PPARγ和MMP-9在慢性阻塞性肺病肺血管内皮细胞的表达及意义
|
摘要
目的:通过对慢性阻塞性肺疾病(COPD)患者肺组织标本中肺血管内皮细胞过氧化物酶体增殖激活受体γ(peroxisome proliferators activated receptor gamma,PPARγ)和金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)表达的研究,探讨PPARγ、MMP-9在慢性阻塞性肺疾病肺血管炎症和肺血管重塑中的作用。
方法:收集在我院胸外科住院,需要手术治疗且有吸烟史的男性鳞癌患者的临床资料及正常肺组织。按其肺功能结果将30例病人分成二组,对照组:(肺功能正常组);COPD组:(COPD稳定期组),每组15例。均于术前行肺功能检查和心脏超声检查根据三尖瓣反流压差估测肺动脉收缩压(PASP),记录吸烟指数,入选患者无其他肺部疾病及其他系统慢性病变,取其肺叶切除后无癌细胞浸润的外周肺组织,行苏木精一伊红(HE)染色,光镜下观察肺组织基本结构,并行维多利亚蓝+立春红S染色,计算肺腺泡内肌化动脉、部分肌化动脉、非肌化动脉数目,图像分析观察及测定肺小动脉管壁面积/血管总面积、管腔面积/血管总面积、内膜面积/血管总面积及血管旁胶原纤维面积。应用免疫组织化学方法检测肺血管内皮细胞PPARγ、MMP-9表达,并进行相关分析。
结果:1)正常的肺血管内皮细胞表达PPARγ,COPD组肺血管内皮细胞所含PPARγ的阳性标记物百分比(2.65%±0.89%)低于对照组(12.28%±4.23%)(P<0.01),所含MMP-9的阳性标记物百分比(38.53%±11.73%)高于对照组(12.83%±3.89%)。2)COPD组与对照组比较,肺功能明显下降,符合COPD诊断标准。3)肺腺泡内动脉病理图像分析:与对照组比较,COPD组病人肺小动脉管壁充血水肿,炎性细胞浸润增多,管腔面积减小,内膜面积、管壁面积与血管总面积之比值增大,血管旁胶原纤维面积增加。4)相关分析:肺血管内皮细胞PPARγ表达与MMP-9表达呈负相关(r=-0.85,P<0.01),与炎性细胞及肺小动脉肌化动脉比例、部分肌化动脉比例、血管旁胶原纤维面积成负相关(r分别=-0.604、-0.759、-0.485、-0.86,P值均<0.01);MMP-9表达与炎性细胞及肺小动脉肌化动脉比例、部分肌化动脉比例、血管旁胶原纤维面积成正相关(r分别=0.524、0.961、0.574、0.954,P值均<0.01);血管管壁面积和血管旁胶原纤维面积呈正相关(r=0.878,P<0.01);所有吸烟者的吸烟指数与肺小动脉肌化动脉比例、部分肌化动脉比例成正相关(r分别=0.889、0.764,P值均<0.01)。
结论:吸烟者和慢性阻塞性肺病患者均存在不同程度的肺血管炎症反应和肺血管重塑,在此过程中,MMP-9促进炎症反应,参与肺血管重塑过程,而PPARγ改善炎症反应,发挥抗重塑的作用。
Objective:In order to investigate the effect of peroxisome proliferators activated receptor gamma and matrix metalloproteinase-9 in pulmonary vascular inflammation and remodeling in patients with chronic obstructive pulmonary disease(COPD) by detecting the expression of PPARγand MMP-9 of pulmonary vascular endothelial cells.
Methods:Lung specimens were collected from the male patients who with lung carcinoma and smoking history and need to be operated in thoracic surgery,30 patients were divided into 2 groups, control group:patients with normal pulmonary function(non-COPD group) and patients with COPD (COPD group),each of 15 cases,matched with age.Air flow obstruction was determined by pulmonary function test and pulmonary artery pressure were examined by continuous wave Doppler echocardiographic measurement of the tricuspid regurgitant jet,and the smoking index were recorded in all patients before the operations.The remodeling of pulmonary artery remodeling was observed with HE staining under microscope and triple strains,lumen area,arteries walls,intimal area,muscular arteries,partial muscular arteries,non partial muscular arteries were measured,the expression of PPARγand MMP-9 of pulmonary vascular endothelial cells were measured by means of immunohisto-chemistry,analysis were made.
