TNF-α在大鼠慢性阻塞性肺疾病发病中的作用及rhTNFR：Fc的干预影响
|
摘要
目的探讨肿瘤坏死因子-α(TNF-α)在大鼠慢性阻塞性肺疾病(COPD)发病中的作用及重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白(rhTNFR：FC)的干预影响。
方法48只大鼠随机分为4组：正常对照组、COPD组、重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白干预组及假干预组。单纯吸烟法建立COPD模型，干预组皮下注射rhTNFR：Fc进行干预，假干预组皮下注射空白模拟制剂。各组随机抽取半数大鼠以小动物肺功能测定系统测定肺功能。酶联免疫吸附法(ELISA)测定各组血清和支气管肺泡灌洗液(BALF)中的TNF-α浓度。支气管肺泡灌洗计数BALF中白细胞总数、中性粒细胞和巨噬细胞计数及其百分比，肺组织切片行苏木素-伊红染色观察形态学改变，并定量测定肺平均内衬间隔(MLI)、平均肺泡数(MAN)，利用脱氧核糖核酸末端转移酶介导的dUTP缺口末端标记(TUNEL)技术对肺泡隔凋亡细胞的阳性率进行检测，ELISA检测BALF中血管内皮细胞生长因子(VEGF)含量，Western blot检测血管内皮细胞生长因子受体2(VEGFR-2)蛋白、基质金属酶-9蛋白(MMP-9)的表达，使用自动生化分析仪测定各组大鼠血清白蛋白含量。
结果
(1)COPD组0.3秒用力呼气量占用力肺活量比值(FEV_(0.3)／FVC)和呼气峰流速(PEF)较正常对照组和rhTNFR：Fc干预组降低(P＜0.05)，但和假干预组比较差异无统计学意义(p＞0.05)。假干预组FEV_(0.3)／FVC、PEF较rhTNFR：Fc干预组降低(p＜0.05)。
(2)COPD组血清中TNF-α浓度高于正常组(P＜0.05)、rhTNFR：Fc干预组(P＜0.05)，和假干预组比较差异无统计学意义(p＞0.05)。假干预组血清中TNF-α浓度高于rh／NFR：Fc干预组，差异有显著性(p＜0.05)。COPD组BALF中TNF-α浓度高于正常对照组(P＜0.05)，但和rhTNFR：Fc干预组、假干预组比较差异均无统计学意义(p＞0.05)。
(3)COPD组BALF中白细胞总数、中性粒细胞计数及百分比高于正常组(P＜0.01，P＜0.05，P＜0.05)、rhTNFR：Fc干预组(P＜0.01，P＜0.05，P＜0.05，)，和假干预组比较差异无统计学意义(p＞0.05)。假干预组BALF中细胞总数、中性粒细胞计数及百分比高于rhTNFR：Fc干预组(P＜0.01，p＜0.05，P＜0.05)。
(4)COPD组MLI比正常对照组增高(p＜0.05)，其MAN比正常对照组、rhTNFR：Fc干预组降低(P＜0.05)，但MLI、MAN和假干预组比较差异均无统计学意义(p＞0.05)。假干预组MAN低于rhTNFR：Fc干预组(p＜0.05)。
(5)COPD组肺泡隔细胞凋亡指数(AI)高于正常对照组、rhTNFR：FC干预组(P＜0.05)，和假干预组比较差异无统计学意义(p＞0.05)。假干预组肺泡隔细胞AI高于rhTNFR：FC干预组，差异有统计学意义(P＜0.05)。
(6)COPD组BALF中VEGF含量较正常对照组降低(P＜0.05)，肺组织中VEGFR-2蛋白表达较正常对照组降低(P＜0.05)，和假干预组比较差异无统计学意义(p＞0.05)。COPD组肺组织中MMP-9表达较rhTNFR：Fc干预组升高(P＜0.05)。
(7)COPD组体重较正常对照组、rhTNFR：Fc干预组体重降低，(P＜0.01)，和假干预组比较差异无统计学意义(p＞0.05)。COPD组血清白蛋白较正常对照组降低(p＜0.05)，但与rhTNFR：Fc干预组和假干预组比较差异无统计学意义(p＞0.05)。
(8) (COPD组+假干预组)血清中TNF-α浓度与FEV_(0.3)／FVC、PEF呈负相关(r=-0.67，F=-0.77，p＜0.05)。(COPD组+假干预组)BALF中TNF-α浓度与FEV_(0.3)／FVC、PEF呈负相关(r=-0.83，r=-0.76，p＜0.05)。COPD组大鼠血清TNF-α浓度与体重呈负相关(r=-0.75，p＜0.05)，与血清白蛋白浓度呈负相关(r=-0.73，p＜0.05)。
结论
(1)TNF-α与吸烟大鼠COPD形成有关，并参与肺部病理变化、气道炎症形成、损害肺功能、导致营养不良，促进肺泡隔细胞凋亡。
(2)VEGF含量降低和肺组织VEGFR-2表达下降可能和吸烟大鼠肺气肿形成有关。
(3)rhTNFR：Fc通过抑制TNF-α对改善吸烟大鼠肺部病理、减轻气道炎症、延缓肺功能损害、降低肺泡隔细胞凋亡凋亡、改善营养状态具有一定作用。
Objective
To investigate the role of TNF-αand the influence of recombinant human tumor necrosis factor-Fc on pathogenesis of chronic obstructive pulmonary disease of rats.
Methods
Forty eight rats were randomly divided into a normal control group, a COPD group, a rhTNFR: Fc-interfered group and a sham interfered group. Rat models of COPD were established by exposure to cigarette smoking daily for 80 days. rhTNFR: Fc-interfered group was interfered with rhTNFR: Fc, the sham interfered group injected with certain praeparatum as control for rhTNFR: Fc-interfered group. Lung function was detected in half rats of every group, the levels of Tumor necrosis factor alpha(TNF-α)in serum and BALF measured with ELISA. Total cell counts, neutrophil counts and neutrophil proportion in BALF were examined. Lung tissure section stained by hematoxylin and eosin (HE) was observed to study the morphological alternations. Mean linear intercept (MLI) and mean alveolar numbers (MAN) were measured. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) methods were carried out to examined the percentage of positive cells and distribution of apoptotic cells. The concentration of VEGF in BALF was examined with ELISA, the expression of VEGFR-2 and MMP-9 measured by Western blot and levels of albulmin in serum measured by automatic biochemistry analyzer.
Results
Compared with the normal control and rhTNFR: Fc-interfered group, FEV_(0.3)/FVC and PEF were lower in COPD rats (P＜0.05); Compared with rhTNFR: Fc-interfered group, FEV_(0.3)/FVC and PEF were lower in sham interfered group(P＜0.05). The levels of TNF-αin serum were higher in COPD group than in the normal control (P＜0.05) and rhTNFR: Fc-interfered group (P＜0.05). Significanct differences were found between the levels of TNF-αin serum of rhTNFR: Fc-interfered group and sham interfered group(P＜0.05). The levels of TNF-αin BALF were higher in COPD group than in the normal control(P＜0.05), but no significanct differences were found between the levels in COPD group and rhTNFR: Fc-interfered group. Total cell counts and neutrophil counts and neutrophil proportion in BALF were higher in COPD group than in the normal control and rhTNFR: Fc-interfered group (P＜0.01, p＜0.05), and they were also higher in rhTNFR: Fc-interfered group than in sham interfered group (P＜0.01, p＜0.05). MLI in COPD rats was higher than that in the normal control(p＜0.05) while MAN was decreased on the contrary(p＜0.05), compared with normal control and rhTNFR: Fc-interfered group. Significanct differences were found between MAN in rhTNFR: Fc-interfered group and sham interfered group. The number of TUNEL＋cells in alveolar septa was significantly increased in COPD group as compared with normal control and rhTNFR: Fc-interfered group(P＜0.05), so was it in the latter compared with sham interfered group.
