ERK1/2信号通道在哮喘支气管平滑肌表型转化、迁移和分泌调控中作用的研究
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摘要
支气管哮喘是一种世界范围内广泛发病的常见病、多发病,其发病机制至今尚未完全阐明。近年的研究发现,气道重建是慢性持续性哮喘和重度哮喘患者难以得到有效治疗的重要原因之一,相关机制正成为目前国内外的研究热点。气道平滑肌细胞作为气道重建中的主要分子,参与了气道重建的始动及发展整个过程。它作为结构细胞不仅通过自身的肥大与增生直接参与气道壁的增厚,而且通过表型转化、迁移功能的改变以及分泌炎症因子和细胞外基质等促进气道重建的发展。然而有关哮喘支气管平滑肌表型转化、迁移功能和分泌功能改变的发生机制目前仍不明确。
细胞外信号调节激酶属于有丝分裂原激活蛋白激酶家族,它是细胞内重要的信号传递分子,参与细胞生长、发育、增殖、分化等多种生理病理过程,它有多种亚型,在平滑肌中主要有ERK1、ERK2(ERK1/2)两种,有研究表明它在哮喘气道慢性炎症和气道高反应性中起到了重要的调控作用,但是有关ERK信号通道在哮喘支气管平滑肌表型转化、迁移和分泌功能改变中作用的研究国内外尚少见报道。本研究旨在通过大鼠慢性哮喘模型和哮喘血清被动致敏人支气管平滑肌细胞探讨ERK1/2信号通道在哮喘支气管平滑肌细胞表型转化、迁移和分泌功能改变中的调控作用,为进一步阐明哮喘气道重建的发病机制提供实验依据。
方法:应用卵清蛋白雾化和激发的方法制备大鼠慢性哮喘模型,应用哮喘患者血清被动致敏人支气管平滑肌细胞,气道病理切片检测气道改变,免疫组织化学、免疫荧光细胞化学、western blot和RT-PCR等方法检测总ERK1/2、磷酸化ERK1/2和平滑肌标志蛋白(alpha-actin和骨桥蛋白)在支气管平滑肌细胞中的表达,透射电镜下观察支气管平滑肌细胞超微结构的改变,平面迁移实验和跨膜迁移实验检测支气管平滑肌细胞迁移能力的改变,ELISA方法检测支气管平滑肌细胞分泌功能的变化。同时,还运用了ERK1/2信号通道的激动剂表皮生长因子、抑制剂PD98059和ERK1/2反义寡核苷酸对ERK1/2信号通道进行了干预。
结果:
1.在慢性哮喘模型大鼠气道中ERK1/2的活性和在蛋白质和核酸水平上的表达均明显增强(P<0.01),且P-ERK的表达与气道管壁厚度显著正相关。
2.慢性哮喘模型大鼠支气管平滑肌细胞超微结构出现大量合成细胞器,同时平滑肌收缩标志蛋白(alpha-actin)的表达下降,合成型标志蛋白(osteopontin)的表达上升(P<0.01)。ERK1/2信号通道激动剂表皮生长因子(epidermal growth factor, EGF)促进了这一转变,而抑制剂PD98059部分抑制了平滑肌细胞表型的转化。
3.慢性哮喘模型大鼠支气管平滑肌细胞的平面迁移和跨膜迁移能力都较正常对照大鼠有明显增强,10μmol/L的PD98059即明显抑制慢性哮喘支气管平滑肌细胞的迁移,而EGF有显著的促进作用,ERK1/2反义寡核苷酸转染能够有效抑制细胞的迁移能力(P<0.01)。
4.慢性哮喘大鼠支气管平滑肌细胞较正常对照分泌转化生长因子、血管内皮生长因子、结缔组织生长因子、RANTES、嗜酸细胞活化趋化因子、纤维结合蛋白和Ⅰ型胶原蛋白的水平均有明显升高(P<0.01)。EGF能够促进正常大鼠BSMC和慢性哮喘大鼠的分泌,但慢性哮喘组的水平要显著高于正常对照,而PD98059降低了慢性哮喘大鼠支气管平滑肌细胞的分泌水平(P<0.01),ERK1/2反义寡核苷酸能够有效的抑制慢性哮喘大鼠支气管平滑肌细胞的分泌(P<0.01)。
5.经鼻吸入ERK1/2反义寡核苷酸下调ERK1/2在慢性哮喘气道平滑肌的表达,并抑制了慢性哮喘模型大鼠气道壁的增厚,阻止了支气管平滑肌细胞的表型转化(P<0.01)。
6.哮喘血清被动致敏的人支气管平滑肌细胞向合成细胞型进一步转化,EGF促进了被动致敏平滑肌细胞的表型转化,PD98059降低合成型标志蛋白的表达,升高收缩型标志蛋白的水平(P<0.05)。ERK1/2反义寡核苷酸能够有效抑制被动致敏人支气管平滑肌细胞的表型转化(P<0.05)。
7.哮喘血清被动致敏的人支气管平滑肌细胞的迁移能力较正常血清对照有明显增强,EGF促进了被动致敏平滑肌细胞的迁移,而PD98059抑制了细胞的迁移能力(P<0.05),ERK1/2反义寡核苷酸转染能够有效的抑制被动致敏人支气管平滑肌细胞的迁移能力的增强(P<0.05)。
8.哮喘血清被动致敏的人支气管平滑肌细胞分泌生长因子、炎性因子和细胞外基质的能力较正常血清对照细胞有明显增强,EGF促进了被动致敏平滑肌细胞的分泌,而PD98059降低细胞的分泌水平(P<0.05),ERK1/2反义寡核苷酸转染能够有效的抑制被动致敏人支气管平滑肌细胞的分泌能力(P<0.05)。
结论:ERK1/2信号通道参与了慢性哮喘模型大鼠支气管平滑肌细胞和哮喘患者血清被动致敏人支气管平滑肌细胞表型转化、迁移和分泌功能变化的调控,提示ERK信号通道在慢性哮喘气道重建发病机制中可能具有重要作用。
Background:
Asthma is a chronic inflammatory disorder of airway that is highly prevalent in world and its pathogenesis remains completely uncertain. Despite an increased use of medications that suppress airway inflammation and repress contraction of smooth muscle, some patients with chronic and severe asthma still hardly get effective treatment due to the development of airway remodeling and subsequent poorly reversible airway obstruction. Of the structural changes in the airway wall remodeling process, bronchial smooth muscle cells (BSMCs) are perhaps the most important component. Recent reports show that BSMCs not only contribute to airway remodeling by its increased content, but also, bronchial smooth muscle cells in chronic asthma are capable to undergo phenotypical transition, enabling them to subserve contractile, proliferative, migratory and secretory functional responses that account for airway remodeling and persistent hyperresponsiveness.
However, despite consensus toward the importance of BSMCs regarding to the phenotypic plastic, migration and secretion, there is relatively little understanding of the cellular and molecular mechanisms underlying these changes seen in the asthmatic BSMCs. Extracellular signal-regulated kinase1/2 (ERK1/2) signaling pathway is one of the most important signalling pathways that modulate asthma in the chronic airway inflammation and hyperresponsiveness. Nevertheless, there are few reports about the role of ERK1/2 signaling pathway in the regulation of asthmatic BSMCs on their phenotypic modulation and migration. So the aim of this study is to profile the impact of ERK1/2 signaling pathway on the phenotypic transition, migration and secretion of BSMCs in chronic asthmatic model of rats, as well as in passively sensitized human BSMCs by asthmatic serum.