Results:1) Normal pulmonary vascular endothelial cells express PPARγ,the expression of PPARγin control group(12.28%±4.23%) was higher than that in COPD group(2.65%±0.89%)(P <0.01 ),and the expression of MMP-9 in COPD group(38.53%±11.73%)was higher than that in control group(12.83%±3.89%).2) Pulmonary function in COPD group drops compared with control group.3) Characteristics of intra-acinar pulmonary muscular arteries:Compared with control group, arteries walls of COPD group congested and swelled,inflammation cells increased,the thickness of intimal layer、walls of intra-acinar pulmonary muscular arteries was significantly higher,the area of its lumen was narrow and the proportion of their muscular arteries was higher,the area of collagen fibrils was increased.4) Correlation analysis:An negative correlations were showed with the expression of PPARγand MMP-9(r = -0.85,p<0.01 ),and inflammation cells,the pulmonary artery of the artery muscle ratio,the area of collagen fibrils,negative correlation was showed(r=-0.604、-0.759、-0.485、-0.862,P< 0.01);An positive correlations were showed in the expression of MMP-9 and inflammation cells(r=0.524,P<0.01 ),an positive correlation was showed with the pulmonary artery of the artery muscle ratio,the area of collagen fibrils,(r= 0.961、0.574、0.954,P<0.01);the artery wall area and the area of collagen fibrils showed positive correlations(r = 0.878,p< 0.01).an positive correlation was showed with the smoking index and the ratio of muscular arteries,partial muscular arteries,the area of collagen flbrils(r=0.889、0.764,P<0.01).
Conclusion:Patients with smoking and COPD have pulmonary vascular inflammation and remodeling,MMP-9 of pulmonary vascular endothelial cells was involved in the inflammation and remodeling process.,but PPARγwas involved in the anti-inflammation and anti-remodeling process.
方法:收集在我院胸外科住院,需要手术治疗且有吸烟史的男性鳞癌患者的临床资料及正常肺组织。按其肺功能结果将30例病人分成二组,对照组:(肺功能正常组);COPD组:(COPD稳定期组),每组15例。均于术前行肺功能检查和心脏超声检查根据三尖瓣反流压差估测肺动脉收缩压(PASP),记录吸烟指数,入选患者无其他肺部疾病及其他系统慢性病变,取其肺叶切除后无癌细胞浸润的外周肺组织,行苏木精一伊红(HE)染色,光镜下观察肺组织基本结构,并行维多利亚蓝+立春红S染色,计算肺腺泡内肌化动脉、部分肌化动脉、非肌化动脉数目,图像分析观察及测定肺小动脉管壁面积/血管总面积、管腔面积/血管总面积、内膜面积/血管总面积及血管旁胶原纤维面积。应用免疫组织化学方法检测肺血管内皮细胞PPARγ、MMP-9表达,并进行相关分析。
结果:1)正常的肺血管内皮细胞表达PPARγ,COPD组肺血管内皮细胞所含PPARγ的阳性标记物百分比(2.65%±0.89%)低于对照组(12.28%±4.23%)(P<0.01),所含MMP-9的阳性标记物百分比(38.53%±11.73%)高于对照组(12.83%±3.89%)。2)COPD组与对照组比较,肺功能明显下降,符合COPD诊断标准。3)肺腺泡内动脉病理图像分析:与对照组比较,COPD组病人肺小动脉管壁充血水肿,炎性细胞浸润增多,管腔面积减小,内膜面积、管壁面积与血管总面积之比值增大,血管旁胶原纤维面积增加。4)相关分析:肺血管内皮细胞PPARγ表达与MMP-9表达呈负相关(r=-0.85,P<0.01),与炎性细胞及肺小动脉肌化动脉比例、部分肌化动脉比例、血管旁胶原纤维面积成负相关(r分别=-0.604、-0.759、-0.485、-0.86,P值均<0.01);MMP-9表达与炎性细胞及肺小动脉肌化动脉比例、部分肌化动脉比例、血管旁胶原纤维面积成正相关(r分别=0.524、0.961、0.574、0.954,P值均<0.01);血管管壁面积和血管旁胶原纤维面积呈正相关(r=0.878,P<0.01);所有吸烟者的吸烟指数与肺小动脉肌化动脉比例、部分肌化动脉比例成正相关(r分别=0.889、0.764,P值均<0.01)。
结论:吸烟者和慢性阻塞性肺病患者均存在不同程度的肺血管炎症反应和肺血管重塑,在此过程中,MMP-9促进炎症反应,参与肺血管重塑过程,而PPARγ改善炎症反应,发挥抗重塑的作用。
Objective:In order to investigate the effect of peroxisome proliferators activated receptor gamma and matrix metalloproteinase-9 in pulmonary vascular inflammation and remodeling in patients with chronic obstructive pulmonary disease(COPD) by detecting the expression of PPARγand MMP-9 of pulmonary vascular endothelial cells.
Methods:Lung specimens were collected from the male patients who with lung carcinoma and smoking history and need to be operated in thoracic surgery,30 patients were divided into 2 groups, control group:patients with normal pulmonary function(non-COPD group) and patients with COPD (COPD group),each of 15 cases,matched with age.Air flow obstruction was determined by pulmonary function test and pulmonary artery pressure were examined by continuous wave Doppler echocardiographic measurement of the tricuspid regurgitant jet,and the smoking index were recorded in all patients before the operations.The remodeling of pulmonary artery remodeling was observed with HE staining under microscope and triple strains,lumen area,arteries walls,intimal area,muscular arteries,partial muscular arteries,non partial muscular arteries were measured,the expression of PPARγand MMP-9 of pulmonary vascular endothelial cells were measured by means of immunohisto-chemistry,analysis were made.