The concentration of VEGF in BALF of COPD group was significantly decreased as compared with normal control group, but no significanct differences were found between the concentration of COPD group and rhTNFR: Fc-interfered group (p＞0.05). The expression of VEGFR-2 protein in COPD group was significantly decreased compared with normal control group while no differences existed between that in COPD group and rhTNFR: Fc-interfered group (p＞0.05). The expression of MMP-9 was decreased in rhTNFR: Fc-interfered group compared with COPD group(P＜0.05).
The weight of COPD group was significantly decreased compared with normal control group and rhTNFR: Fc-interfered group (p＜0.01). No differences were found between the weight of COPD group and the control group for interfered one (p＞0.05), significant differences found between the weight of rhTNFR: Fc-interfered group and control group for interfered one (p＜0.01 ). The levels of albulmin in serum of COPD group were significantly decreased compared with normal control group (p＜0.05), but no differences were found among the levels of COPD group and rhTNFR: Fc-interfered group and control group for interfered one (p＞0.05). Negative correlations were demonstrated between the levels of TNF-αin serum and BALF of (COPD group＋sham interfered group) and PEF and FEV_(0.3)/FVC(p＜0.05). The levels of TNF-αin serum of COPD group revealed negative correlations to the weight (r=-0.75, p＜0.05) and the levels of serum albumin (r=-0.73, p＜0.05).
Conclusions
TNF-αrelates to the pathogenesis of COPD of smoking rats and causes pulmonary pathological changes, airway inflammation, decline of pulmonary function, apoptosis of alveolar septal cells and malnutrition in smoking rats. Decrease of VEGF and VEGFR may contribute to the pathogenesis of emphysema of smoking rats. rhTNFR: Fc may play certain role in the improvement of pulmonary pathological changes, reduction of airway inflammation, decrease of alveolar septal apoptosis, slowdown of pulmonary function impairment of COPD and improvement of nutritional status.
方法48只大鼠随机分为4组：正常对照组、COPD组、重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白干预组及假干预组。单纯吸烟法建立COPD模型，干预组皮下注射rhTNFR：Fc进行干预，假干预组皮下注射空白模拟制剂。各组随机抽取半数大鼠以小动物肺功能测定系统测定肺功能。酶联免疫吸附法(ELISA)测定各组血清和支气管肺泡灌洗液(BALF)中的TNF-α浓度。支气管肺泡灌洗计数BALF中白细胞总数、中性粒细胞和巨噬细胞计数及其百分比，肺组织切片行苏木素-伊红染色观察形态学改变，并定量测定肺平均内衬间隔(MLI)、平均肺泡数(MAN)，利用脱氧核糖核酸末端转移酶介导的dUTP缺口末端标记(TUNEL)技术对肺泡隔凋亡细胞的阳性率进行检测，ELISA检测BALF中血管内皮细胞生长因子(VEGF)含量，Western blot检测血管内皮细胞生长因子受体2(VEGFR-2)蛋白、基质金属酶-9蛋白(MMP-9)的表达，使用自动生化分析仪测定各组大鼠血清白蛋白含量。
结果
(1)COPD组0.3秒用力呼气量占用力肺活量比值(FEV_(0.3)／FVC)和呼气峰流速(PEF)较正常对照组和rhTNFR：Fc干预组降低(P＜0.05)，但和假干预组比较差异无统计学意义(p＞0.05)。假干预组FEV_(0.3)／FVC、PEF较rhTNFR：Fc干预组降低(p＜0.05)。
(2)COPD组血清中TNF-α浓度高于正常组(P＜0.05)、rhTNFR：Fc干预组(P＜0.05)，和假干预组比较差异无统计学意义(p＞0.05)。假干预组血清中TNF-α浓度高于rh／NFR：Fc干预组，差异有显著性(p＜0.05)。COPD组BALF中TNF-α浓度高于正常对照组(P＜0.05)，但和rhTNFR：Fc干预组、假干预组比较差异均无统计学意义(p＞0.05)。
(3)COPD组BALF中白细胞总数、中性粒细胞计数及百分比高于正常组(P＜0.01，P＜0.05，P＜0.05)、rhTNFR：Fc干预组(P＜0.01，P＜0.05，P＜0.05，)，和假干预组比较差异无统计学意义(p＞0.05)。假干预组BALF中细胞总数、中性粒细胞计数及百分比高于rhTNFR：Fc干预组(P＜0.01，p＜0.05，P＜0.05)。
(4)COPD组MLI比正常对照组增高(p＜0.05)，其MAN比正常对照组、rhTNFR：Fc干预组降低(P＜0.05)，但MLI、MAN和假干预组比较差异均无统计学意义(p＞0.05)。假干预组MAN低于rhTNFR：Fc干预组(p＜0.05)。
(5)COPD组肺泡隔细胞凋亡指数(AI)高于正常对照组、rhTNFR：FC干预组(P＜0.05)，和假干预组比较差异无统计学意义(p＞0.05)。假干预组肺泡隔细胞AI高于rhTNFR：FC干预组，差异有统计学意义(P＜0.05)。
(6)COPD组BALF中VEGF含量较正常对照组降低(P＜0.05)，肺组织中VEGFR-2蛋白表达较正常对照组降低(P＜0.05)，和假干预组比较差异无统计学意义(p＞0.05)。COPD组肺组织中MMP-9表达较rhTNFR：Fc干预组升高(P＜0.05)。
(7)COPD组体重较正常对照组、rhTNFR：Fc干预组体重降低，(P＜0.01)，和假干预组比较差异无统计学意义(p＞0.05)。COPD组血清白蛋白较正常对照组降低(p＜0.05)，但与rhTNFR：Fc干预组和假干预组比较差异无统计学意义(p＞0.05)。
(8) (COPD组+假干预组)血清中TNF-α浓度与FEV_(0.3)／FVC、PEF呈负相关(r=-0.67，F=-0.77，p＜0.05)。(COPD组+假干预组)BALF中TNF-α浓度与FEV_(0.3)／FVC、PEF呈负相关(r=-0.83，r=-0.76，p＜0.05)。COPD组大鼠血清TNF-α浓度与体重呈负相关(r=-0.75，p＜0.05)，与血清白蛋白浓度呈负相关(r=-0.73，p＜0.05)。
结论
(1)TNF-α与吸烟大鼠COPD形成有关，并参与肺部病理变化、气道炎症形成、损害肺功能、导致营养不良，促进肺泡隔细胞凋亡。
(2)VEGF含量降低和肺组织VEGFR-2表达下降可能和吸烟大鼠肺气肿形成有关。
(3)rhTNFR：Fc通过抑制TNF-α对改善吸烟大鼠肺部病理、减轻气道炎症、延缓肺功能损害、降低肺泡隔细胞凋亡凋亡、改善营养状态具有一定作用。
Objective
To investigate the role of TNF-αand the influence of recombinant human tumor necrosis factor-Fc on pathogenesis of chronic obstructive pulmonary disease of rats.
