MMP-9/TIMP-1、RANTES在哮喘大鼠气道重塑中的作用及地塞米松干预的影响
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摘要
背景:支气管哮喘(Bronchial Asthma)简称哮喘,是儿童期最常见的慢性呼吸道疾病,是由多种细胞如肥大细胞、嗜酸性粒细胞、T淋巴细胞等参与的慢性气道炎症,临床表现为反复发作性喘息,呼吸困难、胸闷或咳嗽,全球哮喘患病率呈上升趋势。持续气道炎症使气道反复损伤、修复,将导致气道结构变化即发生气道重塑,主要表现为平滑肌细胞增生肥大,上皮下胶原沉积,杯状细胞增生,新血管生成等。其中细胞外基质(extracellular matrix, ECM)在气管上皮下的异常沉积是哮喘特征性病理改变。金属基质蛋白酶(matrix metalloproteinases, MMPs)为调节ECM代谢的主要限速酶,可降解ECM的大多数成分。金属蛋白酶组织抑制剂(tissue inhibitor of metalloproteinases, TIMP)-1可1:1与MMP-9结合,特异性抑制MMP-9的活性。MMP-9/TIMP-1失衡导致细胞外基质代谢异常,可能参与哮喘气道重塑过程。正常T细胞表达和分泌的活性调节蛋白(regulated upon activation normal T cell expressed and secreted, RANTES)属于半胱氨酸-半胱氨酸(Cys-Cys, CC)类趋化因子,又称CCL5,由多种炎性细胞分泌,它对嗜酸性粒细胞、单核细胞、树突状细胞、淋巴细胞、NK细胞等有趋化作用,尤其是对嗜酸性粒细胞强大的趋化作用,可加重哮喘气道炎症,参与气道重塑的发生。
目的:通过光镜观察实验大鼠气道病理变化,计算机图像分析软件量化气道壁增厚情况,了解哮喘气道重塑情况;
检测大鼠气道MMP-9、TIMP-1及肺泡灌洗液RANTES的表达水平,探讨MMP-9/TIMP-1在哮喘气道重塑中的作用,分析MMP-9/TIMP-1与RANTES的相关性。
方法:按照完全随机分组法,将36只雄性Wister大鼠分为哮喘模型组(A组)、地塞米松干预组(B组)、正常对照组(C组)三组。采用卵白蛋白(Ovalbumin, OVA)和氢氧化铝的复合制剂致敏、OVA激发方法。第1、7、14天,A、B组大鼠分别给予腹腔注射10%卵白蛋白与氢氧化铝混悬液1ml/只致敏,C组则相应给予腹腔注射生理盐水1ml/只。第21天A、B组开始雾化吸入1%的卵白蛋白激发喘息发作,每次雾化吸入30分钟,隔天1次,共6周,C组雾化吸入0.9%生理盐水作为对照。B组自雾化激发后1周起雾化前半小时予尾静脉注射地塞米松0.5mg/Kg每周3次,共5周,A、C组对应给予0.9%生理盐水0.5ml尾静脉注射。三组大鼠均于末次雾化吸入后24小时进行1%戊巴比妥钠0.2ml/Kg腹腔注射麻醉开胸,结扎左肺取肺组织固定、包埋;行气管插管,用生理盐水5ml冲洗5次回收右肺肺泡灌洗液,1000转低温离心5分钟,取上清。
制作左肺组织的HE染色切片,光镜观察各组切片中气道的病理学变化,多功能彩色病理图像分析仪测量切片中支气管横截面的基底膜周径(bronchial basement membrane perimeter, Pbm),气道平滑肌面积(airway smooth muscle area, WAm),气道内壁面积(inner way area , WAi),以WAm/Pbm和WAi/Pbm作为气道重塑指标;将左肺组织切片用免疫组化方法标记MMP-9、TIMP-1,并应用多功能彩色病理图像分析仪测定MMP-9、TIMP-1积分光密度(integral optical density, IOD);双抗体夹心酶联免疫吸附试验(ELISA)检测右侧肺泡灌洗液RANTES水平。
采用SPSS10.0统计软件,对组间WAm/Pbm和WAi/Pbm、MMP-9和TIMP-1数据进行单因素方差分析,P<0.05为差异有统计学意义,将MMP-9/TIMP-1与RANTES做相关性分析,计算相关系数r,P<0.05有统计学意义。
结果:哮喘模型组致敏的大鼠,在雾化OVA时均出现喘息发作,雾化6周后,大鼠左肺支气管HE染色的病理切片中出现平滑肌、管壁增厚的重构现象,检测切片中气道平滑肌面积/基底膜周径(WAm/Pbm)和气道内壁面积/基底膜周径( WAi/Pbm )分别为5.78±1.36μm~2/μm, 15.10±3.99μm~2/μm较正常对照组明显增大(P<0.05)。地塞米松干预组在第一周雾化OVA即出现喘息发作,在第二周应用地塞米松后喘息减轻,雾化6周后,其左肺支气管HE染色切片中气道重塑现象不明显,测量气道管壁WAm/Pbm和WAi/Pbm为3.98±1.25μm~2/μm, 9.86±2.47μm~2/μm,较哮喘模型组气道为轻(P<0.05)。
哮喘模型组大鼠左肺组织中MMP-9和TIMP-1的平均积分光密度(IOD)(1.7655±1.0476, 1.958±0.0927)及右肺肺泡灌洗液RANTES表达水平(18.20±4.00?pg/ml)明显高于正常对照组、地塞米松干预组(P<0.05),地塞米松干预组MMP-9和TIMP-1的平均IOD(0.8525±0.0231, 0.876±0.0302)及肺泡灌洗液中RANTES水平(9.28±2.26pg/ml)与正常对照组无明显差别(P>0.05)。MMP-9/TIMP-1在哮喘模型比例失衡,与肺泡灌洗液RANTES水平呈负相关(r=-0.141,P<0.05)。
结论:哮喘时MMP-9、TIMP-1及RANTES的表达水平均提高,可能有加重气道炎症的作用;哮喘时MMP-9/TIMP-1比例失调,与炎性细胞趋化因子RANTES水平呈负相关,与ECM的降解与沉积有关,参与气道重塑的发生;地塞米松对RANTES及MMP-9、TIMP-1表达有明显的抑制作用,减轻气道重塑。
Background: Referred to as asthma, Bronchial Asthma, the most common chronic childhood respiratory disease, is a kind of chronic airway inflammation by a variety of cells such as mast cells, eosinophils, T lymphocytes, and others involving, manifested as recurrent episodes of wheezing, difficulty breathing, chest tightness or cough. The incidence of asthma shows an up trend in the global. Continuous airway inflammation in the airway induced repeatedly airway injuring and repairing, which may lead to structural changes known as airway remodeling which includes airway smooth muscle hypertrophy and hyperplasia, collagen deposition to sub-epithelial basement membrane, hyperplasia of goblet cells, and an increase in vascularity, etc. Extracellular matrix (ECM) protein deposition beneath the basement membrane is characteristic of the airway wall of an asthmatic individual. Matrix metalloproteinases (MMPs) were the main rate-limiting enzymes in ECM metabolism, which could degrade the majority components of ECM. Tissue inhibitor of metalloproteinases (TIMP) -1, which interacted 1: 1 with the domain of MMP-9, inhibited the activity of MMP-9. The imbalance of MMP-9/TIMP-1 leading to abnormal metabolism of extracellular matrix, may be involved in the process of airway remodeling in asthma. Regulated upon activation normal T cell expressed and secreted (RANTES) are cysteine - cysteine type chemokine, also known as CCL5, is a secretion of a variety of inflammatory cells, such as eosinophils, monocytes, dendritic cells, lymphocytes, NK cells and so on. RANTES, which has chemotactic effects, especially for a powerful eosinophil chemotactic role, could aggravate airway inflammation of asthma, and may also be involved in airway remodeling from occurring.