Method:
Wistar rats underwent OVA intraperitoneal injection and eight weeks inhalation for chronic asthma model. Human BSMCs were sensitized by asthmatic serum. Airway reactivity and relative count of eosinophil in alveolar lavage fluid were measured, and histological sections were investigated for morphometric analysis. The expressions of ERK1/2 and P-ERK1/2 at both protein and mRNA levels were detected by western blot and RT-PCR. Phenotype of BSMCs was established under electron microscrope, also with analysis of phenotypic markers (sm-α-actin for contractile and osteopontin for synthetic) in both protein and mRNA levels by western blot or RT-PCR, respectively. Migration of BSMCs was measured by plate test and transmembrane test. Secretion of BSMCs was measured by ELISA and western blot.
Results:
1. ERK1/2 was markedly increased in its expression and activity in the rat model of chronic asthma, and the level of P-ERK1/2 closely related to airway thickness.
2. The phenotype of BSMCs in chronic asthmatic rats switched from a contractile type to a synthetic type with plentiful synthetic organelles gathering around the nucleus and altered expressions of phenotypic markers. EGF urged the over-synthetic function of BSMCs, while MEK inhibitor PD98059 was capable to reverse the phenotypic change of BSMCs.
3. BSMCs of chronic asthmatic rats possessed increased migratory ability. EGF promoted the migration of BSMCs, MEK inhibitor PD98059 was capable to inhibit the change of BSMCs, and ERK1/2 antisense ODN restrained the migration ability of BSMCs.
4. BSMCs of chronic asthmatic rats secreted much more growth factors (TGF-β1 , VEGF and CTGF), cytokines (RANTES and EOTAXIN) and extracellular matrix (Fibronectin and CollangenⅠ) than that of normal controls. EGF stimulated the secretion of both two groups, but the response of chronic asthmatic group was more intense. Both PD98059 and antisense oligonucleotide were able to suppress the secretion of BSMCs in chronic ashmatic rats, but antisense oligonucleotide reduced the level of RANTES nearly to that of normal controls, while PD98059 couldn’t.
5. Local intranasal administration of ERK1/2 antisense oligonucleotides to chronic asthmatic rats led to DNA uptake in lung cells associated with a reduction of intracellular ERK1/2 expression. Such intrapulmonary blockade of ERK1/2 expression caused an abrogation of the increase in the thickness of airway as well as in that of smooth muscle layer. Furthermore, treatment with antisense but not nonsense oligonucleotides inhibited the phenotypic transition of BSMCs in the rat model of chronic asthma.
6. Passively sensitized human BSMCs changed further toward the synthetic phenotype as compared to the controls. EGF pushed the phenotypic transition of human BSMCs, and PD98059 inhibited partly the change in human BSMCs. Meanwhile, ERK1/2 antisense ODN was capable to reverse the phenotypic change of passively sensitized human BSMCs.
7. The migratory ability was increased in passively sensitized BSMCs as compared to the controls. EGF promoted the migration of human BSMCs, MEK inhibitor PD98059 was capable to inhibit the change of BSMCs, and ERK1/2 antisense ODN suppressed the migration ability of BSMCs.
8. Passively sensitized human BSMCs secreted much more growth factors, cytokines and extracellular matrix than that of controls. EGF stimulated the secretion of human BSMCs, and PD98059 was able to suppress the secretion of human BSMCs. While ERK1/2 antisense oligonucleotide induced a dramatic reduction of the secreted factors to levels comparable to that of normal controls.
Conclusion:
ERK1/2 signalling pathway play an important role on the phenotypic modulation, migration and secretion of bronchial smooth muscle cells in the rat model of chronic asthma, as well as in the model of human BSMCs passively sensitized by asthmatic serum.
细胞外信号调节激酶属于有丝分裂原激活蛋白激酶家族,它是细胞内重要的信号传递分子,参与细胞生长、发育、增殖、分化等多种生理病理过程,它有多种亚型,在平滑肌中主要有ERK1、ERK2(ERK1/2)两种,有研究表明它在哮喘气道慢性炎症和气道高反应性中起到了重要的调控作用,但是有关ERK信号通道在哮喘支气管平滑肌表型转化、迁移和分泌功能改变中作用的研究国内外尚少见报道。本研究旨在通过大鼠慢性哮喘模型和哮喘血清被动致敏人支气管平滑肌细胞探讨ERK1/2信号通道在哮喘支气管平滑肌细胞表型转化、迁移和分泌功能改变中的调控作用,为进一步阐明哮喘气道重建的发病机制提供实验依据。
方法:应用卵清蛋白雾化和激发的方法制备大鼠慢性哮喘模型,应用哮喘患者血清被动致敏人支气管平滑肌细胞,气道病理切片检测气道改变,免疫组织化学、免疫荧光细胞化学、western blot和RT-PCR等方法检测总ERK1/2、磷酸化ERK1/2和平滑肌标志蛋白(alpha-actin和骨桥蛋白)在支气管平滑肌细胞中的表达,透射电镜下观察支气管平滑肌细胞超微结构的改变,平面迁移实验和跨膜迁移实验检测支气管平滑肌细胞迁移能力的改变,ELISA方法检测支气管平滑肌细胞分泌功能的变化。同时,还运用了ERK1/2信号通道的激动剂表皮生长因子、抑制剂PD98059和ERK1/2反义寡核苷酸对ERK1/2信号通道进行了干预。
结果:
1.在慢性哮喘模型大鼠气道中ERK1/2的活性和在蛋白质和核酸水平上的表达均明显增强(P<0.01),且P-ERK的表达与气道管壁厚度显著正相关。
2.慢性哮喘模型大鼠支气管平滑肌细胞超微结构出现大量合成细胞器,同时平滑肌收缩标志蛋白(alpha-actin)的表达下降,合成型标志蛋白(osteopontin)的表达上升(P<0.01)。ERK1/2信号通道激动剂表皮生长因子(epidermal growth factor, EGF)促进了这一转变,而抑制剂PD98059部分抑制了平滑肌细胞表型的转化。
3.慢性哮喘模型大鼠支气管平滑肌细胞的平面迁移和跨膜迁移能力都较正常对照大鼠有明显增强,10μmol/L的PD98059即明显抑制慢性哮喘支气管平滑肌细胞的迁移,而EGF有显著的促进作用,ERK1/2反义寡核苷酸转染能够有效抑制细胞的迁移能力(P<0.01)。
4.慢性哮喘大鼠支气管平滑肌细胞较正常对照分泌转化生长因子、血管内皮生长因子、结缔组织生长因子、RANTES、嗜酸细胞活化趋化因子、纤维结合蛋白和Ⅰ型胶原蛋白的水平均有明显升高(P<0.01)。EGF能够促进正常大鼠BSMC和慢性哮喘大鼠的分泌,但慢性哮喘组的水平要显著高于正常对照,而PD98059降低了慢性哮喘大鼠支气管平滑肌细胞的分泌水平(P<0.01),ERK1/2反义寡核苷酸能够有效的抑制慢性哮喘大鼠支气管平滑肌细胞的分泌(P<0.01)。
5.经鼻吸入ERK1/2反义寡核苷酸下调ERK1/2在慢性哮喘气道平滑肌的表达,并抑制了慢性哮喘模型大鼠气道壁的增厚,阻止了支气管平滑肌细胞的表型转化(P<0.01)。
6.哮喘血清被动致敏的人支气管平滑肌细胞向合成细胞型进一步转化,EGF促进了被动致敏平滑肌细胞的表型转化,PD98059降低合成型标志蛋白的表达,升高收缩型标志蛋白的水平(P<0.05)。ERK1/2反义寡核苷酸能够有效抑制被动致敏人支气管平滑肌细胞的表型转化(P<0.05)。
7.哮喘血清被动致敏的人支气管平滑肌细胞的迁移能力较正常血清对照有明显增强,EGF促进了被动致敏平滑肌细胞的迁移,而PD98059抑制了细胞的迁移能力(P<0.05),ERK1/2反义寡核苷酸转染能够有效的抑制被动致敏人支气管平滑肌细胞的迁移能力的增强(P<0.05)。
8.哮喘血清被动致敏的人支气管平滑肌细胞分泌生长因子、炎性因子和细胞外基质的能力较正常血清对照细胞有明显增强,EGF促进了被动致敏平滑肌细胞的分泌,而PD98059降低细胞的分泌水平(P<0.05),ERK1/2反义寡核苷酸转染能够有效的抑制被动致敏人支气管平滑肌细胞的分泌能力(P<0.05)。
结论:ERK1/2信号通道参与了慢性哮喘模型大鼠支气管平滑肌细胞和哮喘患者血清被动致敏人支气管平滑肌细胞表型转化、迁移和分泌功能变化的调控,提示ERK信号通道在慢性哮喘气道重建发病机制中可能具有重要作用。