Methods
Forty eight rats were randomly divided into a normal control group, a COPD group, a rhTNFR: Fc-interfered group and a sham interfered group. Rat models of COPD were established by exposure to cigarette smoking daily for 80 days. rhTNFR: Fc-interfered group was interfered with rhTNFR: Fc, the sham interfered group injected with certain praeparatum as control for rhTNFR: Fc-interfered group. Lung function was detected in half rats of every group, the levels of Tumor necrosis factor alpha(TNF-α)in serum and BALF measured with ELISA. Total cell counts, neutrophil counts and neutrophil proportion in BALF were examined. Lung tissure section stained by hematoxylin and eosin (HE) was observed to study the morphological alternations. Mean linear intercept (MLI) and mean alveolar numbers (MAN) were measured. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) methods were carried out to examined the percentage of positive cells and distribution of apoptotic cells. The concentration of VEGF in BALF was examined with ELISA, the expression of VEGFR-2 and MMP-9 measured by Western blot and levels of albulmin in serum measured by automatic biochemistry analyzer.
Results
Compared with the normal control and rhTNFR: Fc-interfered group, FEV_(0.3)/FVC and PEF were lower in COPD rats (P＜0.05); Compared with rhTNFR: Fc-interfered group, FEV_(0.3)/FVC and PEF were lower in sham interfered group(P＜0.05). The levels of TNF-αin serum were higher in COPD group than in the normal control (P＜0.05) and rhTNFR: Fc-interfered group (P＜0.05). Significanct differences were found between the levels of TNF-αin serum of rhTNFR: Fc-interfered group and sham interfered group(P＜0.05). The levels of TNF-αin BALF were higher in COPD group than in the normal control(P＜0.05), but no significanct differences were found between the levels in COPD group and rhTNFR: Fc-interfered group. Total cell counts and neutrophil counts and neutrophil proportion in BALF were higher in COPD group than in the normal control and rhTNFR: Fc-interfered group (P＜0.01, p＜0.05), and they were also higher in rhTNFR: Fc-interfered group than in sham interfered group (P＜0.01, p＜0.05). MLI in COPD rats was higher than that in the normal control(p＜0.05) while MAN was decreased on the contrary(p＜0.05), compared with normal control and rhTNFR: Fc-interfered group. Significanct differences were found between MAN in rhTNFR: Fc-interfered group and sham interfered group. The number of TUNEL＋cells in alveolar septa was significantly increased in COPD group as compared with normal control and rhTNFR: Fc-interfered group(P＜0.05), so was it in the latter compared with sham interfered group.
The concentration of VEGF in BALF of COPD group was significantly decreased as compared with normal control group, but no significanct differences were found between the concentration of COPD group and rhTNFR: Fc-interfered group (p＞0.05). The expression of VEGFR-2 protein in COPD group was significantly decreased compared with normal control group while no differences existed between that in COPD group and rhTNFR: Fc-interfered group (p＞0.05). The expression of MMP-9 was decreased in rhTNFR: Fc-interfered group compared with COPD group(P＜0.05).
The weight of COPD group was significantly decreased compared with normal control group and rhTNFR: Fc-interfered group (p＜0.01). No differences were found between the weight of COPD group and the control group for interfered one (p＞0.05), significant differences found between the weight of rhTNFR: Fc-interfered group and control group for interfered one (p＜0.01 ). The levels of albulmin in serum of COPD group were significantly decreased compared with normal control group (p＜0.05), but no differences were found among the levels of COPD group and rhTNFR: Fc-interfered group and control group for interfered one (p＞0.05). Negative correlations were demonstrated between the levels of TNF-αin serum and BALF of (COPD group＋sham interfered group) and PEF and FEV_(0.3)/FVC(p＜0.05). The levels of TNF-αin serum of COPD group revealed negative correlations to the weight (r=-0.75, p＜0.05) and the levels of serum albumin (r=-0.73, p＜0.05).
Conclusions
TNF-αrelates to the pathogenesis of COPD of smoking rats and causes pulmonary pathological changes, airway inflammation, decline of pulmonary function, apoptosis of alveolar septal cells and malnutrition in smoking rats. Decrease of VEGF and VEGFR may contribute to the pathogenesis of emphysema of smoking rats. rhTNFR: Fc may play certain role in the improvement of pulmonary pathological changes, reduction of airway inflammation, decrease of alveolar septal apoptosis, slowdown of pulmonary function impairment of COPD and improvement of nutritional status.
引文
[1] Snider GL,Kleinerman LJ,Thurlbeck WM,et al.The definition of emphysema: report of a National,Heart, Lung and Blood Institute. Division of Lung Diseases Workshop.Am Rev Respir Dis, 1985,132:182-185.
[2] Barnes PJ,Shapiro SD,Pauwels RA.Chronic obstructive pulmonary disease:molecular and cellular mechanisms.Eur Respir J,2003,22(4): 672-688.
[3] 张永，程德云，王慧，等．慢性阻塞性肺疾病大鼠肺内白细胞介素-8和肿瘤坏死因子-α与气道炎症的关系研究．中国呼吸与危重监护杂志,2003,2(6)：355-359．
[4] Hester van der Vaart,Gerard H Koeter, Dirkje S Postma, et al.First Study of Infliximab Treatment in Patients with Chronic Obstructive Pulmonary Disease.American Journal of Respiratory and Critical Care Medicine,2005,172(4):4655.
[5] Cristina Russo,Francesca D'Angelo,Riccardo Polosa.Study of Inflixlmab Treatment in Smokers with COPD: What Next?.Amedcan Journal of Resp-iratory and Critical Care Medicine,2005,172(12) 1606-1608.
[6] 陈劲龙，冉丕鑫．血管内皮生长因子与烟雾暴露所致大鼠肺气肿发病关系的研究．中华结核和呼吸杂志,2003，26：671-674．
[7] 陈涛，吴亚梅．胶原酶/组织金属蛋白酶抑制剂-1免疫活性及其在慢性阻塞性肺疾病肺结构改变中的作用．中国呼吸与危重监护杂志,2004，3：387-391．
[8] 罗红，陈平，王修文等．慢性阻塞性肺疾病患者气道炎症与肺泡巨噬细胞白细胞介素8活性的研究．中华结核和呼吸杂志,1999，22(10)：635-636．
[9] 陈平，蔡珊，朱应群等．肺泡巨噬细胞在慢性阻塞性肺疾病气道炎症中的作用．中华内科杂志,2001，40(4)：232-235.
[10] 刘杰波，陈平．慢性支气管炎气道巨噬细胞计数及淋巴细胞功能相关抗原1的研究．中华结核和呼吸杂志,2001,24(5)：280-282．
[11] 彭红胨平，蔡珊．慢性支气管炎患者肺泡巨噬细胞及诱导痰中内皮素的研究．中华结核和呼吸杂志,2001,24(6)：351-354．
[12] 蔡珊，陈平，朱应群等．慢性阻塞性肺疾病气道炎症与肺泡巨噬细胞炎症蛋白1α、明胶酶B活性的研究．中华结核和呼吸杂志,2001,24(7)：429-432
[13] 郑灵，张劲农．阻塞性肺气肿损伤与抗损伤机制．国外医学呼吸系统分册,2005，25(10)：736-738．
[14] 庞宝森，李远红，张洪玉．慢性阻塞性肺疾病动物模型的研究进展．心肺血管病杂志，2005，24(1)：45-46．
[15] Wright JL,Churg A.Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig.Am Rev Respir Dis, 1990,142(6Pt 1): 1422-1428.