Objectives: To learn the situation of airway remodeling by observing dthe rats airway pathological changes with light microscopy, and quantifiing the airway wall thickening of rats bronchi with multi-function color pathological image analysis system.
To observe the expression of MMP-9, TIMP-1 in the lung tissue and RANTES in bronchoalveolar lavage fluid (BALF) of each group rats and study the correlation between MMP-9/TIMP-1 and RANTES.
Methods: Thirty-six young male Wistar rats were randomly divided into three groups: asthmtic model group (Group A), Dexamethason (DEX) intervention group (Group B) and normal control group (Group C). At 1, 7, 14 days, 10% of Ovalbumin (OVA) and aluminum hydroxide [Al2(OH)3] compound preparation (1 ml) was applied to sensitize the rats in Group A and B by injection Intraperitoneally each. Group C were given intraperitoneal injection of normal saline at the same dosage as normal control. On the 21th day, the rats in Group A and B inhaled 1% of OVA atomization 30 min each time to excite wheezing, every other day for 6 weeks, Group C inhalation with normal saline instead. One week after the excitation, Group B began to be intervened via tail vein injection with DEX (0.5mg/Kg) half an hour before inhalation three times a week, Group A and C tail vein injection with normal saline. At the last meeting 24 hours after inhalation the rats of three groups were taken thoracotomy under anesthesia with an intraperitoneal injection of 1% pentobarbital sodium (0.2ml/Kg). The left lung main bronchus of the rats was ligated and cut to be fixed and embedded. The BALF of right lungs were collected.
Pathological changes in left lung airway of each group were observed in the left lung organization slices. Bronchial basement membrane perimeter (Pbm),airway smooth muscle area (WAm), inner way area (WAi) were measured by multi-function color pathological image analysis system, and WAm/Pbm and WAi/Pbm taken as indicators of airway remodeling. Immunohistochemistry assays was used to determine the status of MMP-9 and TIMP-1 expression in the left lung organization slices, and mean integral ?optical density (IOD) of MMP-9 and TIMP-1 were also measured by multi-function color pathological image analysis system. The contents of RANTES in BALF of right lungs were determined by enzyme linked immunosorbent assay (ELISA).
All data were processed by SPSS 10.0 statistical software. Data comparisons between groups were tested by One-Way ANOVA analysis, and the correlation coefficient of correlation analysis between MMP-9/TIMP-1 and RANTES was calculated, P <0.05 as statistically significant difference.
Results: There is wheezing onset of the rats in asthmatic model group during OVA inhalation. Airway remodeling such as airway wall and smooth muscle thickening could observed in the left lung bronchial biopsy. WAm/Pbm and WAi/Pbm of the rats left airway in asthmatic model group slices are 5.78±1.36μm~2/μm, 15.10±3.99μm~2/μm, higher than that in normal control group (P<0.05). The rats in DEX intervention group wheeze after OVA inhalation in the first week, and there is a relief after DEX intervention in the following weeks. Airway remodeling in DEX intervention group was not seen. WAm/Pbm and WAi/Pbm of the rats left airway in DEX intervention group slices are 3.98±1.25μm~2/μm, 9.86±2.47μm~2/μm, lower than that in asrhmatic model group (P<0.05).
The MMP-9 and TIMP-1 mean IOD values (1.7655±1.0476, 1.958±0.0927)of rats left lung and the RANTES expression (18.20±4.00 pg/ml ) of rats right BALF in asthmatic model group are significantly higher than those in normal control group and DEX intervention group (P<0.05). The MMP-9 and TIMP-1 mean IOD values (0.8525±0.0231, 0.876±0.0302) of rats left lung and the RANTES expression (9.28±2.26pg/ml) of rats right BALF in DEX intervention group are no differences with those in normal control group. The imbalance of MMP-9/TIMP-1 in asthmatic model group was negatively correlated with RANTES of BALF (r=-0.141, P<0.05).
Conclusions: The expression of MMP-9, TIMP-1 and RANTES all increase conspicuously in asthma, which could promote the progress of airway inflammation. The imbalance of MMP-9/TIMP-1 in asthmatic model group was negatively correlated with RANTES, contribution to ECM degradation and deposition related to participation in the occurrence of airway remodeling. DEX could inhibite MMP-9, TIMP-1 and RANTES expression, reducing airway remodeling.