Background:
Asthma is a chronic inflammatory disorder of airway that is highly prevalent in world and its pathogenesis remains completely uncertain. Despite an increased use of medications that suppress airway inflammation and repress contraction of smooth muscle, some patients with chronic and severe asthma still hardly get effective treatment due to the development of airway remodeling and subsequent poorly reversible airway obstruction. Of the structural changes in the airway wall remodeling process, bronchial smooth muscle cells (BSMCs) are perhaps the most important component. Recent reports show that BSMCs not only contribute to airway remodeling by its increased content, but also, bronchial smooth muscle cells in chronic asthma are capable to undergo phenotypical transition, enabling them to subserve contractile, proliferative, migratory and secretory functional responses that account for airway remodeling and persistent hyperresponsiveness.
However, despite consensus toward the importance of BSMCs regarding to the phenotypic plastic, migration and secretion, there is relatively little understanding of the cellular and molecular mechanisms underlying these changes seen in the asthmatic BSMCs. Extracellular signal-regulated kinase1/2 (ERK1/2) signaling pathway is one of the most important signalling pathways that modulate asthma in the chronic airway inflammation and hyperresponsiveness. Nevertheless, there are few reports about the role of ERK1/2 signaling pathway in the regulation of asthmatic BSMCs on their phenotypic modulation and migration. So the aim of this study is to profile the impact of ERK1/2 signaling pathway on the phenotypic transition, migration and secretion of BSMCs in chronic asthmatic model of rats, as well as in passively sensitized human BSMCs by asthmatic serum.
Method:
Wistar rats underwent OVA intraperitoneal injection and eight weeks inhalation for chronic asthma model. Human BSMCs were sensitized by asthmatic serum. Airway reactivity and relative count of eosinophil in alveolar lavage fluid were measured, and histological sections were investigated for morphometric analysis. The expressions of ERK1/2 and P-ERK1/2 at both protein and mRNA levels were detected by western blot and RT-PCR. Phenotype of BSMCs was established under electron microscrope, also with analysis of phenotypic markers (sm-α-actin for contractile and osteopontin for synthetic) in both protein and mRNA levels by western blot or RT-PCR, respectively. Migration of BSMCs was measured by plate test and transmembrane test. Secretion of BSMCs was measured by ELISA and western blot.
Results:
1. ERK1/2 was markedly increased in its expression and activity in the rat model of chronic asthma, and the level of P-ERK1/2 closely related to airway thickness.
2. The phenotype of BSMCs in chronic asthmatic rats switched from a contractile type to a synthetic type with plentiful synthetic organelles gathering around the nucleus and altered expressions of phenotypic markers. EGF urged the over-synthetic function of BSMCs, while MEK inhibitor PD98059 was capable to reverse the phenotypic change of BSMCs.
3. BSMCs of chronic asthmatic rats possessed increased migratory ability. EGF promoted the migration of BSMCs, MEK inhibitor PD98059 was capable to inhibit the change of BSMCs, and ERK1/2 antisense ODN restrained the migration ability of BSMCs.
4. BSMCs of chronic asthmatic rats secreted much more growth factors (TGF-β1 , VEGF and CTGF), cytokines (RANTES and EOTAXIN) and extracellular matrix (Fibronectin and CollangenⅠ) than that of normal controls. EGF stimulated the secretion of both two groups, but the response of chronic asthmatic group was more intense. Both PD98059 and antisense oligonucleotide were able to suppress the secretion of BSMCs in chronic ashmatic rats, but antisense oligonucleotide reduced the level of RANTES nearly to that of normal controls, while PD98059 couldn’t.
5. Local intranasal administration of ERK1/2 antisense oligonucleotides to chronic asthmatic rats led to DNA uptake in lung cells associated with a reduction of intracellular ERK1/2 expression. Such intrapulmonary blockade of ERK1/2 expression caused an abrogation of the increase in the thickness of airway as well as in that of smooth muscle layer. Furthermore, treatment with antisense but not nonsense oligonucleotides inhibited the phenotypic transition of BSMCs in the rat model of chronic asthma.
6. Passively sensitized human BSMCs changed further toward the synthetic phenotype as compared to the controls. EGF pushed the phenotypic transition of human BSMCs, and PD98059 inhibited partly the change in human BSMCs. Meanwhile, ERK1/2 antisense ODN was capable to reverse the phenotypic change of passively sensitized human BSMCs.
7. The migratory ability was increased in passively sensitized BSMCs as compared to the controls. EGF promoted the migration of human BSMCs, MEK inhibitor PD98059 was capable to inhibit the change of BSMCs, and ERK1/2 antisense ODN suppressed the migration ability of BSMCs.
8. Passively sensitized human BSMCs secreted much more growth factors, cytokines and extracellular matrix than that of controls. EGF stimulated the secretion of human BSMCs, and PD98059 was able to suppress the secretion of human BSMCs. While ERK1/2 antisense oligonucleotide induced a dramatic reduction of the secreted factors to levels comparable to that of normal controls.
Conclusion:
ERK1/2 signalling pathway play an important role on the phenotypic modulation, migration and secretion of bronchial smooth muscle cells in the rat model of chronic asthma, as well as in the model of human BSMCs passively sensitized by asthmatic serum.