[16] Stolk J,Rudolphus A,Davies P, et al.Induction of emphysema and bronchial mucus cell hyperplasia by intratracheal instillation of lipopolysaccharide in the hamster.J Pathol, 1992,167(3):349-356.
[17] Boyd RL,Fisher MJ,Jaeger MJ.Non-invasive lung function tests in rats with progressive papain-induced emphysema.Respir Physiol, 1980,40(2): 181-190.
[18] Chitano P, Hosselet JJ,Mapp CE.Effect of oxidant air pollutants on the respiratory system:insights from experimental animal research.Eur Respir J,1995,8:1357-1371.
[19] Taraseviciene-Stewart L,Scerbavicius R, Choe KH,et al.An animal model of autoimmune emphysema.Am J Respir Crit Care Med,2005,171(7):734-742.
[20] Mukhopadhyay S,Hoidal JR, Mukherjee TK.Role of TNF alpha in pulmonary pathophysiology.Respir Res,2006,7(1): 125.
[21] 林挺岩，李玉珠，李志鹰，等．慢性阻塞性肺病血白细胞介素-8、肿瘤坏死因子α、内皮素与肺功能的关系．福建医科大学学报,2000,34(4)：347-349．
[22] 董平，孔令敏，陈文靖，等．COPD急性发作期白介素-8、肿瘤坏死因子-α的表达与预后分析．中国厂矿医学．2002,15(2)：99-100．
[23] De Boer WI.Cytokines and therapy in COPD:a promising combina-tion?.Chest,2002,121 (3):209-218.
[24] 王胜，徐凤珍，陈余清．慢性阻塞性肺疾病患者痰液白细胞介素8，6和肿瘤坏死因子测定及其意义．中华结核和呼吸杂志,2000，23(8)：465-467．
[25] 李亚清，张珍祥，徐永健，等．COPD患者肺泡巨噬细胞源性MMP-9的表达及其酶活性变化．中华内科杂志,2006,45(1)：38-41．
[26] Andrew Churg,Rong D.Wang, Hsin Tai,et al.Tumor Necrosis Factor-αtDrives 70% of Cigarette Smoke-induced Emphysema in the Mouse.American Journal of Respiratory and Critical Care Medicine,2004,170:492-498.
[27] 胡大为，鲍春德，陈顺乐，等．重组人Ⅱ型肿瘤坏死因子受体．抗体融合蛋白治疗类风湿关节炎双盲随机多中心对照临床研究．中华风湿病学杂志,2005,9(11)：664-668．
[28] Gerbitz A,Nickoloff BJ,Olkiewicz K, et al.A role for tumor necrosis factor-alpha-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome.Transplantation,2004,78 (4):494-502.
[29] 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．中华结核和呼吸杂志．2005,28(3)：169-172．
[30] Thompson AB,Daughton D,Robbins RA,et al.Intralurninal airway inflammation in chronic bronchitis.Am Rev Respir Dis, 1989,140:1527.
[31] 林挺岩，李志鹰，刘青，等．老年慢性阻塞性肺病血白介素-8、肿瘤坏死因子、内皮素临床研究．中国老年学杂志,2004,21：16-17．
[32] 农凌波，肖正伦．肿瘤坏死因子α、白细胞介素1β对牛肺动脉内皮细胞凋亡的影响及意义．中华结核和呼吸杂志,2003,26(11)：668-670．
[33] 金惠铭，刘清行，曹翔等．TNF-α引起的微血管内皮细胞功能障碍及其细胞分子机制．微循环学杂志,2000,10(3)：5-6．
[34] Chen J,Li D,Zhang X,et al.Tumor necrosis factor-alpha-induced apoptosis of human coronary artery endothelial cells: modulation by the peroxisome proliferator-activated receptor-gamma ligand pioglitazone.JCardiovasc Phar-macol Ther.2004,9(1):35-41.
[35] Kasahara Y,Tuder RM, Cool CD,et al.Endothelial Cell Death and Decreased Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor2 in Emphysema.Am J Respir Crit Care Med,2001,163(3Pt 1):737-44.
[36] Gerber HP,McMurtrey A, Kowalski J,et al.Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway:requirement for Flr/KDR activation.J Biol Chem,1998, 273:30336-30343.
[37] Alon T,Hemo I,Itin A,et al.Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.Nat Med, 1995,1 (10): 1024-1028.
[38] 王悦虹，白春学，洪群英，等．血管内皮细胞生长因子及其受体在大鼠肺气肿模型中的表达．复旦学报(医学版)，2004,31(5)：488-491．
[39] 王悦虹，白春学，毛翎，等．血管内皮生长因子及其受体在肺气肿患者肺组织中的表达．中华内科杂志,2005,44(4)：276-279．
[40] Liebow AA.Pulmonary emphysema with special reference to vascular changes.Am Rev Respir Dis,1959,80:67-93.
[41] Hoshino S,Yoshida M,Inoue K,et al.Cigarette smoke extract induces endothelial cell injury via JNK pathway.Bioehem Biophys Res Commun,2005,329(1):58-63.
[42] Zhang J,Jin B,Li L,et al.Nitric oxide-induced persistent inhibition and nitrosylation of active site eysteine residues of mitochondrial cytochrome-c oxidase in lung endothelial cells.Am J Physiol Cell Physiol,2005,288 (4):C840-849.
[43] Petrache I,Fijalkowska I,Zhen L.A novel antiapoptotic role for alphal-antitrypsin in the prevention of pulmonary emphysema. Am J Respir Crit Care Med, 2006, 173(11): 1222-1228.
[44] Grassi V,Carminati L, Cossi S,et al.Chronic obstructive lung disease.Systemic manifestations.Recenti Prog Med,2003,94(5):217-26.
[45] 蔡柏蔷．慢性阻塞性肺疾病患者的营养支持．见：蔡柏蔷主编．呼吸内科学．北京：中国协和医科大学出版社,2000,372-385．
[46] Deveci F,Tug T,Turgut T,et al.Nutfitional status,pulmonary functions,and exercise performance in COPD cases.Tuberk Toraks,2005,53(4):330-339.
[47] 詹娟，孙圣华．COPD患者缺氧对TNF-α系统的激活及与营养不良的相关性．医学临床研究,2003,20(12)：881-884．
[1] Pauwels RA,Buist AS,Calverley PM,Jenkins CR, Hurd SS:Global strategy for the diagnosis,management,and prevention of chronic obstructive pulmonary disease.NHLB I/WHO Global Initiative for Chronic Obstructive Lung Disease(GOLD) Workshop summary. Am J Respir Crit Care Med 2001,163:1256-1276.
[2] Barnes PJ,Shapiro SD,Pauwels RA.Chronic obstructive pulmonary disease: molecular and cellular mechanisms.Eur Respir J,2003,22(4):672-688.
[3] Naoko Yokohori,Kazutetsu Aoshiba,Atsushi Nagai.Increased Levels of Cell Death and Proliferation in Alveolar Wall Cells in Patients With Pulmonary Emp- hysema. Chest.2004,125:626-632.