目的:通过光镜观察实验大鼠气道病理变化,计算机图像分析软件量化气道壁增厚情况,了解哮喘气道重塑情况;
检测大鼠气道MMP-9、TIMP-1及肺泡灌洗液RANTES的表达水平,探讨MMP-9/TIMP-1在哮喘气道重塑中的作用,分析MMP-9/TIMP-1与RANTES的相关性。
方法:按照完全随机分组法,将36只雄性Wister大鼠分为哮喘模型组(A组)、地塞米松干预组(B组)、正常对照组(C组)三组。采用卵白蛋白(Ovalbumin, OVA)和氢氧化铝的复合制剂致敏、OVA激发方法。第1、7、14天,A、B组大鼠分别给予腹腔注射10%卵白蛋白与氢氧化铝混悬液1ml/只致敏,C组则相应给予腹腔注射生理盐水1ml/只。第21天A、B组开始雾化吸入1%的卵白蛋白激发喘息发作,每次雾化吸入30分钟,隔天1次,共6周,C组雾化吸入0.9%生理盐水作为对照。B组自雾化激发后1周起雾化前半小时予尾静脉注射地塞米松0.5mg/Kg每周3次,共5周,A、C组对应给予0.9%生理盐水0.5ml尾静脉注射。三组大鼠均于末次雾化吸入后24小时进行1%戊巴比妥钠0.2ml/Kg腹腔注射麻醉开胸,结扎左肺取肺组织固定、包埋;行气管插管,用生理盐水5ml冲洗5次回收右肺肺泡灌洗液,1000转低温离心5分钟,取上清。
制作左肺组织的HE染色切片,光镜观察各组切片中气道的病理学变化,多功能彩色病理图像分析仪测量切片中支气管横截面的基底膜周径(bronchial basement membrane perimeter, Pbm),气道平滑肌面积(airway smooth muscle area, WAm),气道内壁面积(inner way area , WAi),以WAm/Pbm和WAi/Pbm作为气道重塑指标;将左肺组织切片用免疫组化方法标记MMP-9、TIMP-1,并应用多功能彩色病理图像分析仪测定MMP-9、TIMP-1积分光密度(integral optical density, IOD);双抗体夹心酶联免疫吸附试验(ELISA)检测右侧肺泡灌洗液RANTES水平。
采用SPSS10.0统计软件,对组间WAm/Pbm和WAi/Pbm、MMP-9和TIMP-1数据进行单因素方差分析,P<0.05为差异有统计学意义,将MMP-9/TIMP-1与RANTES做相关性分析,计算相关系数r,P<0.05有统计学意义。
结果:哮喘模型组致敏的大鼠,在雾化OVA时均出现喘息发作,雾化6周后,大鼠左肺支气管HE染色的病理切片中出现平滑肌、管壁增厚的重构现象,检测切片中气道平滑肌面积/基底膜周径(WAm/Pbm)和气道内壁面积/基底膜周径( WAi/Pbm )分别为5.78±1.36μm~2/μm, 15.10±3.99μm~2/μm较正常对照组明显增大(P<0.05)。地塞米松干预组在第一周雾化OVA即出现喘息发作,在第二周应用地塞米松后喘息减轻,雾化6周后,其左肺支气管HE染色切片中气道重塑现象不明显,测量气道管壁WAm/Pbm和WAi/Pbm为3.98±1.25μm~2/μm, 9.86±2.47μm~2/μm,较哮喘模型组气道为轻(P<0.05)。
哮喘模型组大鼠左肺组织中MMP-9和TIMP-1的平均积分光密度(IOD)(1.7655±1.0476, 1.958±0.0927)及右肺肺泡灌洗液RANTES表达水平(18.20±4.00?pg/ml)明显高于正常对照组、地塞米松干预组(P<0.05),地塞米松干预组MMP-9和TIMP-1的平均IOD(0.8525±0.0231, 0.876±0.0302)及肺泡灌洗液中RANTES水平(9.28±2.26pg/ml)与正常对照组无明显差别(P>0.05)。MMP-9/TIMP-1在哮喘模型比例失衡,与肺泡灌洗液RANTES水平呈负相关(r=-0.141,P<0.05)。
结论:哮喘时MMP-9、TIMP-1及RANTES的表达水平均提高,可能有加重气道炎症的作用;哮喘时MMP-9/TIMP-1比例失调,与炎性细胞趋化因子RANTES水平呈负相关,与ECM的降解与沉积有关,参与气道重塑的发生;地塞米松对RANTES及MMP-9、TIMP-1表达有明显的抑制作用,减轻气道重塑。
Background: Referred to as asthma, Bronchial Asthma, the most common chronic childhood respiratory disease, is a kind of chronic airway inflammation by a variety of cells such as mast cells, eosinophils, T lymphocytes, and others involving, manifested as recurrent episodes of wheezing, difficulty breathing, chest tightness or cough. The incidence of asthma shows an up trend in the global. Continuous airway inflammation in the airway induced repeatedly airway injuring and repairing, which may lead to structural changes known as airway remodeling which includes airway smooth muscle hypertrophy and hyperplasia, collagen deposition to sub-epithelial basement membrane, hyperplasia of goblet cells, and an increase in vascularity, etc. Extracellular matrix (ECM) protein deposition beneath the basement membrane is characteristic of the airway wall of an asthmatic individual. Matrix metalloproteinases (MMPs) were the main rate-limiting enzymes in ECM metabolism, which could degrade the majority components of ECM. Tissue inhibitor of metalloproteinases (TIMP) -1, which interacted 1: 1 with the domain of MMP-9, inhibited the activity of MMP-9. The imbalance of MMP-9/TIMP-1 leading to abnormal metabolism of extracellular matrix, may be involved in the process of airway remodeling in asthma. Regulated upon activation normal T cell expressed and secreted (RANTES) are cysteine - cysteine type chemokine, also known as CCL5, is a secretion of a variety of inflammatory cells, such as eosinophils, monocytes, dendritic cells, lymphocytes, NK cells and so on. RANTES, which has chemotactic effects, especially for a powerful eosinophil chemotactic role, could aggravate airway inflammation of asthma, and may also be involved in airway remodeling from occurring.