引文
1. Vignola AM, Mirabella F, Costanzo G, et al. Airway remodeling in asthma. Chest, 2003, 137:339-346.
2. Kim HR, Hai CM. Mechanisms of mechanical strain memory in airway smooth muscle. Can J Physiol Pharmacol, 2005,83:811-815.
3. Salmon M, Walsh DA, Konto H, et al. Repeated allergen exposure of sensitized Brown Norway rats induces airway cell DNA synthesis and remodeling. Eur Respir J,1999,14:633- 641.
4.李超乾,徐永健,张珍祥,等.卡介苗预防哮喘大鼠模型形成及其与γδT细胞关系的研究.中华结核和呼吸杂志, 2002,25:162-165.
5. Bai A, Eidelman DH, Hogg JC, et al. Proposed nomenclature for quantifying subdivisions of the bronchial wall. J Appl Physiol, 1994,77:1011-1014.
6. Yamazaki T, Komuro I, Yazaki Y. Signalling pathways for cardiac hypertrophy. Cell Signal, 1998 ,10:693-698.
7. Schauwienold D, Plum C, Helbing T, et al. ERK1/2-dependent contractile protein expression in vascular smooth muscle cells. Hypertension, 2003, 41: 546-552.
8. Zhai W, Eynott PR, Oltmanns U, et al. Mitogen-activated protein kinase signalling pathways in IL-1{beta}-dependent rat airway smooth muscle proliferation. Br J Pharmacol, 2004,143:1042-1049.
9. Chwieralski CE, Schnurra I, Thim L, et al. Epidermal Growth Factor and Trefoil Factor Family 2 Synergistically Trigger Chemotaxis on BEAS-2B Cells via Different Signaling Cascades. Am J Respir Cell Mol Biol, 2004,31:528-537.
10. Kazi AS, Lotfi S, Goncharova EA, et al. Vascular endothelial growth factor-inducedsecretion of fibronectin is ERK dependent. Am J Physiol Lung Cell Mol Physiol. 2004 ,286:L539-545.
11. Duan W, Chan JH, Wong CH, et al. Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model. J Immunol, 2004 ,172:7053-7059.
12. Laporte JC, Moore PE, Baraldo S, et al. Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med, 2001,164:141-148.
1. Tang ML, Wilson JW, Stewart AG, et al. Airway remodelling in asthma: Current understanding and implications for future therapies. Pharmacol Ther. 2006 Jun 5; [Epub ahead of print].
2. Moir LM, Leung SY, Eynott PR, et al. Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats. Am J Physiol Lung Cell Mol Physiol, 2003, 284: L148-59.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol, 2003, 137(2-3):295-308.
4.李超乾,徐永健,张珍祥,等.卡介苗预防哮喘大鼠模型形成及其与γδT细胞关系的研究.中华结核和呼吸杂志, 2002,25:162-165.
5. Salmon M, Walsh DA, Konto H, et al. Repeated allergen exposure of sensitized Brown Norway rats induces airway cell DNA synthesis and remodeling. Eur Respir J,1999,14:633- 641.
6. Hirst SJ, Walker TR, Chilvers ER, et al. Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma. Eur Respir J, 2000,16:159-177.
7. Wilson E, Parrish AR, Bral CM, et al. Collagen suppresses the proliferative phenotype of allylamine-injured vascular smooth muscle cells. Artherosclerosis, 2002,162:289-297.
8. Brewster CE, Howarth PH, Djukanovic R, et al. Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol, 1990, 3:507-511.
9. Schauwienold D, Plum C, Helbing T, et al. ERK1/2-dependent contractile protein expression in vascular smooth muscle cells. Hypertension, 2003, 41: 546-552.
10. Panettieri RA, Murray RK, Eszterhas AJ, et al. Repeated allergen inhalations induce DNA synthesis in airway smooth muscle and epithelial cells in vivo. Am J Physiol,1998,274: L417-L424.
1. Johnson PR, Burgess JK. Airway smooth muscle and fibroblasts in the pathogenesis of asthma. Curr Allergy Asthma Rep 2004,4:102-108.
2. Madison JM. Migration of Airway smooth muscle cells. Am J Respir Cell Mol Biol 2003, 29;8-11.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol 2003 137:295-308.
4. Jiang Y(姜勇), Gong XW. Regulation of inflammatory responses by MAPK signal transduction pathways. Acta Physiol Sin (生理学报) 2000, 52:267-271(Chinese, English abstract).
5. Li CQ(李超乾), Xu YJ, Yang DL, Shi HZ, Liu XS, Xiong WN, Chen SX, Ni W, Zhang ZX. A study of helper T cell (Th)1/Th2 immune response pattern of gammadeltaT cells in asthma. Zhonghua Nei Ke Za Zhi 2004;43(5):342-4(Chinese, English abstract)..
6. Bai A, Eidelman DH, Hogg JC, James AL, Lambert RK, Ludwig MS, Martin J, McDonald DM, Mitzner WA, Okazawa M.Proposed nomenclature for quantifying subdivisions of the bronchial wall. J Appl Physiol 1994,77:1011-1014.
7. Liu XS(刘先胜), XU YJ, Zhang ZX, Ni W, Chen SX. Effect of protein kinase C on K(V) channel in rat bronchial smooth muscle. Acta Physiol Sin (生理学报) 2003, 55:135-141(Chinese, English abstract).
8. Sarkar R, Meinberg EG, Stanley JC,Gondon D, Webb RC. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells, Circ Res 1996,78:225-230.
9. Gizycki, MJ, Adelroth E, Rogers AV, O`Byrne PM, Jeffery PK. Myofibroblast involvement in the allergen-induced late response in mild atopic asthma. Am J Respir Cell Mol Biol 1997, 16:664–673.
10. Wang TH (王庭槐), Tan Z, Fu XD, Yang D, Hu FX, Li YY. Effect of ERK on 17β-estradiol-induced inhibition of VSMC proliferation in rats after vascular injury. Acta Physiol Sin (生理学报) 2003; 55(4): 411-416 (Chinese, English abstract).
11. Zhu JH(朱建华),Liu Z, Huang ZY, Li S. Effects of angiotensin II on extracellular signal-regulated protein kinases signaling pathway in cultured vascular smooth muscle cells from Wistar-Kyoto rats and spontaneously hypertensive rats. Acta Physiol Sin (生理学报) 2005; 57(5):587-592 (Chinese, English abstract).
1. Vignola AM, Mirabella F, Costanzo G, et al. Airway remodeling in asthma. Chest, 2003, 137:339-346.
2. Howarth PH, Knox AJ, Amrani Y, et al. Synthetic responses in airway smooth muscle. J Allergy Clin Immunol, 2004,114:S32-50.
3. Kim HR, Hai CM. Mechanisms of mechanical strain memory in airway smooth muscle. Can J Physiol Pharmacol, 2005,83:811-815.
4.李超乾,徐永健,张珍祥,等.卡介苗预防哮喘大鼠模型形成及其与γδT细胞关系的研究.中华结核和呼吸杂志, 2002,25:162-165.
5. Bai A, Eidelman DH, Hogg JC, et al. Proposed nomenclature for quantifying subdivisions of the bronchial wall. J Appl Physiol, 1994,77:1011-1014.