[4] 农凌波，肖正伦．肿瘤坏死因子α、白细胞介素1β对牛肺动脉内皮细胞凋亡的影 响及意义．中华结核和呼吸杂志,2003,26(11)：668-670．
[5] 张敬芳，王光浩．TNF-α诱导HUVEC的损伤及其意义．荆门职业技术学院学报,2002,17(6)：82-84．
[6] 金惠铭，刘清行，曹翔，等．TNF-α引起的微血管内皮细胞功能障碍及其细胞分子机制．微循环学杂志,2000,10(3)：5-6．
[7] Chen J,Li D, Zhang X, et al.Tumor necrosis factor-alpha-induced apoptosis of human coronary artery endothelial cells:modulation by the peroxisome proliferator-activated receptor-gamma ligand pioglitazone.J Cardiovasc Pharmacol Ther,2004,9(1):35-41.
[8] Gerbitz A,Nickoloff BJ,Olkiewicz K,et al.A role for tumor necrosis factor-alpha-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome.Transplantation,2004,78 (4):494-502.
[9] Aoshiba K,Yasui S,Nagai A.Apoptosis of Alveolar Macrophages by Cigarette Smoke.Chest,2000,117(5 Suppl 1): 320S.
[10] W. I. de Boer, PhD.Cytokines and Therapy in COPDA Promising Combination? Chest 2002,121:209S-218S.
[11] 罗红，陈平，王修文，等．慢性阻塞性肺疾病患者气道炎症与肺泡巨噬细胞白细胞介素8活性的研究．中华结核和呼吸杂志，1999；22(10)：635-636．
[12] 陈平，蔡珊，朱应群，等．肺泡巨噬细胞在慢性阻塞性肺疾病气道炎症中的作用．中华内科杂志,200l,40(4)：232-235．
[13] 刘杰波，陈平．慢性支气管炎气道巨噬细胞计数及淋巴细胞功能相关抗原1的研究．中华结核和呼吸杂志,200 1,24(5)：280-282．
[14] 彭红，陈平，蔡珊．慢性支气管炎患者肺泡巨噬细胞及诱导痰中内皮素的研究．中华结核和呼吸杂志,200l,24(6)：351-354．
[15] 蔡珊，陈平，朱应群等．慢性阻塞性肺疾病气道炎症与肺泡巨噬细胞炎症蛋白1α明胶酶B活性的研究冲华结核和呼吸杂志,2001,24(7)：429-432．
[16] 张永，程德云，王慧，等．慢性阻塞性肺疾病大鼠肺内白细胞介素．8和肿瘤坏死因子-α与气道炎症的关系研究。中国呼吸与危重监护杂志,2003,2(6)：355-359．
[17] 林挺岩，李玉珠，李志鹰，等．慢性阻塞性肺病血白细胞介素-8、肿瘤坏死因子α、内皮素与肺功能的关系．福建医科大学学报,2000,34(4)：347-349．
[18] 董平，孔令敏，陈文靖，等．COPD急性发作期白介素-8、肿瘤坏死因子-α的表达与预后分析．中国厂矿医学．2002,15(2)：99-100．
[19] UlichTR,YinS,GuoK,etal.Intracheal injection of endotoxin and cytokine: interleukin-6 and transforming growth factor beta inhibit acute inflammation.Am J Pathol, 1991,138:1097.
[20] Hasday JD,McCreaSS,etal.Dysredulation of airway cytokine expression in chronic obstctive pulmonary disease and asthma.Am J Respin Care Med, 1994,150(supple):54.
[21] 王胜，徐凤珍，陈余清．慢性阻塞性肺疾病患者痰液白细胞介素8，6和肿瘤坏死因子测定及其意义．中华结核和呼吸杂志,2000,23(8)：465-467．
[22] Andrew Churg, Rong D.Wang,Hsin Tai,et al.Tumor Necrosis Factor-αDrives 70% of Cigarette Smoke-induced Emphysema in the Mouse.American Journal of Respiratory and Critical Care Medicine ,2004,170:492-498.
[23] 李亚清，张珍祥，徐永健，等．COPD患者肺泡巨噬细胞源性MMP-9的表达及其酶活性变化．中华内科杂志,2006,45(1)：38-41．
[24] 林厅岩，李志鹰，刘青，等．老年慢性阻塞性肺病血白介素-8、肿瘤坏死因子、内皮素临床研究．中国老年学杂志,2004,24(1)：16-17．
[25] 王伟，徐少华，柳相珍，等．慢性阻塞性肺疾病急性发作期外周血及痰中IL-8和TNF-α测定的意义．现代免疫学,2004,24(1)：63-65．
[26] 蔡柏蔷．慢性阻塞性肺疾病患者的营养支持．见：蔡柏蔷主编．呼吸内科学．北京：中国协和医科大学出版社,2000,372-385．
[27] Grassi V,Carminati L, Cossi S,et al.Chronic obstructive lung disease.Systemic manifestations.Recenti Prog Med,2003,94(5):217-26.
[28] 徐卫国，罗勇，吴靖川，等．不同营养状态COPD肿瘤坏死因子-α测定及其临床意义．中国实用内科杂志，1999,19(11)：654-655．
[29] Pitsiou G,Kyriazis G,Hatzizisi O,et al.Tumor necrosis factor-alpha serum levels,weight loss and tissue oxygenation in chronic obstructive pulmonary disease.Respir Med.2002,96(8):594-8.
[30] 徐卫国，罗勇，董欢霁，等．COPD患者静息能量消耗与肿瘤坏死因子-α的相关性研究．上海第二医科大学学报,2005,25(10)：1054-1056．
[31] Auwerx J, Staels B. Leptin. Lancet 1998, 351:737-742.
[32] Tartaglia LA. The leptin receptor. J Biol Chem 1997,272:6093-6096.
[33] CalikogluM,SahinG,UnluA,etal.Leptin and TNFalpha.Levels in patients with chronic obstructive pulmonary disease and Their relationship to nutritional parameters.Respiration,2004,71 (1):45-50.
[34] Yang YM,Sun TY,Liu XM.The role of serum leptin and tumor necrosis factor-alpha in malnutrition of male chronic obstructive pulmonary disease patients.Chin Med J (Engl),2006,119(8):628-33.
[35] 詹娟，孙圣华．COPD患者缺氧对TNF-α系统的激活及与营养不良的相关性．医学临床研究,2003,20(12)：881-884．
[36] Taylor CT, Fueki N,Agah A,et al.Critieal role of cAMP response element binding protein expression in hypoxia-elicited induction of epithelial tumor necrosis factor-alpha.J Biol them, 1999,274(27): 19447-54.
[37] 吴健峰，曾勉．慢性阻塞性肺疾病急性加重期患者诱导痰中的TNF-α和可溶性TNF受体55水平．中华内科杂志,2005,44(4)：307-308．
[38] 胡大伟，鲍春德，陈顺乐，等．重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗类风湿关节炎双盲随机多中心对照临床研究．中华风湿病学杂志,2005,9(11)：664-668．
[39] Hester van der Vaart, Gerard H Koeter, Dirkje S Postma,et al.First Study of Infliximab Treatment in Patients with Chronic Obstructive Pulmonary Disease.American Journal of Respiratory and Critical Care Medicine,2005,172(4):4655.
[40] 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．中华结核和呼吸杂志,2005,28(3)：169-172．
[41] Hoshino S,Yoshida M,Inoue K, et al.Cigarette smoke extract induces endothelial cell injury via JNK pathway.Biochem Biophys Res Commtm,2005,329(1):58-63.
[42] Petrache I,Fijalkowska I,Zhen L.A novel antiapoptotic role for alphal-antitrypsin in the prevention of pulmonary emphysema.Am J Respir Crit Care Med,2006,173(11):1222-1228.