Results:1) Normal pulmonary vascular endothelial cells express PPARγ,the expression of PPARγin control group(12.28%±4.23%) was higher than that in COPD group(2.65%±0.89%)(P <0.01 ),and the expression of MMP-9 in COPD group(38.53%±11.73%)was higher than that in control group(12.83%±3.89%).2) Pulmonary function in COPD group drops compared with control group.3) Characteristics of intra-acinar pulmonary muscular arteries:Compared with control group, arteries walls of COPD group congested and swelled,inflammation cells increased,the thickness of intimal layer、walls of intra-acinar pulmonary muscular arteries was significantly higher,the area of its lumen was narrow and the proportion of their muscular arteries was higher,the area of collagen fibrils was increased.4) Correlation analysis:An negative correlations were showed with the expression of PPARγand MMP-9(r = -0.85,p<0.01 ),and inflammation cells,the pulmonary artery of the artery muscle ratio,the area of collagen fibrils,negative correlation was showed(r=-0.604、-0.759、-0.485、-0.862,P< 0.01);An positive correlations were showed in the expression of MMP-9 and inflammation cells(r=0.524,P<0.01 ),an positive correlation was showed with the pulmonary artery of the artery muscle ratio,the area of collagen fibrils,(r= 0.961、0.574、0.954,P<0.01);the artery wall area and the area of collagen fibrils showed positive correlations(r = 0.878,p< 0.01).an positive correlation was showed with the smoking index and the ratio of muscular arteries,partial muscular arteries,the area of collagen flbrils(r=0.889、0.764,P<0.01).
Conclusion:Patients with smoking and COPD have pulmonary vascular inflammation and remodeling,MMP-9 of pulmonary vascular endothelial cells was involved in the inflammation and remodeling process.,but PPARγwas involved in the anti-inflammation and anti-remodeling process.
引文
1 Henderson WR JR,Tang LO,Chu SJ,et al.A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model.Am J Respir Crit Care Med,2002;165:108-116
2 Peinado VI,Barbera JA,Abate P,et al.Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease.Am j Respir Crit Care Med,1999,159:1605-1611
3 Barbera JA,Peinado VI,Santos S.Pulmonary hypertension in chronic obstructive pulmonary disease.Eur Respir J,2003,21:892-905
4 Barbera JA,Peinado VI,Santos S.Pulmonary hypertension in COPD:old and new concepts[J].Monaldi Arch ChestDis,2000,55(6):445-449
5 Santos S,Peinado VI,Ramrez J,et al.Enhanced expression of vascular endothelial growt
6 Peinado VI,Barberd JA,Ramrez J,et al.Endothelial dysfunction in pulmonary arteries of patients with mild COPD.Am J Physiol,1998,274(6):908-913
7 Davies P,Burke G,Reid L.The structure of the wall of rat intra-acinar pulmonary artery:an electron microscopic study of microdissected preparations[J].Microvasc Res,1986,32:50-63
8 孙本韬。肺血管的超微结构及生理功能。见:程显声主编。肺血管疾病学[M]。北京:北京医科大学、中国协和医科大学联合出版社,1993.15-23
9 Hammad H,de Heer HJ,Soullie T,et al.Activation of peroxisome Proliferator-activated receptor γ in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma.AmJ Pathol,2004,164(1):263-271.
10 朱朝霞,徐永健,邹晖等。烟雾暴露和低氧单独及联合作用对大鼠肺血管重建及蛋白激酶C -a表达的影响。中华结核和呼吸杂志,2005,28(12):825-829
11 Santos S,Peinado VI,Ramrez J,et al.Characterization of pulmonary vascular remodeling in smokers and patients with mild COPD.Eur Respir J,2002,19(4):632-638.
12 VamecqJ,LatruffeN.Medicalsignif icance of peroxisome proliferator-activated receptors .Lancet,1999,354(9173):141-148
13 RicoteM,LiAC,WillsonTM,etal.The peroxisome proliferator activated receptorγis a negative regulator of macrophage activation.Nature,1998,391(6662):79-82
14 WoerlyG,HondaK,LoyensM,etal.Peroxisome Proliferator-activated receptorγalpha and gamma down-regulate allergic inflammation and eosinophil activation.J ExP Med,2003,198(3):411-421
15 Angeli V,Hammad H,Staels B,etal.Peroxisome Proliferator-activated receptors Inhibits the migration of dendritic cells:Consequences for the immune response JImmunol,2003,170(10):5295-5301
16 Hammad H,de Heer HJ,Soullie T,etal.Activation of peroxisome Proliferator-activated receptor γ in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma.AmJ Pathol,2004,164(1):263-271
17 Birrell MA,Patel HJ,McCluskie K,etal.PPAR γ agonists as therapy for diseases involving airway neutrophilia.Eur ResPir J,2004,24:18-23
18 Wang AC,Dai X,Luu B,etal.Peroxisome Proliferator-activated receptor γ regulates airway epithelial cell activation.Am J Respir Cell Mol Biol,2001,24(6),688-693.