Objectives: To learn the situation of airway remodeling by observing dthe rats airway pathological changes with light microscopy, and quantifiing the airway wall thickening of rats bronchi with multi-function color pathological image analysis system.
To observe the expression of MMP-9, TIMP-1 in the lung tissue and RANTES in bronchoalveolar lavage fluid (BALF) of each group rats and study the correlation between MMP-9/TIMP-1 and RANTES.
Methods: Thirty-six young male Wistar rats were randomly divided into three groups: asthmtic model group (Group A), Dexamethason (DEX) intervention group (Group B) and normal control group (Group C). At 1, 7, 14 days, 10% of Ovalbumin (OVA) and aluminum hydroxide [Al2(OH)3] compound preparation (1 ml) was applied to sensitize the rats in Group A and B by injection Intraperitoneally each. Group C were given intraperitoneal injection of normal saline at the same dosage as normal control. On the 21th day, the rats in Group A and B inhaled 1% of OVA atomization 30 min each time to excite wheezing, every other day for 6 weeks, Group C inhalation with normal saline instead. One week after the excitation, Group B began to be intervened via tail vein injection with DEX (0.5mg/Kg) half an hour before inhalation three times a week, Group A and C tail vein injection with normal saline. At the last meeting 24 hours after inhalation the rats of three groups were taken thoracotomy under anesthesia with an intraperitoneal injection of 1% pentobarbital sodium (0.2ml/Kg). The left lung main bronchus of the rats was ligated and cut to be fixed and embedded. The BALF of right lungs were collected.
Pathological changes in left lung airway of each group were observed in the left lung organization slices. Bronchial basement membrane perimeter (Pbm),airway smooth muscle area (WAm), inner way area (WAi) were measured by multi-function color pathological image analysis system, and WAm/Pbm and WAi/Pbm taken as indicators of airway remodeling. Immunohistochemistry assays was used to determine the status of MMP-9 and TIMP-1 expression in the left lung organization slices, and mean integral ?optical density (IOD) of MMP-9 and TIMP-1 were also measured by multi-function color pathological image analysis system. The contents of RANTES in BALF of right lungs were determined by enzyme linked immunosorbent assay (ELISA).
All data were processed by SPSS 10.0 statistical software. Data comparisons between groups were tested by One-Way ANOVA analysis, and the correlation coefficient of correlation analysis between MMP-9/TIMP-1 and RANTES was calculated, P <0.05 as statistically significant difference.
Results: There is wheezing onset of the rats in asthmatic model group during OVA inhalation. Airway remodeling such as airway wall and smooth muscle thickening could observed in the left lung bronchial biopsy. WAm/Pbm and WAi/Pbm of the rats left airway in asthmatic model group slices are 5.78±1.36μm~2/μm, 15.10±3.99μm~2/μm, higher than that in normal control group (P<0.05). The rats in DEX intervention group wheeze after OVA inhalation in the first week, and there is a relief after DEX intervention in the following weeks. Airway remodeling in DEX intervention group was not seen. WAm/Pbm and WAi/Pbm of the rats left airway in DEX intervention group slices are 3.98±1.25μm~2/μm, 9.86±2.47μm~2/μm, lower than that in asrhmatic model group (P<0.05).
The MMP-9 and TIMP-1 mean IOD values (1.7655±1.0476, 1.958±0.0927)of rats left lung and the RANTES expression (18.20±4.00 pg/ml ) of rats right BALF in asthmatic model group are significantly higher than those in normal control group and DEX intervention group (P<0.05). The MMP-9 and TIMP-1 mean IOD values (0.8525±0.0231, 0.876±0.0302) of rats left lung and the RANTES expression (9.28±2.26pg/ml) of rats right BALF in DEX intervention group are no differences with those in normal control group. The imbalance of MMP-9/TIMP-1 in asthmatic model group was negatively correlated with RANTES of BALF (r=-0.141, P<0.05).
Conclusions: The expression of MMP-9, TIMP-1 and RANTES all increase conspicuously in asthma, which could promote the progress of airway inflammation. The imbalance of MMP-9/TIMP-1 in asthmatic model group was negatively correlated with RANTES, contribution to ECM degradation and deposition related to participation in the occurrence of airway remodeling. DEX could inhibite MMP-9, TIMP-1 and RANTES expression, reducing airway remodeling.