[43] Demedts IK, Demoor T,Braeke KR, et al.Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res,2006,7(1):53.
[44] Voelkel NF,Cool CD.Pulrnonary vascular involvement in chronic obstructive pulmonary disease.Eur Respir J Suppl,2003,46:28s-32s.
[45] 王悦虹，白春学，洪群英，等．血管内皮细胞生长因子及其受体在大鼠肺气肿模型中的表达．复旦学报(医学版)，2004,31(5)：488-491．
[46] 王悦虹，白春学，毛翎，等．血管内皮生长因子及其受体在肺气肿患者肺组织中的表达．中华内科杂志,2005,44(4)：276-279．
[47] Kasahara Y, Tuder RM,Cool CD,et al.Endothelial Cell Death and Decreased Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor2 in Emphysema.Am J Respir Crit Care Med,2001,163(3Pt 1):737-44.
[48] Gerber HP,MeMurtrey A,Kowalski J,et al.Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway:requirement for Flr/KDR activation. J Biol Chem, 1998,273:30336-30343.
[49]Alon T,Hemo I,Itin A,et al.Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.Nat Med,1995,l (10):1024-1028.
[50]Kasahara Y,Tuder RM,Taraseviciene-Stewart L,et al.Inhibition of VEGF receptors causes lung cell apoptosis and emphysema.J Clin Invest,2000,106 (11):1311-1319.
[51] Zhang J,Jin B,Li L,et al.Nitric oxide-induced persistent inhibition and nitrosylation of active site cysteine residues of mitochondrial cytochrome-c oxidase in lung endothelial cells.Am J Physiol Cell Physiol,2005,288 (4):C840-849.
[52] Rubin M.Tuder, Irina Petrache,Jack A.Elias,et al.Apoptosis and Emphysema American Journal of Respiratory Cell and Molecular Biology. 2003,28:551-554.
[53]Zhao B,Smith G,Cai J,et al.VEGF-C Promotes Survival of Retinal Vascular Endothelial Cells via VEGFR-2. Br J Ophthalmol.2007,91(4):538-45.
[54]Tuder RM,Zhen L,Cho CY,et al.Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade.Am J Respir Cell Mol Biol, 2003,29(l):88-97.
[2] Barnes PJ,Shapiro SD,Pauwels RA.Chronic obstructive pulmonary disease:molecular and cellular mechanisms.Eur Respir J,2003,22(4): 672-688.
[3] 张永，程德云，王慧，等．慢性阻塞性肺疾病大鼠肺内白细胞介素-8和肿瘤坏死因子-α与气道炎症的关系研究．中国呼吸与危重监护杂志,2003,2(6)：355-359．
[4] Hester van der Vaart,Gerard H Koeter, Dirkje S Postma, et al.First Study of Infliximab Treatment in Patients with Chronic Obstructive Pulmonary Disease.American Journal of Respiratory and Critical Care Medicine,2005,172(4):4655.
[5] Cristina Russo,Francesca D'Angelo,Riccardo Polosa.Study of Inflixlmab Treatment in Smokers with COPD: What Next?.Amedcan Journal of Resp-iratory and Critical Care Medicine,2005,172(12) 1606-1608.
[6] 陈劲龙，冉丕鑫．血管内皮生长因子与烟雾暴露所致大鼠肺气肿发病关系的研究．中华结核和呼吸杂志,2003，26：671-674．
[7] 陈涛，吴亚梅．胶原酶/组织金属蛋白酶抑制剂-1免疫活性及其在慢性阻塞性肺疾病肺结构改变中的作用．中国呼吸与危重监护杂志,2004，3：387-391．
[8] 罗红，陈平，王修文等．慢性阻塞性肺疾病患者气道炎症与肺泡巨噬细胞白细胞介素8活性的研究．中华结核和呼吸杂志,1999，22(10)：635-636．
[9] 陈平，蔡珊，朱应群等．肺泡巨噬细胞在慢性阻塞性肺疾病气道炎症中的作用．中华内科杂志,2001，40(4)：232-235.
[10] 刘杰波，陈平．慢性支气管炎气道巨噬细胞计数及淋巴细胞功能相关抗原1的研究．中华结核和呼吸杂志,2001,24(5)：280-282．
[11] 彭红胨平，蔡珊．慢性支气管炎患者肺泡巨噬细胞及诱导痰中内皮素的研究．中华结核和呼吸杂志,2001,24(6)：351-354．
[12] 蔡珊，陈平，朱应群等．慢性阻塞性肺疾病气道炎症与肺泡巨噬细胞炎症蛋白1α、明胶酶B活性的研究．中华结核和呼吸杂志,2001,24(7)：429-432
[13] 郑灵，张劲农．阻塞性肺气肿损伤与抗损伤机制．国外医学呼吸系统分册,2005，25(10)：736-738．
[14] 庞宝森，李远红，张洪玉．慢性阻塞性肺疾病动物模型的研究进展．心肺血管病杂志，2005，24(1)：45-46．
[15] Wright JL,Churg A.Cigarette smoke causes physiologic and morphologic changes of emphysema in the guinea pig.Am Rev Respir Dis, 1990,142(6Pt 1): 1422-1428.
[16] Stolk J,Rudolphus A,Davies P, et al.Induction of emphysema and bronchial mucus cell hyperplasia by intratracheal instillation of lipopolysaccharide in the hamster.J Pathol, 1992,167(3):349-356.
[17] Boyd RL,Fisher MJ,Jaeger MJ.Non-invasive lung function tests in rats with progressive papain-induced emphysema.Respir Physiol, 1980,40(2): 181-190.
[18] Chitano P, Hosselet JJ,Mapp CE.Effect of oxidant air pollutants on the respiratory system:insights from experimental animal research.Eur Respir J,1995,8:1357-1371.
[19] Taraseviciene-Stewart L,Scerbavicius R, Choe KH,et al.An animal model of autoimmune emphysema.Am J Respir Crit Care Med,2005,171(7):734-742.
[20] Mukhopadhyay S,Hoidal JR, Mukherjee TK.Role of TNF alpha in pulmonary pathophysiology.Respir Res,2006,7(1): 125.
[21] 林挺岩，李玉珠，李志鹰，等．慢性阻塞性肺病血白细胞介素-8、肿瘤坏死因子α、内皮素与肺功能的关系．福建医科大学学报,2000,34(4)：347-349．
[22] 董平，孔令敏，陈文靖，等．COPD急性发作期白介素-8、肿瘤坏死因子-α的表达与预后分析．中国厂矿医学．2002,15(2)：99-100．
[23] De Boer WI.Cytokines and therapy in COPD:a promising combina-tion?.Chest,2002,121 (3):209-218.
[24] 王胜，徐凤珍，陈余清．慢性阻塞性肺疾病患者痰液白细胞介素8，6和肿瘤坏死因子测定及其意义．中华结核和呼吸杂志,2000，23(8)：465-467．
[25] 李亚清，张珍祥，徐永健，等．COPD患者肺泡巨噬细胞源性MMP-9的表达及其酶活性变化．中华内科杂志,2006,45(1)：38-41．
[26] Andrew Churg,Rong D.Wang, Hsin Tai,et al.Tumor Necrosis Factor-αtDrives 70% of Cigarette Smoke-induced Emphysema in the Mouse.American Journal of Respiratory and Critical Care Medicine,2004,170:492-498.