19 Ward JE,Gould H,Harris T,etal.PPAR γ Iigands,15-deoxy-deltal2,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth proliferation through different mechanisms.BrJ pharmacol,2004,141(3) 517-525
20 BenayounL,Letuve S,Druilhe A,etal.Regulation of Peroxisome Proliferator-activated receptor γ expression in human asthmatic airways:relationship with Proliferation,apoptosis,and airwa remodeling.Am J ResPir Crit care Med,2001,164(8ptl):1487-1494
21 Lee KS,Park SJ,Hwang PH,etal.PPAR γ modulates allergic inflammation through up-regulation of PTEN.FASEB J,2005,19(8):1033-1035
22 Honda K,Marquillies P,Capron M,etal.Peroxisome Proliferator-activated receptor γ expressed in airways and inhibits features of airway remodeling in a mouse asthma model.J Allergy Clin Immunol,2004,113(5):882-885
23 王建春,等。急性肺损伤大鼠肺组织PPAR-γ表达的研究。第三军医大学学报,2008,30(6):074,174,864,964
24 韩伟,等。过氧化物酶增殖活化受体γ在支气管哮喘小鼠血管重塑中的作用。中华结核和呼吸杂志,2006,29(7):484-485
25 Segura Valdezl L,Pardo A,Gaxiola M,etal.Upregulation of gelatinases A and B,colla-genasesland2,,and increased parenchymal cell death in COPD.Chest,2000,117:684-694
26 Novotna J,Herget J.Exposure to chronic hypoxia induces qualitative changes of collagen in the walls of peripheral pulmonary arteries[J].Life Sci,1998,62(1):1-12.
27 M Hetzel,D Walcher Inhibition of MMP-9 expression by PPARγ activators in human bronchial epithelial cells.Tharax2003;58:778-783
28 Mercedes Ricote,Andrew C.The peroxisome proliferator-activated receptor γ is a negative regulator of macrophage activation.Nature,vol.39,Jan 1,1998
1 Kubo K,Ge RL,Koizumi T,et al.Pulmonary artery remodeling modifies pulmonary hypertension during exercise in severe emphysema.Respir Physiol,2000;120:71-79
2 Peinado VI,Barbera JA,Abate P,et al.Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease.Am j Respir Crit Care Med,1999,159:1605-1611
3 Barbera JA,Peinado VI,Santos S.Pulmonary hypertension in chronic obstructive pulmonary disease.Eur Respir J,2003,21:892-905
4 Barbera JA,Peinado V I,Santos S.Pulmonary hypertension in COPD:old and new concepts[J].Monaldi Arch ChestDis,2000,55(6):445-449
5 Santos S,Peinado VI,Ramrez J,et al.Enhanced expression of vascular endothelial growt h factor in pulmonary arteries of smokers and patient s with moderate chronic obstructive pulmonary disease.Am J Respir Crit Care Med,2003,167(9):1250-1256.
6 Peinado VI,Barberd JA,Ramrez J,et al.Endothelial dysfunction in pulmonary arteries of patients with mild COPD.Am J Physiol,1998,274(6):908-913
7 Davies P,Burke G,Reid L.The structure of the wall of rat intra-acinar pulmonary artery:an electron microscopic study of microdissected preparations[J].Microvasc Res,1986,32:50-63
8 孙本韬。肺血管的超微结构及生理功能。见:程显声主编。肺血管疾病学[M]。北京:北京医科大学、中国协和医科大学联合出版社,1993.15-23
9 Saetta M,Baraldo S,Corbino L,etal.CD8~(?) ve cells in the lung of smokers with chronic obstructive pulmonary disease.Am J Respir Crit Med,1999,160:711-717
10 Sirianni FE,Milaninezhad A,Chu FS,et al.Alteration of fibroblast architecture and loss of Basal lamina apertures in human emphysematous lung.Am J Respir Crit Care Med,2006,173:632-638
11 Santos S,Peinado VI,Ramrez J,et al.Characterization of pulmonary vascular remodeling in smokers and patients with mild COPD.Eur Respir J,2002,19(4):632-638.
12 Peter J,Barnes D.Sc.Chronic obstructive pulmonary disease.NEng J Med,2000,343(4):269-280
13 Jin HM,Liu QH,Cao X,et al.Dysfunction of microvascular endothelial cells induced by TNFα:cellular and molecmechanism.Clin Hemorheol Microcircul,2000,23(224):109-112
14 Coggins MP, Bloch KD. Nitric oxide in the pulmonary vasculature. Arterioscler Thromb Vasc Biol,2007, 27:1877-1885
15 Barber (?)JA , Peinado VI , Santos S , et al . Reduced expression of endothelial nit -ric oxide synthase in pulmonary arteries of smokers. Am J Respir Crit Care Med , 2001 , 164 (4):709-713
16 Ozaki M, Kawashima S, Yamashita T, et al. Reduced hypoxic pulmonary vascular remodeling by nitri oxide from the endothelium. Hypertension, 2001, 37: 322-327
17 Geraci MW, Gao B, Shepherd DC, etal. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertention. J Clin Invest, 1999,103:1509-1515
18 Millhorn DE, Raymond R, Conforti L, etc. Relation of the rat vascular endothelial growth factor gene by hypoxia. Biol Chem, 1995, 27:1333-1340.