引文
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6李惠民,赵顺英,江载芳.支气管上皮在大鼠哮喘模型气道炎症和重塑中的作用.中国实用儿科杂志, 2007, 22(7): 526-529
7叶任高,路再英主编.内科学.第6版.北京:人民卫生出版社. 2004年12月: 64, 66
8 Based on the workshop report: Global strategy for asthma management and prevention revised (2002). NIH publication No. 02-3659
9全国儿童哮喘防治协作组.中国城区儿童哮喘患病率调查.中华儿科杂志, 2003, 41(2):123-127
10陈谱,何韶衡.支气管哮喘的病理学研究进展.中华儿科杂志, 2005, 43(3): 235-238
11 Corbel M, Belleguic C, Boichot E, et al. Involvement of gelatinases (MMP-2 and MMP-9) in the development of airway inflammation and pulmonary fibrosis[J]. Cell Biol Toxicol, 2002, 18 (1): 51-61
12 Hegele RG. The pathology of asthma: brief review. Immunopharmacology, 2000, 48(3): 257-62
13 Tagaya E, Tamaoki J. Mechanisms of Airway Remodeling in Asthma. Allergol Int, 2007, 56(4): 331-340
14 Jefferg PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit care Med, 2001, 164(10 Pt 2): s28-38
15 Sacco O, Silvestri M, Sabatini F, et al. Epithelial cells and fibroblasts: structural repair and remodelling in the airways. Paediatr Respir Rev, 2004, 5(Suppl A): s35-40
16 Benayoun L, Druilhe A, Dombret MC, et al. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med, 2003, 167(10):1360-8
17 Lepperta D, Lindberg RL, Kappos L, et al. Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Research Reviews, 2001, 36(2-3): 249-257
18 Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling. [J]. Am J Respir Cell Mol Biol, 2003, 28(1): 12-24
19 Lee CW, Lin CC, LinWN, et al. TNF-αinduces MMP-9 expression via activation of Src/EGFR, PDGFR /PI3K/Akt cascade and promotion of NF-κB/p300 binding in human tracheal smooth muscle cells. [J]. Am J Physiol Lung CellMol Physiol, 2007, 292 (3): L799-L812
20 Brown RD, Jones GM, Laird RE, et al. Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts. [J]. Biochem Biophys Res Commun, 2007, 362(1): 200-205
21李雷,李淑兰.基质金属蛋白酶9与肺组织重构.中国临床康复, 2006, 10(17): 149-151
22 Sadatmansoori S, MacDougall J, Khademi S, et al. Construction, Expression, and Characterization of a baculovirally expressed catalytic domain of human matrix metalloproteinase-9. Protein Expr Purif, 2001, 23(3):447-452
23 Lemjabbar H, Gosset P, Lamblin C, et al. Contribution of 92 kDa gelatinase/type IV collagenase in bronchial inflammation during status asthmaticus. Am J Respir Crit Care Med. 1999, 159(4 Pt 1):1298-307
24 Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. [J]. Biochem Pharmacol, 2008,75(2): 346-359
25 Lambert E, Bridoux L, Devy J, et al. TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival. Int J Biochem Cell Biol, 2009, 41(5): 1102-1115
26李锋,刘荣玉.基质金属蛋白酶-9与支气管哮喘[J].国外医学呼吸系统分册, 2004, 24(5): 343-345
27 Lim DH, Cho JY, MillerM, et al. Reduced peribronchial fibrosis in allergen-challenged MMP-9-deficient mice. Am J Physiol Lung Cell Mol Physiol, 2006, 291(2): L265-L271
28 Lee KS, Jin SM, Lee H, et al. Imbalance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in toluene disoeynate induced asthma. Clin Exp Allegry, 2004, 34(2): 276-284
29 Hoshino M, Takehashi M, Takai Y, et al. Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and inhibitor of metalloproteinase-1 expression in asthma[J]. J Allergy Clin Immunol, 1999,104(2pt1): 356-363
30 Ndukwu MN, Halyko AJ, Halayko AJ, et al. Bronehoalveolar lavage fluid from asthmatic subjeets is mitogenic for human airway smoothmusele[J]. Am J Respir Crit Care Med, 1999, 160(5): 2062-2066
31 Belleguic C, Corbel M, Germain N, et al. Increased release of matrix metalloproteinase-9 in the plasma of acute severe asthmatic patients[J]. Clin Exp Allergy, 2002, 32(2): 217-223
32 Palmans E, Kips JC, Pauwels RA. Prolonged allergen exposure induces structural airway changes in sensitized rats[J]. Am J Respir Crit Care Med, 2000, 161 (2 Pt1): 627-635
33 Vignola AM, Rieeobono L, Mirabella A, et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis[J]. Am J Respir Crit Care Med, 1998, 158(6): 1945-1950
34李臻,张远强.β-趋化性细胞因子RANTES的研究进展[J].生命科学进展, 2006, 37(1): 79-82
35 Appay V, Rowland-Jones SL. RANTES: a versatile and controversial chemokine. Trends Immunol, 2001, 22(2): 83-87
36 Rojas-Ramos E, Avalos AF, Perez-Fernandez L, et al. Role of the chemokines RANTES, monocyte chemotactic proteins-3 and-4, and eotaxins-1 and-2 in child-hood asthma[J]. Eur Respir J, 2003, 22(2): 310-316
37武建文,喻书彻.哮喘患儿血清RANTES的测定及其意义[J].大连医科大学学报, 2006, 28(6): 487-488
38叶飒,沈华浩. C-C家族趋化因子受体3及其拮抗剂与支气管哮喘[J].国外医学呼吸系统分册, 2005, 25(4): 251-253
39 Al-Abdulhadi SA, Helms PJ, Main M,et al. Preferential transmission and association of the-403 G→A promoter RANTES polymorphism with atopic asthma[J]. Genes Immun, 2005, 6(1): 24-30
40 Yao TC, Kuo ML, See LC, et al. The RANTES promoter polymorphism: a genetic risk factor for near-fatal asthma in Chinese children[J]. J Allergy Clin Immunol, 2003, 111(6): 1285-1292
41 Wu B, Li P, Liu Y, et al. 3D structure of human FK506-binding protein 52: implications for the assembly of the glucocorticoid receptor/ Hsp90/ immunophilin heterocomplex. Proc Natl Acad Sci U S A, 2004, 101(22): 8348-8353
42 Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase-2 inhibits interleukin-1β-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol, 2000, 20(18): 6891-6903