6.刘先胜,徐永健,张珍祥,等.钾通道阻滞剂对大鼠支气管平滑肌细胞增殖的影响.药学学报,2003,38:333-336.
7. Cotts A, Chen G, Stenphen N, et al. Release of biologically active TGF-βfrom airway smooth muscle cells induces autocrine synthesis of collagen. Am J Physiol Lung Cell Mol Physiol, 2001,280:999-1008.
8. Hallsworth MP, Moir LM, Lai D, et al. Inhibitors of Mitogen-activated Protein Kinases Differentially Regulate Eosinophil-activating Cytokine Release from Human Airway Smooth Muscle. Am J Respir Crit Care Med, 2001,164: 688–697.
9. Duan W, Chan JH, Wong CH, et al. Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model. J Immunol, 2004,172:7053-7059.
1. Tang ML, Wilson JW, Stewart AG, et al. Airway remodelling in asthma: Current understanding and implications for future therapies. Pharmacol Ther. 2006 Jun 5; [Epub ahead of print].
2. Moir LM, Leung SY, Eynott PR, et al. Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats. Am J Physiol Lung Cell Mol Physiol, 2003, 284: L148-59.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol, 2003, 137(2-3):295-308.
4.李超乾,徐永健,张珍祥,等.卡介苗预防哮喘大鼠模型形成及其与γδT细胞关系的研究.中华结核和呼吸杂志, 2002,25:162-165.
5. Salmon M, Walsh DA, Konto H, et al. Repeated allergen exposure of sensitized Brown Norway rats induces airway cell DNA synthesis and remodeling. Eur Respir J,1999,14:633- 641.
6. Makoto Tanaka1 and Jonathan W Nyce. Respirable antisense oligonucleotides: a new drug class for respiratory disease. Respiratory Research, 2001, 2:5-9.
7. Duan W, Chan JH, Mckay K, et al. Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med. 2005 ,171:571-8.
1. Tang ML, Wilson JW, Stewart AG, et al. Airway remodelling in asthma: Current understanding and implications for future therapies. Pharmacol Ther. 2006 Jun 5; [Epub ahead of print].
2. Moir LM, Leung SY, Eynott PR, et al. Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats. Am J Physiol Lung Cell Mol Physiol, 2003, 284: L148-59.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol, 2003, 137(2-3):295-308.
4.刘先胜,徐永健,张珍祥,等.钾通道阻滞剂对大鼠支气管平滑肌细胞增殖的影响.药学学报,2003,38:333-336.
5. Schauwienold D, Plum C, Helbing T, et al. ERK1/2-dependent contractile protein expression in vascular smooth muscle cells. Hypertension, 2003, 41: 546-552.
6. Black JL, Johnson PR. What determines asthma phenotype? Is it the interaction between allergy and the smooth muscle? Am J Respir Crit Care Med, 2000, 161:S207-S210.
7. Hakonarson H, Herrich D, Gonzalez Serrano P, et al. Autocrine role of interleukin 1b in altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J Clin Invest, 1997,99:117-124.
8. Hakonarson H, Grunstein M. Autologously up-regulated Fc receptor expression and action in airway smooth muscle mediates its altered responsiveness in the atopic asthmatic sensitized state. Proc NatI Acad Sci USA, 1998,95:5257-5262.
1. Johnson PR, Burgess JK. Airway smooth muscle and fibroblasts in the pathogenesis of asthma. Curr Allergy Asthma Rep 2004,4:102-108.
2. Madison JM. Migration of Airway smooth muscle cells. Am J Respir Cell Mol Biol 2003, 29;8-11.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol 2003 137:295-308.
4. Liu XS(刘先胜), XU YJ, Zhang ZX, Ni W, Chen SX. Effect of protein kinase C on K(V) channel in rat bronchial smooth muscle. Acta Physiol Sin (生理学报) 2003, 55:135-141(Chinese, English abstract).
5. Sarkar R, Meinberg EG, Stanley JC,Gondon D, Webb RC. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells, Circ Res 1996,78:225-230.
6. Goetze Y, Xi XP, Tawano Y, et al. TNF-–Induced Migration of Vascular Smooth Muscle Cells Is MAPK Dependent. Hypertension, 1999,33:183-189.
7. Black JL, Johnson PR. What determines asthma phenotype? Is it the interaction between allergy and the smooth muscle? Am J Respir Crit Care Med, 2000, 161:S207-S210.
1. Johnson PR, Burgess JK. Airway smooth muscle and fibroblasts in the pathogenesis of asthma. Curr Allergy Asthma Rep 2004,4:102-108.
2. Howarth PH, Knox AJ, Amrani Y, et al. Synthetic responses in airway smooth muscle. J Allergy Clin Immunol, 2004,114:S32-50.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol 2003 137:295-308.
4.刘先胜,徐永健,张珍祥,等.钾通道阻滞剂对大鼠支气管平滑肌细胞增殖的影响.药学学报,2003,38:333-336.
5. Hakonarson H, Herrich D, Gonzalez Serrano P, et al. Autocrine role of interleukin 1b in altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J Clin Invest, 1997,99:117-124.
6. Cotts A, Chen G, Stenphen N, et al. Release of biologically active TGF-βfrom airway smooth muscle cells induces autocrine synthesis of collagen. Am J Physiol Lung Cell Mol Physiol, 2001,280:999-1008.
7. Hallsworth MP, Moir LM, Lai D, et al. Inhibitors of Mitogen-activated Protein Kinases Differentially Regulate Eosinophil-activating Cytokine Release from Human Airway Smooth Muscle. Am J Respir Crit Care Med, 2001,164: 688–697.
8. Jin ZG, Melaragno MG, Liao DF, et al. Cyclophilin A Is a Secreted Growth Factor Induced by Oxidative Stress. Circulation research, 2000,87:789-791.
1. Duan W, Chan JH, Wong CH, et al. Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model. J Immunol. 2004,172(11):7053-7059
2. Bozinovski S, Jones JE, Vlahos R, et al. Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFkappa B and AP-1 in vivo. J Biol Chem. 2002 ,277(45):42808-42814.
3. Maa SH, Wang CH, Liu CY,et al. Endogenous nitric oxide downregulates the Bcl-2 expression of eosinophils through mitogen-activated protein kinase in bronchial asthma. J Allergy Clin Immunol. 2003,112(4):761-767
4. Hall DJ, Cui J, Bates ME, et al. Transduction of a dominant-negative H-Ras into human eosinophils attenuates extracellular signal-regulated kinase activation and interleukin-5-mediated cell viability. Blood. 2001,98(7):2014-2021.
5. Holub A, Byrnes J, Anderson S, et al. Ligand density modulates eosinophil signaling and migration. J Leukoc Biol. 2003,73(5):657-664.
6. Esnault S, Malter JS. Extracellular signal-regulated kinase mediates granulocyte-macrophage colony-stimulating factor messenger RNA stabilization in tumor necrosis factor-alpha plus fibronectin-activated peripheral blood eosinophils. Blood. 2002 ,99(11):4048-4052.
7. Bates ME, Green VL, Bertics PJ. ERK1 and ERK2 activation by chemotactic factors in human eosinophils is interleukin 5-dependent and contributes to leukotriene C(4) biosynthesis. J Biol Chem. 2000,275(15):10968-10975.