19 Barbera JA, Peinado VI, Santos S.Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J,2003, 21:892-905.
20 Stenmark K, Durmowicz AG, Dempsey EC. Modulation of vascular wall cell phenotype in pulmonary hypertensionIn: Bishop JE, Reeves JT, Laurent GJ, editors. Pulmonary vascular remodellingLondon, Portland Press, 1995; pp. 171-212.。
21 Cooper AL, Beasley D.Hypoxia stimulates prolixferation and interleukin-alpha production in human vascular smooth muscle cells[J]. Am J Physiol, 1999, 277(4) :H1326-27.
22 Platoshyn O, YU Y, Golovina VA, et al. Chronic hypoxia cecreses K(V) channel expression and function in pulmonary artery myocytes[J].Am J Physiol Lung Cell Mol Physiol, 2001, 280(4):801-812
23 Grosskreutz CL , Anand-Apte B , Duplaa C , et al . Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro. Microvasc Res ,1999 ,58 (2) :128-136
24 Ishida A , Murray J , Saito Y, et al . Expression of vascular .endothelial growth factor receptors in smooth muscle cells. J Cell Physiol ,2001 ,188 (3) :359-368.
25 Shi Y, James E , O' BrienJE, et al. Andrew Zalewski. Transforming Growth Factor- β 1 Expression and Myofibroblast Formation During Arterial Repair . Arteriosclerosis , Thromb Vascul Biol ,1996 ,16 (10) :1298-1305.
26 Kranenburg AR , DeBoer WI , VanKrieken J H , et al . Enhanced expression of f ibroblast growth factors and receptor FGFR-1 during vascular remodeling in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol ,2002 ,27 (5) :517-525.
27 Novotna J, Herget J. Exposure to chronic hypoxia induces qualitative changes of collagen in the walls of peripheral pulmonary arteries[J]. Life Sci, 1998, 62(1): 1 -12.
28 Pin Mei Yao,Jean-Marie Buhler Expression of Matrix Metalloproteinase Gelatinases A and B by Cultured Epithelial Cells from Human Bronchial Explants The Journal of Biological Chemistry vol.271.No.26 June28.15580-15589
29 姜泊。细胞凋亡基础与临床[M]。北京:人民军医出版社,1999.275
30 于文成,郭彩宏。慢性阻塞性肺疾病患者肺动脉高压时肺动脉平滑肌细胞的增殖与凋亡。中华结核与呼吸杂志,2007,30(9):657-661
31 曹国强,钱桂生,林莉等。慢性阻塞性肺疾病大鼠肺组织细胞凋亡和增殖的变化[J]。中华结核和呼吸杂志,2005,28(3):169-172
32 张健全,钟小宁,蒋明,等。慢性支气管炎、肺气肿时肺动脉高压与肺血管壁改建与炎症的关系.中国病理生理杂志,2006,22:1811-1815
33 钟小宁,郭韶梅。慢性支气管炎与肺气肿大鼠肺血管炎症的实验研究。中华结核和呼吸杂志,2006,29:435-439.
34 Celermajer DS,Adams MR,Clarkson P,etc.Passive smoking and impaired endothelium -dependent arterial dilatation in healthy young adults.New England Journal o f Medicine,1996,334:150-154
35 Yunchao Su,WengangCao Zhaosheng Han etc.Cigarette smoke extract inhibits angiogenesis of Pulmonary artery endothelial cellsrthe role of calpain.Am J Physiol Lung Cell Mol Physiol,2004,287(4):794-800.
36 Brian R Clapp,Hingorani Aroon D,Kharbanda Rajesh K,etc.Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress.Cardiovascular Research,2004,64(1):172-178
37 HM Jin,QH Lin,XCao,etc..Dysfunction of micro vascular endothelial eells induced by TNF-a:cellular and molecular mechanism.Clinical and Hemorheology Microcirculation ,2000,23(2-4):109-112
38 Rahman l,Macnne W.Role of oxidants/antioxidants in smoking-induced lung diseases.Free Radical Biology and Medicine,1996,21:669-681.
39 Damle NK,Doyle LV.Ability of human T lymphocytes to adhere to vascular endothelial cells and to augment endothelial Permeability to macromolecules is linked to their state of Post thymic maturation.J,Immunol,1990,144:1233-1240
40 Wright JL,Tai H,Churg A.Vasoactive mediators and pulmonary hypertension after cigarette smoke exposure in the guinea pig.J Appl Physiol,2006,100:672-678
41 KanazawaH,Yoshikawa J.Elevated oxidative stress and reciprocal reduction of vascular endothelial growth factor level with severity of COPD.Chest,2005,128:3191-3197.
42 Wright JL,Tai H,Dai J,et al.Cigarette smoke induces rapid changes in gene expression in pulmonary arteies.Lab Invest,2002,82(10):1391-1398.
43 Pantovia C, Adnot S, Eddahibi S, et al. Heart and lung VEGF mRNA ex pression in rats with monocrotaline-or hypoxia induced pulmonary hypertension [J] . Am J Physiol, 1998; 275: H1948-56.
44 Stenmark KR, Davie NJ, Reeves JT,et al. Hypoxia, Leukocytes, and the pulmonary circulation. J Appl Physiol, 2005, 98:715-721.