43 Dostert A, Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action. Curr Pharm Des, 2004, 10(23): 2807-2816
44 Goncharova EA, Billington CK, Irani C, et al. Cyclic AMP-mobilizing agents and glucocorticoids modulate human smooth muscle cell migration. Am J Respir Cell Mol Biol, 2003, 29(1): 19-27
45 Bonacci JV, Harris T, Stewart AG. Impact of extracellular matrix and strain on proliferation of bovine airway smooth muscle. Clin Exp PharmacolPhysiol, 2003 May-Jun, 30(5-6):324-8
46李昌崇,张维溪。儿童支气管哮喘诊断治疗进展.实用儿科杂志, 2008, 23(16): 1230-1232
1 Etsuko, Tagaya, Jun Tamaoki. Mechanisms of Airway Remodeling in Asthma. Allergology International, 2007, 56: 331-340
2钟南山主编.支气管哮喘,第一版.北京:人民卫生出版社, 2006
3 Yamauchi K, Inoue H. Airway remodeling in asthma and irreversible airflow limitation-ECM deposition in airway and possible therapy for remodeling[J]. Allergol Int, 2007, 56(4): 321-329
4 Ohbayashi H, Shimokata K. Matrix Metalloproteinase-9 and AirwayRemodeling in Asthma. Curr Drug Targets Inflamm Allergy. 2005 Apr; 4(2):177-81
5叶新民,钟南山。基质金属蛋白酶与支气管哮喘气道重塑。中华哮喘杂志(电子版),2009年10月,第3卷,第5期,367-371
6袁发焕.细胞外基质、基质金属蛋白酶及其抑制因子的研究进展.国外医学临床生物化学与检验学分册, 2000年, 21(2): 62-65
7 David Lepperta, Raija L.P. Lindbergb, Ludwig Kapposa, et al. Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Research Reviews. 2001, 36(2-3): 249 -57
8 Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling[J]. Am J Respir Cell Mol Biol, 2003, 28(1): 12-24
9 Sadatmansoori S, MacDougall J, Khademi S, et al. Construction, Expression, and Characterization of a baculovirally expressed catalytic domain of human matrix metalloproteinase-9. Protein Expr Purif, 2001, 23(3): 447-452
10 Gueders MM, Foidart JM, Noel A, et al. Matrix metalloproteinases (MMP) and tissue inhibitors of MMP in the respiratory tract: potential implications in asthma and other lung diseases. Eur J Pharmacol, 2006, 533: 133-144
11 Cha H, Kopetzki E, Huber R. Structural Basis of the Adaptive Molecula Recognition by MMP9. J Mol Biol, 2002, 320(5): 1065–1079
12王萍,秦晓群.基质金属蛋白酶-9与支气管哮喘. J Clin Res, 2007, 24(3): 507-509
13 Lee CW, Lin CC, Lin WN, et al. TNF-αinduces MMP-9 expression via activation of Src/EGFR, PDGFR /PI3K/Akt cascade and promotion of NF-κB/p300 binding in human tracheal smooth muscle cells[J]. Am J Physiol Lung Cell Mol Physiol, 2007, 292 (3): L799-L812
14 Liang KC, Lee CW, Lin WN, et al. Interleukin-1beta induces MMP-9 expression via p42/p44 MAPK, p38 MAPK, JNK, and nuclear factor-kappaB signaling pathways in human tracheal smooth muscle cells. J Cell Physiol, 2007, 211(3): 759-770
15 Lee KS, Min KH, Kim SR, et al. Vascular endothelial growth factor modulates matrix metalloproteinase-9 expression in asthma. Am J Respir Crit Care Med, 2006, 174(2): 161-170
16 Kim HM, Bae SJ, Kim DW, et al. Inhibitory role of magnolol on proliferative capacity and matrixmetalloproteinase-9 expression in TNF-α-induced vascular smooth muscle cells[J]. Int Immuno- pharmacol, 2007, 7(8): 1083-1091
17李雷,李淑兰.基质金属蛋白酶9与肺组织重构. Chinese Journal of Clinical Rehabilitation, 2006, 10(17): 149-151
18 Aoudjit F, Potworowski EF, St-Pierre Y. Bi-directional induction of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 during T lymphoma/endothelial cell contact: Implication of ICAM-1. J Immunol, 1998, 160(6):2967-2973
19 Romanic AM, Madri JA. The induction of 72-kD gelatinase in T cells upon adhesion to endothelial cells is VCAM-1 dependent. J Cell Biol, 1994, 125(5): 1165-1178
20 Malik N, Greenfield BW, Wahl AF, et al. Actication of human monocytes through CD40 induces matrix metalloproteinases. J Immunol, 1996, 156(10): 3952-3960
21 Hamada T, Duarte S, Tsuchihashi S, et al. Inducible nitric oxide synthase deficiency impairs matrix metalloproteinase-9 activity and disrupts leukocyte migration in hepatic ischemia/reperfusion injury. Am J Pathol, 2009, 174(6): 2265-2277
22赵凤娟,张庆瑜.基质金属蛋白酶9与胃癌的研究进展.医学综述, 2009,15(13): 1950-1953
23刘加强.关于基质金属蛋白酶9(MMP-9)的最新进展.牙体牙髓牙周病学杂志, 2005, 15(3): 168-171
24 Levitt NC, Eskens FA, O'Byrne KJ, et al. Phase I and pharmacological study of the oral matrix metalloproteinase inhibitor, MMI270 (CGS27023A), in patients with advanced solid cancer. Clin Cancer Res, 2001, 7(7): 1912-1922
25 Rudek MA, Figg WD, Dyer V, et al. Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J Clin Oncol, 2001, 19(2): 584-592
26 Anderson CL, Brown CJ. Epigenetic predisposition to expression of TIMP1 from the human inactive X chromosome. BMC Genet, 2005, 6: 48
27 Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease[J]. Biochem Pharmacol, 2008, 75(2): 346-359
28 Brew K, Dinakarpandian D, Nagase H. Tissue inhibitors of metalloproteinases: evolution, structure and function. Biochim Biophys Acta. 2000, 1477(1-2):267-283
29 Lambert E, Bridoux L, Devy J, et al. TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival. Int J Biochem Cell Biol, 2009, 41(5): 1102-1115
30 Jung KK, Liu XW, Chirco R, et al. Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J, 2006, 25(17): 3934-3942