[27] 胡大为，鲍春德，陈顺乐，等．重组人Ⅱ型肿瘤坏死因子受体．抗体融合蛋白治疗类风湿关节炎双盲随机多中心对照临床研究．中华风湿病学杂志,2005,9(11)：664-668．
[28] Gerbitz A,Nickoloff BJ,Olkiewicz K, et al.A role for tumor necrosis factor-alpha-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome.Transplantation,2004,78 (4):494-502.
[29] 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．中华结核和呼吸杂志．2005,28(3)：169-172．
[30] Thompson AB,Daughton D,Robbins RA,et al.Intralurninal airway inflammation in chronic bronchitis.Am Rev Respir Dis, 1989,140:1527.
[31] 林挺岩，李志鹰，刘青，等．老年慢性阻塞性肺病血白介素-8、肿瘤坏死因子、内皮素临床研究．中国老年学杂志,2004,21：16-17．
[32] 农凌波，肖正伦．肿瘤坏死因子α、白细胞介素1β对牛肺动脉内皮细胞凋亡的影响及意义．中华结核和呼吸杂志,2003,26(11)：668-670．
[33] 金惠铭，刘清行，曹翔等．TNF-α引起的微血管内皮细胞功能障碍及其细胞分子机制．微循环学杂志,2000,10(3)：5-6．
[34] Chen J,Li D,Zhang X,et al.Tumor necrosis factor-alpha-induced apoptosis of human coronary artery endothelial cells: modulation by the peroxisome proliferator-activated receptor-gamma ligand pioglitazone.JCardiovasc Phar-macol Ther.2004,9(1):35-41.
[35] Kasahara Y,Tuder RM, Cool CD,et al.Endothelial Cell Death and Decreased Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor2 in Emphysema.Am J Respir Crit Care Med,2001,163(3Pt 1):737-44.
[36] Gerber HP,McMurtrey A, Kowalski J,et al.Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway:requirement for Flr/KDR activation.J Biol Chem,1998, 273:30336-30343.
[37] Alon T,Hemo I,Itin A,et al.Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.Nat Med, 1995,1 (10): 1024-1028.
[38] 王悦虹，白春学，洪群英，等．血管内皮细胞生长因子及其受体在大鼠肺气肿模型中的表达．复旦学报(医学版)，2004,31(5)：488-491．
[39] 王悦虹，白春学，毛翎，等．血管内皮生长因子及其受体在肺气肿患者肺组织中的表达．中华内科杂志,2005,44(4)：276-279．
[40] Liebow AA.Pulmonary emphysema with special reference to vascular changes.Am Rev Respir Dis,1959,80:67-93.
[41] Hoshino S,Yoshida M,Inoue K,et al.Cigarette smoke extract induces endothelial cell injury via JNK pathway.Bioehem Biophys Res Commun,2005,329(1):58-63.
[42] Zhang J,Jin B,Li L,et al.Nitric oxide-induced persistent inhibition and nitrosylation of active site eysteine residues of mitochondrial cytochrome-c oxidase in lung endothelial cells.Am J Physiol Cell Physiol,2005,288 (4):C840-849.
[43] Petrache I,Fijalkowska I,Zhen L.A novel antiapoptotic role for alphal-antitrypsin in the prevention of pulmonary emphysema. Am J Respir Crit Care Med, 2006, 173(11): 1222-1228.
[44] Grassi V,Carminati L, Cossi S,et al.Chronic obstructive lung disease.Systemic manifestations.Recenti Prog Med,2003,94(5):217-26.
[45] 蔡柏蔷．慢性阻塞性肺疾病患者的营养支持．见：蔡柏蔷主编．呼吸内科学．北京：中国协和医科大学出版社,2000,372-385．
[46] Deveci F,Tug T,Turgut T,et al.Nutfitional status,pulmonary functions,and exercise performance in COPD cases.Tuberk Toraks,2005,53(4):330-339.
[47] 詹娟，孙圣华．COPD患者缺氧对TNF-α系统的激活及与营养不良的相关性．医学临床研究,2003,20(12)：881-884．
[1] Pauwels RA,Buist AS,Calverley PM,Jenkins CR, Hurd SS:Global strategy for the diagnosis,management,and prevention of chronic obstructive pulmonary disease.NHLB I/WHO Global Initiative for Chronic Obstructive Lung Disease(GOLD) Workshop summary. Am J Respir Crit Care Med 2001,163:1256-1276.
[2] Barnes PJ,Shapiro SD,Pauwels RA.Chronic obstructive pulmonary disease: molecular and cellular mechanisms.Eur Respir J,2003,22(4):672-688.
[3] Naoko Yokohori,Kazutetsu Aoshiba,Atsushi Nagai.Increased Levels of Cell Death and Proliferation in Alveolar Wall Cells in Patients With Pulmonary Emp- hysema. Chest.2004,125:626-632.
[4] 农凌波，肖正伦．肿瘤坏死因子α、白细胞介素1β对牛肺动脉内皮细胞凋亡的影 响及意义．中华结核和呼吸杂志,2003,26(11)：668-670．
[5] 张敬芳，王光浩．TNF-α诱导HUVEC的损伤及其意义．荆门职业技术学院学报,2002,17(6)：82-84．
[6] 金惠铭，刘清行，曹翔，等．TNF-α引起的微血管内皮细胞功能障碍及其细胞分子机制．微循环学杂志,2000,10(3)：5-6．
[7] Chen J,Li D, Zhang X, et al.Tumor necrosis factor-alpha-induced apoptosis of human coronary artery endothelial cells:modulation by the peroxisome proliferator-activated receptor-gamma ligand pioglitazone.J Cardiovasc Pharmacol Ther,2004,9(1):35-41.
[8] Gerbitz A,Nickoloff BJ,Olkiewicz K,et al.A role for tumor necrosis factor-alpha-mediated endothelial apoptosis in the development of experimental idiopathic pneumonia syndrome.Transplantation,2004,78 (4):494-502.
[9] Aoshiba K,Yasui S,Nagai A.Apoptosis of Alveolar Macrophages by Cigarette Smoke.Chest,2000,117(5 Suppl 1): 320S.
[10] W. I. de Boer, PhD.Cytokines and Therapy in COPDA Promising Combination? Chest 2002,121:209S-218S.
[11] 罗红，陈平，王修文，等．慢性阻塞性肺疾病患者气道炎症与肺泡巨噬细胞白细胞介素8活性的研究．中华结核和呼吸杂志，1999；22(10)：635-636．
[12] 陈平，蔡珊，朱应群，等．肺泡巨噬细胞在慢性阻塞性肺疾病气道炎症中的作用．中华内科杂志,200l,40(4)：232-235．
[13] 刘杰波，陈平．慢性支气管炎气道巨噬细胞计数及淋巴细胞功能相关抗原1的研究．中华结核和呼吸杂志,200 1,24(5)：280-282．
[14] 彭红，陈平，蔡珊．慢性支气管炎患者肺泡巨噬细胞及诱导痰中内皮素的研究．中华结核和呼吸杂志,200l,24(6)：351-354．
[15] 蔡珊，陈平，朱应群等．慢性阻塞性肺疾病气道炎症与肺泡巨噬细胞炎症蛋白1α明胶酶B活性的研究冲华结核和呼吸杂志,2001,24(7)：429-432．
[16] 张永，程德云，王慧，等．慢性阻塞性肺疾病大鼠肺内白细胞介素．8和肿瘤坏死因子-α与气道炎症的关系研究。中国呼吸与危重监护杂志,2003,2(6)：355-359．
[17] 林挺岩，李玉珠，李志鹰，等．慢性阻塞性肺病血白细胞介素-8、肿瘤坏死因子α、内皮素与肺功能的关系．福建医科大学学报,2000,34(4)：347-349．
[18] 董平，孔令敏，陈文靖，等．COPD急性发作期白介素-8、肿瘤坏死因子-α的表达与预后分析．中国厂矿医学．2002,15(2)：99-100．
[19] UlichTR,YinS,GuoK,etal.Intracheal injection of endotoxin and cytokine: interleukin-6 and transforming growth factor beta inhibit acute inflammation.Am J Pathol, 1991,138:1097.