45 Pak O, Aldashev A. Welsh D, et al. The effects of hypoxia on the cells of the pulmonary vasculature. Eur Respir J, 2007, 30:364-372.
46 Hu R, Dai A, Tan S. Hypoxia-inducible factor 1 alpha upregulates the expression of inducible nitric oxide synthase gene in pulmonary arteries of hyposic rat [J]. Chin Med J, 2002, 115(11): 1833-1837
47 Sweeney M ,Yuan JX. Hypoxic pulmonary vasoconstriction: role of voltagegated potassium channels[J]. Respir Res, 2000, 1(1): 40-48
48 Barman SA. Potassium channels modulate hypoxic pulmonary vasoconstriction [J]. Am J Physiol, 1998, 275(i):64-70.
2 Peinado VI,Barbera JA,Abate P,et al.Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease.Am j Respir Crit Care Med,1999,159:1605-1611
3 Barbera JA,Peinado VI,Santos S.Pulmonary hypertension in chronic obstructive pulmonary disease.Eur Respir J,2003,21:892-905
4 Barbera JA,Peinado VI,Santos S.Pulmonary hypertension in COPD:old and new concepts[J].Monaldi Arch ChestDis,2000,55(6):445-449
5 Santos S,Peinado VI,Ramrez J,et al.Enhanced expression of vascular endothelial growt
6 Peinado VI,Barberd JA,Ramrez J,et al.Endothelial dysfunction in pulmonary arteries of patients with mild COPD.Am J Physiol,1998,274(6):908-913
7 Davies P,Burke G,Reid L.The structure of the wall of rat intra-acinar pulmonary artery:an electron microscopic study of microdissected preparations[J].Microvasc Res,1986,32:50-63
8 孙本韬。肺血管的超微结构及生理功能。见:程显声主编。肺血管疾病学[M]。北京:北京医科大学、中国协和医科大学联合出版社,1993.15-23
9 Hammad H,de Heer HJ,Soullie T,et al.Activation of peroxisome Proliferator-activated receptor γ in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma.AmJ Pathol,2004,164(1):263-271.
10 朱朝霞,徐永健,邹晖等。烟雾暴露和低氧单独及联合作用对大鼠肺血管重建及蛋白激酶C -a表达的影响。中华结核和呼吸杂志,2005,28(12):825-829
11 Santos S,Peinado VI,Ramrez J,et al.Characterization of pulmonary vascular remodeling in smokers and patients with mild COPD.Eur Respir J,2002,19(4):632-638.
12 VamecqJ,LatruffeN.Medicalsignif icance of peroxisome proliferator-activated receptors .Lancet,1999,354(9173):141-148
13 RicoteM,LiAC,WillsonTM,etal.The peroxisome proliferator activated receptorγis a negative regulator of macrophage activation.Nature,1998,391(6662):79-82
14 WoerlyG,HondaK,LoyensM,etal.Peroxisome Proliferator-activated receptorγalpha and gamma down-regulate allergic inflammation and eosinophil activation.J ExP Med,2003,198(3):411-421
15 Angeli V,Hammad H,Staels B,etal.Peroxisome Proliferator-activated receptors Inhibits the migration of dendritic cells:Consequences for the immune response JImmunol,2003,170(10):5295-5301
16 Hammad H,de Heer HJ,Soullie T,etal.Activation of peroxisome Proliferator-activated receptor γ in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma.AmJ Pathol,2004,164(1):263-271
17 Birrell MA,Patel HJ,McCluskie K,etal.PPAR γ agonists as therapy for diseases involving airway neutrophilia.Eur ResPir J,2004,24:18-23
18 Wang AC,Dai X,Luu B,etal.Peroxisome Proliferator-activated receptor γ regulates airway epithelial cell activation.Am J Respir Cell Mol Biol,2001,24(6),688-693.
19 Ward JE,Gould H,Harris T,etal.PPAR γ Iigands,15-deoxy-deltal2,14-prostaglandin J2 and rosiglitazone regulate human cultured airway smooth proliferation through different mechanisms.BrJ pharmacol,2004,141(3) 517-525
20 BenayounL,Letuve S,Druilhe A,etal.Regulation of Peroxisome Proliferator-activated receptor γ expression in human asthmatic airways:relationship with Proliferation,apoptosis,and airwa remodeling.Am J ResPir Crit care Med,2001,164(8ptl):1487-1494
21 Lee KS,Park SJ,Hwang PH,etal.PPAR γ modulates allergic inflammation through up-regulation of PTEN.FASEB J,2005,19(8):1033-1035
22 Honda K,Marquillies P,Capron M,etal.Peroxisome Proliferator-activated receptor γ expressed in airways and inhibits features of airway remodeling in a mouse asthma model.J Allergy Clin Immunol,2004,113(5):882-885
23 王建春,等。急性肺损伤大鼠肺组织PPAR-γ表达的研究。第三军医大学学报,2008,30(6):074,174,864,964
24 韩伟,等。过氧化物酶增殖活化受体γ在支气管哮喘小鼠血管重塑中的作用。中华结核和呼吸杂志,2006,29(7):484-485
25 Segura Valdezl L,Pardo A,Gaxiola M,etal.Upregulation of gelatinases A and B,colla-genasesland2,,and increased parenchymal cell death in COPD.Chest,2000,117:684-694
26 Novotna J,Herget J.Exposure to chronic hypoxia induces qualitative changes of collagen in the walls of peripheral pulmonary arteries[J].Life Sci,1998,62(1):1-12.
27 M Hetzel,D Walcher Inhibition of MMP-9 expression by PPARγ activators in human bronchial epithelial cells.Tharax2003;58:778-783
28 Mercedes Ricote,Andrew C.The peroxisome proliferator-activated receptor γ is a negative regulator of macrophage activation.Nature,vol.39,Jan 1,1998
1 Kubo K,Ge RL,Koizumi T,et al.Pulmonary artery remodeling modifies pulmonary hypertension during exercise in severe emphysema.Respir Physiol,2000;120:71-79
2 Peinado VI,Barbera JA,Abate P,et al.Inflammatory reaction in pulmonary muscular arteries of patients with mild chronic obstructive pulmonary disease.Am j Respir Crit Care Med,1999,159:1605-1611
3 Barbera JA,Peinado VI,Santos S.Pulmonary hypertension in chronic obstructive pulmonary disease.Eur Respir J,2003,21:892-905
4 Barbera JA,Peinado V I,Santos S.Pulmonary hypertension in COPD:old and new concepts[J].Monaldi Arch ChestDis,2000,55(6):445-449
5 Santos S,Peinado VI,Ramrez J,et al.Enhanced expression of vascular endothelial growt h factor in pulmonary arteries of smokers and patient s with moderate chronic obstructive pulmonary disease.Am J Respir Crit Care Med,2003,167(9):1250-1256.
6 Peinado VI,Barberd JA,Ramrez J,et al.Endothelial dysfunction in pulmonary arteries of patients with mild COPD.Am J Physiol,1998,274(6):908-913
7 Davies P,Burke G,Reid L.The structure of the wall of rat intra-acinar pulmonary artery:an electron microscopic study of microdissected preparations[J].Microvasc Res,1986,32:50-63
8 孙本韬。肺血管的超微结构及生理功能。见:程显声主编。肺血管疾病学[M]。北京:北京医科大学、中国协和医科大学联合出版社,1993.15-23
9 Saetta M,Baraldo S,Corbino L,etal.CD8~(?) ve cells in the lung of smokers with chronic obstructive pulmonary disease.Am J Respir Crit Med,1999,160:711-717
10 Sirianni FE,Milaninezhad A,Chu FS,et al.Alteration of fibroblast architecture and loss of Basal lamina apertures in human emphysematous lung.Am J Respir Crit Care Med,2006,173:632-638
11 Santos S,Peinado VI,Ramrez J,et al.Characterization of pulmonary vascular remodeling in smokers and patients with mild COPD.Eur Respir J,2002,19(4):632-638.
12 Peter J,Barnes D.Sc.Chronic obstructive pulmonary disease.NEng J Med,2000,343(4):269-280
13 Jin HM,Liu QH,Cao X,et al.Dysfunction of microvascular endothelial cells induced by TNFα:cellular and molecmechanism.Clin Hemorheol Microcircul,2000,23(224):109-112
14 Coggins MP, Bloch KD. Nitric oxide in the pulmonary vasculature. Arterioscler Thromb Vasc Biol,2007, 27:1877-1885
15 Barber (?)JA , Peinado VI , Santos S , et al . Reduced expression of endothelial nit -ric oxide synthase in pulmonary arteries of smokers. Am J Respir Crit Care Med , 2001 , 164 (4):709-713
16 Ozaki M, Kawashima S, Yamashita T, et al. Reduced hypoxic pulmonary vascular remodeling by nitri oxide from the endothelium. Hypertension, 2001, 37: 322-327
17 Geraci MW, Gao B, Shepherd DC, etal. Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertention. J Clin Invest, 1999,103:1509-1515
18 Millhorn DE, Raymond R, Conforti L, etc. Relation of the rat vascular endothelial growth factor gene by hypoxia. Biol Chem, 1995, 27:1333-1340.
19 Barbera JA, Peinado VI, Santos S.Pulmonary hypertension in chronic obstructive pulmonary disease. Eur Respir J,2003, 21:892-905.
20 Stenmark K, Durmowicz AG, Dempsey EC. Modulation of vascular wall cell phenotype in pulmonary hypertensionIn: Bishop JE, Reeves JT, Laurent GJ, editors. Pulmonary vascular remodellingLondon, Portland Press, 1995; pp. 171-212.。
21 Cooper AL, Beasley D.Hypoxia stimulates prolixferation and interleukin-alpha production in human vascular smooth muscle cells[J]. Am J Physiol, 1999, 277(4) :H1326-27.
22 Platoshyn O, YU Y, Golovina VA, et al. Chronic hypoxia cecreses K(V) channel expression and function in pulmonary artery myocytes[J].Am J Physiol Lung Cell Mol Physiol, 2001, 280(4):801-812
23 Grosskreutz CL , Anand-Apte B , Duplaa C , et al . Vascular endothelial growth factor-induced migration of vascular smooth muscle cells in vitro. Microvasc Res ,1999 ,58 (2) :128-136
24 Ishida A , Murray J , Saito Y, et al . Expression of vascular .endothelial growth factor receptors in smooth muscle cells. J Cell Physiol ,2001 ,188 (3) :359-368.