31 Zhou X, Hu H, Huynh ML, et al. Mechanisms of tissue inhibitor of metalloproteinase 1 augmentation by IL-13 on TGF-beta1-stimulated primary human fibroblasts. J Allergy Clin Immunol, 2007, 119(6): 1388-1397
32 Vignola AM, Rieeobono L, Mirabella A, et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis[J]. Am J Respir Crit Care Med, 1998, 158(6): 1945-1950
33 Doherty GM, Kamath SV, de Courcey F, et al. Children with stable asthma have reduced airway matrix metalloproteinase-9 and matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio. Clin Exp Allergy, 2005, 35(9):1168-74
34 Cho JY, Miller M, McElwain K. Remodeling associated expression of matrix metalloproteinase 9 but not tissue inhibitor of metalloproteinase 1in airway epithelium: Modulation by immunostimulatory DNA. J Allergy Clin Immunol, 2006, 117(3): 618-625
35 Borger P, Tamm M, Black JL, et al. Asthma: is it due to an abnormal airway smooth muscle cell[J]. Am JRespirCritCareMed, 2006, 174(4): 367-372
36 Munakata M. Airway remodeling and airway smooth muscle in asthma. Allergol Int, 2006, 55(3): 235-243
37 Burgess JK, Ceresa C, Johnson SR, et al. Tissue and matrix influences on airway smooth muscle function. Pulm Pharmacol Ther, 2009, 22(5): 379-387
38 Demedts IK, Brusselle GG, Bracke KR, et al. Matrix metalloproteinases in asthma and COPD. Curr Opin Pharmacol, 2005, 5(3): 257-263
2 Ohbayashi H, Shimokata K. Matrix Metalloproteinase-9 and Airway Remodeling in Asthma. Curr Drug Targets Inflamm Allergy, 2005, 4(2): 177-181
3钟南山主编.支气管哮喘——基础与临床.第1版.北京:人民卫生出版社, 2006年8月: 439, 241, 180 , 235, 242
4叶新民,钟南山.基质金属蛋白酶与支气管哮喘气道重塑.中华哮喘杂志(电子版), 2009年10月,第3卷,第5期, 367-371
5 Xiao-fang Ch, Yong-liang L, Lin D, et al. The Expression and Effects of RANTES in RSV Infections. Foreign Medical Sciences Section of Pediatrics, May 2005, 32(3): 162-164
6李惠民,赵顺英,江载芳.支气管上皮在大鼠哮喘模型气道炎症和重塑中的作用.中国实用儿科杂志, 2007, 22(7): 526-529
7叶任高,路再英主编.内科学.第6版.北京:人民卫生出版社. 2004年12月: 64, 66
8 Based on the workshop report: Global strategy for asthma management and prevention revised (2002). NIH publication No. 02-3659
9全国儿童哮喘防治协作组.中国城区儿童哮喘患病率调查.中华儿科杂志, 2003, 41(2):123-127
10陈谱,何韶衡.支气管哮喘的病理学研究进展.中华儿科杂志, 2005, 43(3): 235-238
11 Corbel M, Belleguic C, Boichot E, et al. Involvement of gelatinases (MMP-2 and MMP-9) in the development of airway inflammation and pulmonary fibrosis[J]. Cell Biol Toxicol, 2002, 18 (1): 51-61
12 Hegele RG. The pathology of asthma: brief review. Immunopharmacology, 2000, 48(3): 257-62
13 Tagaya E, Tamaoki J. Mechanisms of Airway Remodeling in Asthma. Allergol Int, 2007, 56(4): 331-340
14 Jefferg PK. Remodeling in asthma and chronic obstructive lung disease. Am J Respir Crit care Med, 2001, 164(10 Pt 2): s28-38
15 Sacco O, Silvestri M, Sabatini F, et al. Epithelial cells and fibroblasts: structural repair and remodelling in the airways. Paediatr Respir Rev, 2004, 5(Suppl A): s35-40
16 Benayoun L, Druilhe A, Dombret MC, et al. Airway structural alterations selectively associated with severe asthma. Am J Respir Crit Care Med, 2003, 167(10):1360-8
17 Lepperta D, Lindberg RL, Kappos L, et al. Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Research Reviews, 2001, 36(2-3): 249-257
18 Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling. [J]. Am J Respir Cell Mol Biol, 2003, 28(1): 12-24
19 Lee CW, Lin CC, LinWN, et al. TNF-αinduces MMP-9 expression via activation of Src/EGFR, PDGFR /PI3K/Akt cascade and promotion of NF-κB/p300 binding in human tracheal smooth muscle cells. [J]. Am J Physiol Lung CellMol Physiol, 2007, 292 (3): L799-L812
20 Brown RD, Jones GM, Laird RE, et al. Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts. [J]. Biochem Biophys Res Commun, 2007, 362(1): 200-205
21李雷,李淑兰.基质金属蛋白酶9与肺组织重构.中国临床康复, 2006, 10(17): 149-151
22 Sadatmansoori S, MacDougall J, Khademi S, et al. Construction, Expression, and Characterization of a baculovirally expressed catalytic domain of human matrix metalloproteinase-9. Protein Expr Purif, 2001, 23(3):447-452
23 Lemjabbar H, Gosset P, Lamblin C, et al. Contribution of 92 kDa gelatinase/type IV collagenase in bronchial inflammation during status asthmaticus. Am J Respir Crit Care Med. 1999, 159(4 Pt 1):1298-307
24 Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. [J]. Biochem Pharmacol, 2008,75(2): 346-359
25 Lambert E, Bridoux L, Devy J, et al. TIMP-1 binding to proMMP-9/CD44 complex localized at the cell surface promotes erythroid cell survival. Int J Biochem Cell Biol, 2009, 41(5): 1102-1115
26李锋,刘荣玉.基质金属蛋白酶-9与支气管哮喘[J].国外医学呼吸系统分册, 2004, 24(5): 343-345
27 Lim DH, Cho JY, MillerM, et al. Reduced peribronchial fibrosis in allergen-challenged MMP-9-deficient mice. Am J Physiol Lung Cell Mol Physiol, 2006, 291(2): L265-L271
28 Lee KS, Jin SM, Lee H, et al. Imbalance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in toluene disoeynate induced asthma. Clin Exp Allegry, 2004, 34(2): 276-284
29 Hoshino M, Takehashi M, Takai Y, et al. Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and inhibitor of metalloproteinase-1 expression in asthma[J]. J Allergy Clin Immunol, 1999,104(2pt1): 356-363
30 Ndukwu MN, Halyko AJ, Halayko AJ, et al. Bronehoalveolar lavage fluid from asthmatic subjeets is mitogenic for human airway smoothmusele[J]. Am J Respir Crit Care Med, 1999, 160(5): 2062-2066