[20] Hasday JD,McCreaSS,etal.Dysredulation of airway cytokine expression in chronic obstctive pulmonary disease and asthma.Am J Respin Care Med, 1994,150(supple):54.
[21] 王胜，徐凤珍，陈余清．慢性阻塞性肺疾病患者痰液白细胞介素8，6和肿瘤坏死因子测定及其意义．中华结核和呼吸杂志,2000,23(8)：465-467．
[22] Andrew Churg, Rong D.Wang,Hsin Tai,et al.Tumor Necrosis Factor-αDrives 70% of Cigarette Smoke-induced Emphysema in the Mouse.American Journal of Respiratory and Critical Care Medicine ,2004,170:492-498.
[23] 李亚清，张珍祥，徐永健，等．COPD患者肺泡巨噬细胞源性MMP-9的表达及其酶活性变化．中华内科杂志,2006,45(1)：38-41．
[24] 林厅岩，李志鹰，刘青，等．老年慢性阻塞性肺病血白介素-8、肿瘤坏死因子、内皮素临床研究．中国老年学杂志,2004,24(1)：16-17．
[25] 王伟，徐少华，柳相珍，等．慢性阻塞性肺疾病急性发作期外周血及痰中IL-8和TNF-α测定的意义．现代免疫学,2004,24(1)：63-65．
[26] 蔡柏蔷．慢性阻塞性肺疾病患者的营养支持．见：蔡柏蔷主编．呼吸内科学．北京：中国协和医科大学出版社,2000,372-385．
[27] Grassi V,Carminati L, Cossi S,et al.Chronic obstructive lung disease.Systemic manifestations.Recenti Prog Med,2003,94(5):217-26.
[28] 徐卫国，罗勇，吴靖川，等．不同营养状态COPD肿瘤坏死因子-α测定及其临床意义．中国实用内科杂志，1999,19(11)：654-655．
[29] Pitsiou G,Kyriazis G,Hatzizisi O,et al.Tumor necrosis factor-alpha serum levels,weight loss and tissue oxygenation in chronic obstructive pulmonary disease.Respir Med.2002,96(8):594-8.
[30] 徐卫国，罗勇，董欢霁，等．COPD患者静息能量消耗与肿瘤坏死因子-α的相关性研究．上海第二医科大学学报,2005,25(10)：1054-1056．
[31] Auwerx J, Staels B. Leptin. Lancet 1998, 351:737-742.
[32] Tartaglia LA. The leptin receptor. J Biol Chem 1997,272:6093-6096.
[33] CalikogluM,SahinG,UnluA,etal.Leptin and TNFalpha.Levels in patients with chronic obstructive pulmonary disease and Their relationship to nutritional parameters.Respiration,2004,71 (1):45-50.
[34] Yang YM,Sun TY,Liu XM.The role of serum leptin and tumor necrosis factor-alpha in malnutrition of male chronic obstructive pulmonary disease patients.Chin Med J (Engl),2006,119(8):628-33.
[35] 詹娟，孙圣华．COPD患者缺氧对TNF-α系统的激活及与营养不良的相关性．医学临床研究,2003,20(12)：881-884．
[36] Taylor CT, Fueki N,Agah A,et al.Critieal role of cAMP response element binding protein expression in hypoxia-elicited induction of epithelial tumor necrosis factor-alpha.J Biol them, 1999,274(27): 19447-54.
[37] 吴健峰，曾勉．慢性阻塞性肺疾病急性加重期患者诱导痰中的TNF-α和可溶性TNF受体55水平．中华内科杂志,2005,44(4)：307-308．
[38] 胡大伟，鲍春德，陈顺乐，等．重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗类风湿关节炎双盲随机多中心对照临床研究．中华风湿病学杂志,2005,9(11)：664-668．
[39] Hester van der Vaart, Gerard H Koeter, Dirkje S Postma,et al.First Study of Infliximab Treatment in Patients with Chronic Obstructive Pulmonary Disease.American Journal of Respiratory and Critical Care Medicine,2005,172(4):4655.
[40] 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．中华结核和呼吸杂志,2005,28(3)：169-172．
[41] Hoshino S,Yoshida M,Inoue K, et al.Cigarette smoke extract induces endothelial cell injury via JNK pathway.Biochem Biophys Res Commtm,2005,329(1):58-63.
[42] Petrache I,Fijalkowska I,Zhen L.A novel antiapoptotic role for alphal-antitrypsin in the prevention of pulmonary emphysema.Am J Respir Crit Care Med,2006,173(11):1222-1228.
[43] Demedts IK, Demoor T,Braeke KR, et al.Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res,2006,7(1):53.
[44] Voelkel NF,Cool CD.Pulrnonary vascular involvement in chronic obstructive pulmonary disease.Eur Respir J Suppl,2003,46:28s-32s.
[45] 王悦虹，白春学，洪群英，等．血管内皮细胞生长因子及其受体在大鼠肺气肿模型中的表达．复旦学报(医学版)，2004,31(5)：488-491．
[46] 王悦虹，白春学，毛翎，等．血管内皮生长因子及其受体在肺气肿患者肺组织中的表达．中华内科杂志,2005,44(4)：276-279．
[47] Kasahara Y, Tuder RM,Cool CD,et al.Endothelial Cell Death and Decreased Expression of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor2 in Emphysema.Am J Respir Crit Care Med,2001,163(3Pt 1):737-44.
[48] Gerber HP,MeMurtrey A,Kowalski J,et al.Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway:requirement for Flr/KDR activation. J Biol Chem, 1998,273:30336-30343.
[49]Alon T,Hemo I,Itin A,et al.Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity.Nat Med,1995,l (10):1024-1028.
[50]Kasahara Y,Tuder RM,Taraseviciene-Stewart L,et al.Inhibition of VEGF receptors causes lung cell apoptosis and emphysema.J Clin Invest,2000,106 (11):1311-1319.
[51] Zhang J,Jin B,Li L,et al.Nitric oxide-induced persistent inhibition and nitrosylation of active site cysteine residues of mitochondrial cytochrome-c oxidase in lung endothelial cells.Am J Physiol Cell Physiol,2005,288 (4):C840-849.
[52] Rubin M.Tuder, Irina Petrache,Jack A.Elias,et al.Apoptosis and Emphysema American Journal of Respiratory Cell and Molecular Biology. 2003,28:551-554.
[53]Zhao B,Smith G,Cai J,et al.VEGF-C Promotes Survival of Retinal Vascular Endothelial Cells via VEGFR-2. Br J Ophthalmol.2007,91(4):538-45.
[54]Tuder RM,Zhen L,Cho CY,et al.Oxidative stress and apoptosis interact and cause emphysema due to vascular endothelial growth factor receptor blockade.Am J Respir Cell Mol Biol, 2003,29(l):88-97.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |