Identification of novel stress-induced genes downstream of chop[J]. EMBO J,1998,17(13):3619-30.
[10] Pestonjamasp KN, Pope RK, Wulfkuhle JD, et al.Supervillin (p205): A novel membrane-associated, F-actin-binding protein in the villin/gelsolin superfamily[J]. J Cell Biol, 1997,139(5):1255-69.
[11] Silacci P, Mazzolai L, Gauci C, et al.Gelsolin superfamily proteins: key regulators of cellular functions[J]. Cell Mol Life Sci, 2004,61(19-20):2614-23.
[12] Kwiatkowski DJ, Stossel TP, Orkin SH, et al. Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain[J]. Nature,1986, 323(6087):455-8.
[13] Kwiatkowski DJ, Mehl R, Izumo S, et al. Muscle is the major source of plasma gelsolin[J]. J Biol Chem, 1988, 263(17):8239-43.
[14] Kwiatkowski DJ, Mehl R, Yin HL.Genomic organization and biosynthesis of secreted and cytoplasmic forms of gelsolin[J]. J Cell Biol, 1988, 106(2):375-84.
[15] Osborn TM, Verdrengh M, Stossel TP, et al.Decreased levels of the gelsolin plasma isoform in patients with rheumatoid arthritis[J]. Arthritis Res Ther, 2008,10(5):R117.
[16]史伟峰,陈同钰,鲁常青等.Gelsolin分子在乳腺癌组织中表达的研究[J].《肿瘤》,2002,22(4):289-93.
[17] Bryan J.Gelsolin has three actin-binding sites[J]. J. Cell Biol,1988,106(5): 1553-62.
[18] Ashish,Paine MS,Perryman PB,et al.Global structure changes associated with Ca2+ activation of full-length human plasma gelsolin[J].J Bio Chem,2007,282(35):25884-92.
[19] Yin HL.Gelsolin: calcium- and polyphosphoinositide-regulated actin-modulating protein[J].Bioessays,1987,7(4):176-9.
[20] Oikonomou N, Thanasopoulou A, Tzouvelekis A, et al.Gelsolin expression is necessary for the development of modelled pulmonary inflammation and fibrosis[J]. Thorax, 2009 ,64(6):467-75.
[21]郭海燕.特发性肺纤维化发病机制研究进展[J].《实用医药杂志(山东)》,2006,23(9):1114-6.
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[23] Wilson MS, Wynn TA.Pulmonary fibrosis: pathogenesis, etiology and regulation[J]. Mucosal Immunol,2009,2(2):103-21.
[24] Erukhimov JA, Tang ZL, Johnson BA,et al.Actincontaining sera from patients with adult respiratory distress syndrome are toxic to sheep pulmonary endothelial cells[J]. Am J Respir Crit Care Med, 2000, 162(1):288-94.
[25] Lee PS, Waxman AB, Cotich KL, et al.Plasma gelsolin is a marker and therapeutic agent in animal sepsis[J]. Crit Care Med, 2007,35(3):849-55.
[26] Osborn TM, Verdrengh M, Stossel TP, et al.Decreased levels of the gelsolin plasma isoform in patients with rheumatoid arthritis[J]. Arthritis Res Ther,2008,10(5):R117.
[27] DiNubile MJ. Plasma gelsolin as a biomarker of inflammation[J]. Arthritis Res Ther,2008,10(6):124.
[28] Kopecki Z, Arkell R, Powell BC, et al.Flightless I regulates hemidesmosome formation and integrin-mediated cellular adhesion and migration during wound repair[J]. J Invest Dermatol,2009,129(8):2031-45.
[29] Sun H., Lin K. ,Yin H. L. Gelsolin modulates phospholipase C activity in vivo through phospholipid binding[J]. J Cell Biol,1997, 138(4): 811–20.
[30] Cunningham CC, Stossel TP, Kwiatkowski DJ. Enhanced motility in NIH 3T3 fibroblasts that overexpress gelsolin[J]. Science,1991,251(4998):1233-6.
[31] Witke W, Sharpe AH, Hartwig JH, Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin[J]. Cell, 1995,81(1):41-51.
[32] Sun H Q, Kwiatkowska K, Wooten D C,et al. Effects of CapG overexpression onagonist-induced motility and second messenger generation[J]. J Cell Biol,1995,129(1): 147–156.
[33] Plataki M, Koutsopoulos AV, Darivianaki K, Expression of Apoptotic and Antiapoptotic Markers in Epithelial Cells in Idiopathic Pulmonary Fibrosis[J]. Chest, 2005,127(1):266-74.
[34] Falet H, Hoffmeister KM, Neujahr R,et al. Importance of free actin filament barbed ends for Arp2/3 complex function in platelets and fibroblasts[J]. Proc Natl Acad Sci U S A, 2002,99(26):16782-7.
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