31 Belleguic C, Corbel M, Germain N, et al. Increased release of matrix metalloproteinase-9 in the plasma of acute severe asthmatic patients[J]. Clin Exp Allergy, 2002, 32(2): 217-223
32 Palmans E, Kips JC, Pauwels RA. Prolonged allergen exposure induces structural airway changes in sensitized rats[J]. Am J Respir Crit Care Med, 2000, 161 (2 Pt1): 627-635
33 Vignola AM, Rieeobono L, Mirabella A, et al. Sputum metalloproteinase-9/tissue inhibitor of metalloproteinase-1 ratio correlates with airflow obstruction in asthma and chronic bronchitis[J]. Am J Respir Crit Care Med, 1998, 158(6): 1945-1950
34李臻,张远强.β-趋化性细胞因子RANTES的研究进展[J].生命科学进展, 2006, 37(1): 79-82
35 Appay V, Rowland-Jones SL. RANTES: a versatile and controversial chemokine. Trends Immunol, 2001, 22(2): 83-87
36 Rojas-Ramos E, Avalos AF, Perez-Fernandez L, et al. Role of the chemokines RANTES, monocyte chemotactic proteins-3 and-4, and eotaxins-1 and-2 in child-hood asthma[J]. Eur Respir J, 2003, 22(2): 310-316
37武建文,喻书彻.哮喘患儿血清RANTES的测定及其意义[J].大连医科大学学报, 2006, 28(6): 487-488
38叶飒,沈华浩. C-C家族趋化因子受体3及其拮抗剂与支气管哮喘[J].国外医学呼吸系统分册, 2005, 25(4): 251-253
39 Al-Abdulhadi SA, Helms PJ, Main M,et al. Preferential transmission and association of the-403 G→A promoter RANTES polymorphism with atopic asthma[J]. Genes Immun, 2005, 6(1): 24-30
40 Yao TC, Kuo ML, See LC, et al. The RANTES promoter polymorphism: a genetic risk factor for near-fatal asthma in Chinese children[J]. J Allergy Clin Immunol, 2003, 111(6): 1285-1292
41 Wu B, Li P, Liu Y, et al. 3D structure of human FK506-binding protein 52: implications for the assembly of the glucocorticoid receptor/ Hsp90/ immunophilin heterocomplex. Proc Natl Acad Sci U S A, 2004, 101(22): 8348-8353
42 Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase-2 inhibits interleukin-1β-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol, 2000, 20(18): 6891-6903
43 Dostert A, Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action. Curr Pharm Des, 2004, 10(23): 2807-2816
44 Goncharova EA, Billington CK, Irani C, et al. Cyclic AMP-mobilizing agents and glucocorticoids modulate human smooth muscle cell migration. Am J Respir Cell Mol Biol, 2003, 29(1): 19-27
45 Bonacci JV, Harris T, Stewart AG. Impact of extracellular matrix and strain on proliferation of bovine airway smooth muscle. Clin Exp PharmacolPhysiol, 2003 May-Jun, 30(5-6):324-8
46李昌崇,张维溪。儿童支气管哮喘诊断治疗进展.实用儿科杂志, 2008, 23(16): 1230-1232
1 Etsuko, Tagaya, Jun Tamaoki. Mechanisms of Airway Remodeling in Asthma. Allergology International, 2007, 56: 331-340
2钟南山主编.支气管哮喘,第一版.北京:人民卫生出版社, 2006
3 Yamauchi K, Inoue H. Airway remodeling in asthma and irreversible airflow limitation-ECM deposition in airway and possible therapy for remodeling[J]. Allergol Int, 2007, 56(4): 321-329
4 Ohbayashi H, Shimokata K. Matrix Metalloproteinase-9 and AirwayRemodeling in Asthma. Curr Drug Targets Inflamm Allergy. 2005 Apr; 4(2):177-81
5叶新民,钟南山。基质金属蛋白酶与支气管哮喘气道重塑。中华哮喘杂志(电子版),2009年10月,第3卷,第5期,367-371
6袁发焕.细胞外基质、基质金属蛋白酶及其抑制因子的研究进展.国外医学临床生物化学与检验学分册, 2000年, 21(2): 62-65
7 David Lepperta, Raija L.P. Lindbergb, Ludwig Kapposa, et al. Matrix metalloproteinases: multifunctional effectors of inflammation in multiple sclerosis and bacterial meningitis. Brain Research Reviews. 2001, 36(2-3): 249 -57
8 Atkinson JJ, Senior RM. Matrix metalloproteinase-9 in lung remodeling[J]. Am J Respir Cell Mol Biol, 2003, 28(1): 12-24
9 Sadatmansoori S, MacDougall J, Khademi S, et al. Construction, Expression, and Characterization of a baculovirally expressed catalytic domain of human matrix metalloproteinase-9. Protein Expr Purif, 2001, 23(3): 447-452
10 Gueders MM, Foidart JM, Noel A, et al. Matrix metalloproteinases (MMP) and tissue inhibitors of MMP in the respiratory tract: potential implications in asthma and other lung diseases. Eur J Pharmacol, 2006, 533: 133-144
11 Cha H, Kopetzki E, Huber R. Structural Basis of the Adaptive Molecula Recognition by MMP9. J Mol Biol, 2002, 320(5): 1065–1079
12王萍,秦晓群.基质金属蛋白酶-9与支气管哮喘. J Clin Res, 2007, 24(3): 507-509
13 Lee CW, Lin CC, Lin WN, et al. TNF-αinduces MMP-9 expression via activation of Src/EGFR, PDGFR /PI3K/Akt cascade and promotion of NF-κB/p300 binding in human tracheal smooth muscle cells[J]. Am J Physiol Lung Cell Mol Physiol, 2007, 292 (3): L799-L812
14 Liang KC, Lee CW, Lin WN, et al. Interleukin-1beta induces MMP-9 expression via p42/p44 MAPK, p38 MAPK, JNK, and nuclear factor-kappaB signaling pathways in human tracheal smooth muscle cells. J Cell Physiol, 2007, 211(3): 759-770
15 Lee KS, Min KH, Kim SR, et al. Vascular endothelial growth factor modulates matrix metalloproteinase-9 expression in asthma. Am J Respir Crit Care Med, 2006, 174(2): 161-170
16 Kim HM, Bae SJ, Kim DW, et al. Inhibitory role of magnolol on proliferative capacity and matrixmetalloproteinase-9 expression in TNF-α-induced vascular smooth muscle cells[J]. Int Immuno- pharmacol, 2007, 7(8): 1083-1091
17李雷,李淑兰.基质金属蛋白酶9与肺组织重构. Chinese Journal of Clinical Rehabilitation, 2006, 10(17): 149-151
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