25 Shi Y, James E , O' BrienJE, et al. Andrew Zalewski. Transforming Growth Factor- β 1 Expression and Myofibroblast Formation During Arterial Repair . Arteriosclerosis , Thromb Vascul Biol ,1996 ,16 (10) :1298-1305.
26 Kranenburg AR , DeBoer WI , VanKrieken J H , et al . Enhanced expression of f ibroblast growth factors and receptor FGFR-1 during vascular remodeling in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol ,2002 ,27 (5) :517-525.
27 Novotna J, Herget J. Exposure to chronic hypoxia induces qualitative changes of collagen in the walls of peripheral pulmonary arteries[J]. Life Sci, 1998, 62(1): 1 -12.
28 Pin Mei Yao,Jean-Marie Buhler Expression of Matrix Metalloproteinase Gelatinases A and B by Cultured Epithelial Cells from Human Bronchial Explants The Journal of Biological Chemistry vol.271.No.26 June28.15580-15589
29 姜泊。细胞凋亡基础与临床[M]。北京:人民军医出版社,1999.275
30 于文成,郭彩宏。慢性阻塞性肺疾病患者肺动脉高压时肺动脉平滑肌细胞的增殖与凋亡。中华结核与呼吸杂志,2007,30(9):657-661
31 曹国强,钱桂生,林莉等。慢性阻塞性肺疾病大鼠肺组织细胞凋亡和增殖的变化[J]。中华结核和呼吸杂志,2005,28(3):169-172
32 张健全,钟小宁,蒋明,等。慢性支气管炎、肺气肿时肺动脉高压与肺血管壁改建与炎症的关系.中国病理生理杂志,2006,22:1811-1815
33 钟小宁,郭韶梅。慢性支气管炎与肺气肿大鼠肺血管炎症的实验研究。中华结核和呼吸杂志,2006,29:435-439.
34 Celermajer DS,Adams MR,Clarkson P,etc.Passive smoking and impaired endothelium -dependent arterial dilatation in healthy young adults.New England Journal o f Medicine,1996,334:150-154
35 Yunchao Su,WengangCao Zhaosheng Han etc.Cigarette smoke extract inhibits angiogenesis of Pulmonary artery endothelial cellsrthe role of calpain.Am J Physiol Lung Cell Mol Physiol,2004,287(4):794-800.
36 Brian R Clapp,Hingorani Aroon D,Kharbanda Rajesh K,etc.Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress.Cardiovascular Research,2004,64(1):172-178
37 HM Jin,QH Lin,XCao,etc..Dysfunction of micro vascular endothelial eells induced by TNF-a:cellular and molecular mechanism.Clinical and Hemorheology Microcirculation ,2000,23(2-4):109-112
38 Rahman l,Macnne W.Role of oxidants/antioxidants in smoking-induced lung diseases.Free Radical Biology and Medicine,1996,21:669-681.
39 Damle NK,Doyle LV.Ability of human T lymphocytes to adhere to vascular endothelial cells and to augment endothelial Permeability to macromolecules is linked to their state of Post thymic maturation.J,Immunol,1990,144:1233-1240
40 Wright JL,Tai H,Churg A.Vasoactive mediators and pulmonary hypertension after cigarette smoke exposure in the guinea pig.J Appl Physiol,2006,100:672-678
41 KanazawaH,Yoshikawa J.Elevated oxidative stress and reciprocal reduction of vascular endothelial growth factor level with severity of COPD.Chest,2005,128:3191-3197.
42 Wright JL,Tai H,Dai J,et al.Cigarette smoke induces rapid changes in gene expression in pulmonary arteies.Lab Invest,2002,82(10):1391-1398.
43 Pantovia C, Adnot S, Eddahibi S, et al. Heart and lung VEGF mRNA ex pression in rats with monocrotaline-or hypoxia induced pulmonary hypertension [J] . Am J Physiol, 1998; 275: H1948-56.
44 Stenmark KR, Davie NJ, Reeves JT,et al. Hypoxia, Leukocytes, and the pulmonary circulation. J Appl Physiol, 2005, 98:715-721.
45 Pak O, Aldashev A. Welsh D, et al. The effects of hypoxia on the cells of the pulmonary vasculature. Eur Respir J, 2007, 30:364-372.
46 Hu R, Dai A, Tan S. Hypoxia-inducible factor 1 alpha upregulates the expression of inducible nitric oxide synthase gene in pulmonary arteries of hyposic rat [J]. Chin Med J, 2002, 115(11): 1833-1837
47 Sweeney M ,Yuan JX. Hypoxic pulmonary vasoconstriction: role of voltagegated potassium channels[J]. Respir Res, 2000, 1(1): 40-48
48 Barman SA. Potassium channels modulate hypoxic pulmonary vasoconstriction [J]. Am J Physiol, 1998, 275(i):64-70.