8. Kampen GT, Stafford S, Adachi T, et al. Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases. Blood. 2000,95(6):1911-1917.
9. Pahl A, Zhang M, Kuss H, et al. Regulation of IL-13 synthesis in human lymphocytes: implications for asthma therapy. Br J Pharmacol. 2002 ,135(8):1915-1926.
10. Wuyts WA, Vanaudenaerde BM , Dupont LJ, et al. Involvement of p38 MAPK, JNK,p42/p44 ERK and NF-kappaB in IL-1beta-induced chemokine release in human airway smooth muscle cells. Respir Med. 2003,97(7):811-817.
11. Hallsworth MP, Moir LM, Lai D, et al. Inhibitors of mitogen-activated protein kinases differentially regulate eosinophil-activating cytokine release from human airway smooth muscle. Am J Respir Crit Care Med. 2001,164(4):688-697.
12. Peng Q, Matsuda T, Hirst SJ. Signaling pathways regulating interleukin-13-stimulated chemokine release from airway smooth muscle. Am J Respir Crit Care Med. 2004,169(5):596-603.
13. Baraldo S, Faffe DS, Moore PE, et al. Interleukin-9 influences chemokine release in airway smooth muscle: role of ERK. Am J Physiol Lung Cell Mol Physiol. 2003,284(6):L1093-1102.
14. Feoktistov I, Goldstein AE, Biaggioni I. Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells. Mol Pharmacol. 1999 ,55(4):726-734.
15. Drost EM, MacNee W. Potential role of IL-8, platelet-activating factor and TNF-alpha in the sequestration of neutrophils in the lung: effects on neutrophil deformability, adhesion receptor expression, and chemotaxis. Eur J Immunol. 2002,32(2):393-403.
16. Hewson CA, Edbrooke MR, Johnston SL. PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-alpha, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J Mol Biol. 2004,344(3):683-695.
17. Cui CH, Adachi T, Oyamada H, et al. The role of mitogen-activated protein kinases in eotaxin-induced cytokine production from bronchial epithelial cells. Am J Respir Cell Mol Biol. 2002,27(3):329-335.
18. Laporte JC, Moore PE, Baraldo S, et al. Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med. 2001 ,164(1):141-148.
19. Inoue H, Kato R, Fukuyama S, et al. Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. J Exp Med. 2005 ,201(1):73-82.
20. Zhang Y, Adner M, Cardell LO. Interleukin-1beta attenuates endothelin B receptor-mediated airway contractions in a murine in vitro model of asthma: roles ofendothelin converting enzyme and mitogen-activated protein kinase pathways. Clin Exp Allergy. 2004,34(9):1480-1487.
21. Zhai W, Eynott PR, Oltmanns U, et al. Mitogen-activated protein kinase signalling pathways in IL-1{beta}-dependent rat airway smooth muscle proliferation. Br J Pharmacol. 2004,143(8) :1042-1049
22. Karpova, AK, Abe MK, Li J, et al. MEK1 is required for PDGF-induced ERK activation and DNA synthesis in tracheal monocytes. Am J Physiol Lung Cell Mol Physiol 1997,272: L558-L565.
23. Lee JH, Johnson PR, Roth M, et al. ERK activation and mitogenesis in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2001 ,280(5):L1019-1029.
24. Huang CD, Chen HH, Wang CH, et al. Human neutrophil-derived elastase induces airway smooth muscle cell proliferation. Life Sci. 2004,74(20):2479-2492.
25. Song R, Mahidhara RS, Liu F, et al. Carbon monoxide inhibits human airway smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Am J Respir Cell Mol Biol. 2002 ,27(5):603-610.
26. Kazi AS, Lotfi S, Goncharova EA, et al. Vascular endothelial growth factor-induced secretion of fibronectin is ERK dependent. Am J Physiol Lung Cell Mol Physiol. 2004,286(3):L539-545.
27. Chwieralski CE, Schnurra I, Thim L, et al. Epidermal Growth Factor and Trefoil Factor Family 2 Synergistically Trigger Chemotaxis on BEAS-2B Cells via Different Signaling Cascades. Am J Respir Cell Mol Biol. 2004 ,31(5):528-537.
2. Kim HR, Hai CM. Mechanisms of mechanical strain memory in airway smooth muscle. Can J Physiol Pharmacol, 2005,83:811-815.
3. Salmon M, Walsh DA, Konto H, et al. Repeated allergen exposure of sensitized Brown Norway rats induces airway cell DNA synthesis and remodeling. Eur Respir J,1999,14:633- 641.
4.李超乾,徐永健,张珍祥,等.卡介苗预防哮喘大鼠模型形成及其与γδT细胞关系的研究.中华结核和呼吸杂志, 2002,25:162-165.
5. Bai A, Eidelman DH, Hogg JC, et al. Proposed nomenclature for quantifying subdivisions of the bronchial wall. J Appl Physiol, 1994,77:1011-1014.
6. Yamazaki T, Komuro I, Yazaki Y. Signalling pathways for cardiac hypertrophy. Cell Signal, 1998 ,10:693-698.
7. Schauwienold D, Plum C, Helbing T, et al. ERK1/2-dependent contractile protein expression in vascular smooth muscle cells. Hypertension, 2003, 41: 546-552.
8. Zhai W, Eynott PR, Oltmanns U, et al. Mitogen-activated protein kinase signalling pathways in IL-1{beta}-dependent rat airway smooth muscle proliferation. Br J Pharmacol, 2004,143:1042-1049.
9. Chwieralski CE, Schnurra I, Thim L, et al. Epidermal Growth Factor and Trefoil Factor Family 2 Synergistically Trigger Chemotaxis on BEAS-2B Cells via Different Signaling Cascades. Am J Respir Cell Mol Biol, 2004,31:528-537.
10. Kazi AS, Lotfi S, Goncharova EA, et al. Vascular endothelial growth factor-inducedsecretion of fibronectin is ERK dependent. Am J Physiol Lung Cell Mol Physiol. 2004 ,286:L539-545.
11. Duan W, Chan JH, Wong CH, et al. Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model. J Immunol, 2004 ,172:7053-7059.
12. Laporte JC, Moore PE, Baraldo S, et al. Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med, 2001,164:141-148.
1. Tang ML, Wilson JW, Stewart AG, et al. Airway remodelling in asthma: Current understanding and implications for future therapies. Pharmacol Ther. 2006 Jun 5; [Epub ahead of print].
2. Moir LM, Leung SY, Eynott PR, et al. Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats. Am J Physiol Lung Cell Mol Physiol, 2003, 284: L148-59.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol, 2003, 137(2-3):295-308.
4.李超乾,徐永健,张珍祥,等.卡介苗预防哮喘大鼠模型形成及其与γδT细胞关系的研究.中华结核和呼吸杂志, 2002,25:162-165.
5. Salmon M, Walsh DA, Konto H, et al. Repeated allergen exposure of sensitized Brown Norway rats induces airway cell DNA synthesis and remodeling. Eur Respir J,1999,14:633- 641.
6. Hirst SJ, Walker TR, Chilvers ER, et al. Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma. Eur Respir J, 2000,16:159-177.
7. Wilson E, Parrish AR, Bral CM, et al. Collagen suppresses the proliferative phenotype of allylamine-injured vascular smooth muscle cells. Artherosclerosis, 2002,162:289-297.
8. Brewster CE, Howarth PH, Djukanovic R, et al. Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Biol, 1990, 3:507-511.
9. Schauwienold D, Plum C, Helbing T, et al. ERK1/2-dependent contractile protein expression in vascular smooth muscle cells. Hypertension, 2003, 41: 546-552.
10. Panettieri RA, Murray RK, Eszterhas AJ, et al. Repeated allergen inhalations induce DNA synthesis in airway smooth muscle and epithelial cells in vivo. Am J Physiol,1998,274: L417-L424.
1. Johnson PR, Burgess JK. Airway smooth muscle and fibroblasts in the pathogenesis of asthma. Curr Allergy Asthma Rep 2004,4:102-108.
2. Madison JM. Migration of Airway smooth muscle cells. Am J Respir Cell Mol Biol 2003, 29;8-11.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol 2003 137:295-308.
4. Jiang Y(姜勇), Gong XW. Regulation of inflammatory responses by MAPK signal transduction pathways. Acta Physiol Sin (生理学报) 2000, 52:267-271(Chinese, English abstract).
5. Li CQ(李超乾), Xu YJ, Yang DL, Shi HZ, Liu XS, Xiong WN, Chen SX, Ni W, Zhang ZX. A study of helper T cell (Th)1/Th2 immune response pattern of gammadeltaT cells in asthma. Zhonghua Nei Ke Za Zhi 2004;43(5):342-4(Chinese, English abstract)..
6. Bai A, Eidelman DH, Hogg JC, James AL, Lambert RK, Ludwig MS, Martin J, McDonald DM, Mitzner WA, Okazawa M.Proposed nomenclature for quantifying subdivisions of the bronchial wall. J Appl Physiol 1994,77:1011-1014.
7. Liu XS(刘先胜), XU YJ, Zhang ZX, Ni W, Chen SX. Effect of protein kinase C on K(V) channel in rat bronchial smooth muscle. Acta Physiol Sin (生理学报) 2003, 55:135-141(Chinese, English abstract).
8. Sarkar R, Meinberg EG, Stanley JC,Gondon D, Webb RC. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells, Circ Res 1996,78:225-230.
9. Gizycki, MJ, Adelroth E, Rogers AV, O`Byrne PM, Jeffery PK. Myofibroblast involvement in the allergen-induced late response in mild atopic asthma. Am J Respir Cell Mol Biol 1997, 16:664–673.
10. Wang TH (王庭槐), Tan Z, Fu XD, Yang D, Hu FX, Li YY. Effect of ERK on 17β-estradiol-induced inhibition of VSMC proliferation in rats after vascular injury. Acta Physiol Sin (生理学报) 2003; 55(4): 411-416 (Chinese, English abstract).
11. Zhu JH(朱建华),Liu Z, Huang ZY, Li S. Effects of angiotensin II on extracellular signal-regulated protein kinases signaling pathway in cultured vascular smooth muscle cells from Wistar-Kyoto rats and spontaneously hypertensive rats. Acta Physiol Sin (生理学报) 2005; 57(5):587-592 (Chinese, English abstract).
1. Vignola AM, Mirabella F, Costanzo G, et al. Airway remodeling in asthma. Chest, 2003, 137:339-346.
2. Howarth PH, Knox AJ, Amrani Y, et al. Synthetic responses in airway smooth muscle. J Allergy Clin Immunol, 2004,114:S32-50.
3. Kim HR, Hai CM. Mechanisms of mechanical strain memory in airway smooth muscle. Can J Physiol Pharmacol, 2005,83:811-815.
4.李超乾,徐永健,张珍祥,等.卡介苗预防哮喘大鼠模型形成及其与γδT细胞关系的研究.中华结核和呼吸杂志, 2002,25:162-165.
5. Bai A, Eidelman DH, Hogg JC, et al. Proposed nomenclature for quantifying subdivisions of the bronchial wall. J Appl Physiol, 1994,77:1011-1014.
6.刘先胜,徐永健,张珍祥,等.钾通道阻滞剂对大鼠支气管平滑肌细胞增殖的影响.药学学报,2003,38:333-336.
7. Cotts A, Chen G, Stenphen N, et al. Release of biologically active TGF-βfrom airway smooth muscle cells induces autocrine synthesis of collagen. Am J Physiol Lung Cell Mol Physiol, 2001,280:999-1008.
8. Hallsworth MP, Moir LM, Lai D, et al. Inhibitors of Mitogen-activated Protein Kinases Differentially Regulate Eosinophil-activating Cytokine Release from Human Airway Smooth Muscle. Am J Respir Crit Care Med, 2001,164: 688–697.
9. Duan W, Chan JH, Wong CH, et al. Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model. J Immunol, 2004,172:7053-7059.
1. Tang ML, Wilson JW, Stewart AG, et al. Airway remodelling in asthma: Current understanding and implications for future therapies. Pharmacol Ther. 2006 Jun 5; [Epub ahead of print].
2. Moir LM, Leung SY, Eynott PR, et al. Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats. Am J Physiol Lung Cell Mol Physiol, 2003, 284: L148-59.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol, 2003, 137(2-3):295-308.
4.李超乾,徐永健,张珍祥,等.卡介苗预防哮喘大鼠模型形成及其与γδT细胞关系的研究.中华结核和呼吸杂志, 2002,25:162-165.
5. Salmon M, Walsh DA, Konto H, et al. Repeated allergen exposure of sensitized Brown Norway rats induces airway cell DNA synthesis and remodeling. Eur Respir J,1999,14:633- 641.
6. Makoto Tanaka1 and Jonathan W Nyce. Respirable antisense oligonucleotides: a new drug class for respiratory disease. Respiratory Research, 2001, 2:5-9.
7. Duan W, Chan JH, Mckay K, et al. Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med. 2005 ,171:571-8.
1. Tang ML, Wilson JW, Stewart AG, et al. Airway remodelling in asthma: Current understanding and implications for future therapies. Pharmacol Ther. 2006 Jun 5; [Epub ahead of print].
2. Moir LM, Leung SY, Eynott PR, et al. Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats. Am J Physiol Lung Cell Mol Physiol, 2003, 284: L148-59.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol, 2003, 137(2-3):295-308.
4.刘先胜,徐永健,张珍祥,等.钾通道阻滞剂对大鼠支气管平滑肌细胞增殖的影响.药学学报,2003,38:333-336.
5. Schauwienold D, Plum C, Helbing T, et al. ERK1/2-dependent contractile protein expression in vascular smooth muscle cells. Hypertension, 2003, 41: 546-552.
6. Black JL, Johnson PR. What determines asthma phenotype? Is it the interaction between allergy and the smooth muscle? Am J Respir Crit Care Med, 2000, 161:S207-S210.
7. Hakonarson H, Herrich D, Gonzalez Serrano P, et al. Autocrine role of interleukin 1b in altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J Clin Invest, 1997,99:117-124.
8. Hakonarson H, Grunstein M. Autologously up-regulated Fc receptor expression and action in airway smooth muscle mediates its altered responsiveness in the atopic asthmatic sensitized state. Proc NatI Acad Sci USA, 1998,95:5257-5262.
1. Johnson PR, Burgess JK. Airway smooth muscle and fibroblasts in the pathogenesis of asthma. Curr Allergy Asthma Rep 2004,4:102-108.
2. Madison JM. Migration of Airway smooth muscle cells. Am J Respir Cell Mol Biol 2003, 29;8-11.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol 2003 137:295-308.
4. Liu XS(刘先胜), XU YJ, Zhang ZX, Ni W, Chen SX. Effect of protein kinase C on K(V) channel in rat bronchial smooth muscle. Acta Physiol Sin (生理学报) 2003, 55:135-141(Chinese, English abstract).
5. Sarkar R, Meinberg EG, Stanley JC,Gondon D, Webb RC. Nitric oxide reversibly inhibits the migration of cultured vascular smooth muscle cells, Circ Res 1996,78:225-230.
6. Goetze Y, Xi XP, Tawano Y, et al. TNF-–Induced Migration of Vascular Smooth Muscle Cells Is MAPK Dependent. Hypertension, 1999,33:183-189.
7. Black JL, Johnson PR. What determines asthma phenotype? Is it the interaction between allergy and the smooth muscle? Am J Respir Crit Care Med, 2000, 161:S207-S210.
1. Johnson PR, Burgess JK. Airway smooth muscle and fibroblasts in the pathogenesis of asthma. Curr Allergy Asthma Rep 2004,4:102-108.
2. Howarth PH, Knox AJ, Amrani Y, et al. Synthetic responses in airway smooth muscle. J Allergy Clin Immunol, 2004,114:S32-50.
3. Zhou L, Hershenson MB. Mitogenic signaling pathway in airway smooth muscle. Respir Physiol Neurobiol 2003 137:295-308.
4.刘先胜,徐永健,张珍祥,等.钾通道阻滞剂对大鼠支气管平滑肌细胞增殖的影响.药学学报,2003,38:333-336.
5. Hakonarson H, Herrich D, Gonzalez Serrano P, et al. Autocrine role of interleukin 1b in altered responsiveness of atopic asthmatic sensitized airway smooth muscle. J Clin Invest, 1997,99:117-124.
6. Cotts A, Chen G, Stenphen N, et al. Release of biologically active TGF-βfrom airway smooth muscle cells induces autocrine synthesis of collagen. Am J Physiol Lung Cell Mol Physiol, 2001,280:999-1008.
7. Hallsworth MP, Moir LM, Lai D, et al. Inhibitors of Mitogen-activated Protein Kinases Differentially Regulate Eosinophil-activating Cytokine Release from Human Airway Smooth Muscle. Am J Respir Crit Care Med, 2001,164: 688–697.
8. Jin ZG, Melaragno MG, Liao DF, et al. Cyclophilin A Is a Secreted Growth Factor Induced by Oxidative Stress. Circulation research, 2000,87:789-791.
1. Duan W, Chan JH, Wong CH, et al. Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model. J Immunol. 2004,172(11):7053-7059
2. Bozinovski S, Jones JE, Vlahos R, et al. Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFkappa B and AP-1 in vivo. J Biol Chem. 2002 ,277(45):42808-42814.
3. Maa SH, Wang CH, Liu CY,et al. Endogenous nitric oxide downregulates the Bcl-2 expression of eosinophils through mitogen-activated protein kinase in bronchial asthma. J Allergy Clin Immunol. 2003,112(4):761-767
4. Hall DJ, Cui J, Bates ME, et al. Transduction of a dominant-negative H-Ras into human eosinophils attenuates extracellular signal-regulated kinase activation and interleukin-5-mediated cell viability. Blood. 2001,98(7):2014-2021.
5. Holub A, Byrnes J, Anderson S, et al. Ligand density modulates eosinophil signaling and migration. J Leukoc Biol. 2003,73(5):657-664.
6. Esnault S, Malter JS. Extracellular signal-regulated kinase mediates granulocyte-macrophage colony-stimulating factor messenger RNA stabilization in tumor necrosis factor-alpha plus fibronectin-activated peripheral blood eosinophils. Blood. 2002 ,99(11):4048-4052.
7. Bates ME, Green VL, Bertics PJ. ERK1 and ERK2 activation by chemotactic factors in human eosinophils is interleukin 5-dependent and contributes to leukotriene C(4) biosynthesis. J Biol Chem. 2000,275(15):10968-10975.
8. Kampen GT, Stafford S, Adachi T, et al. Eotaxin induces degranulation and chemotaxis of eosinophils through the activation of ERK2 and p38 mitogen-activated protein kinases. Blood. 2000,95(6):1911-1917.
9. Pahl A, Zhang M, Kuss H, et al. Regulation of IL-13 synthesis in human lymphocytes: implications for asthma therapy. Br J Pharmacol. 2002 ,135(8):1915-1926.
10. Wuyts WA, Vanaudenaerde BM , Dupont LJ, et al. Involvement of p38 MAPK, JNK,p42/p44 ERK and NF-kappaB in IL-1beta-induced chemokine release in human airway smooth muscle cells. Respir Med. 2003,97(7):811-817.
11. Hallsworth MP, Moir LM, Lai D, et al. Inhibitors of mitogen-activated protein kinases differentially regulate eosinophil-activating cytokine release from human airway smooth muscle. Am J Respir Crit Care Med. 2001,164(4):688-697.
12. Peng Q, Matsuda T, Hirst SJ. Signaling pathways regulating interleukin-13-stimulated chemokine release from airway smooth muscle. Am J Respir Crit Care Med. 2004,169(5):596-603.
13. Baraldo S, Faffe DS, Moore PE, et al. Interleukin-9 influences chemokine release in airway smooth muscle: role of ERK. Am J Physiol Lung Cell Mol Physiol. 2003,284(6):L1093-1102.
14. Feoktistov I, Goldstein AE, Biaggioni I. Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells. Mol Pharmacol. 1999 ,55(4):726-734.
15. Drost EM, MacNee W. Potential role of IL-8, platelet-activating factor and TNF-alpha in the sequestration of neutrophils in the lung: effects on neutrophil deformability, adhesion receptor expression, and chemotaxis. Eur J Immunol. 2002,32(2):393-403.
16. Hewson CA, Edbrooke MR, Johnston SL. PMA induces the MUC5AC respiratory mucin in human bronchial epithelial cells, via PKC, EGF/TGF-alpha, Ras/Raf, MEK, ERK and Sp1-dependent mechanisms. J Mol Biol. 2004,344(3):683-695.
17. Cui CH, Adachi T, Oyamada H, et al. The role of mitogen-activated protein kinases in eotaxin-induced cytokine production from bronchial epithelial cells. Am J Respir Cell Mol Biol. 2002,27(3):329-335.
18. Laporte JC, Moore PE, Baraldo S, et al. Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med. 2001 ,164(1):141-148.
19. Inoue H, Kato R, Fukuyama S, et al. Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. J Exp Med. 2005 ,201(1):73-82.
20. Zhang Y, Adner M, Cardell LO. Interleukin-1beta attenuates endothelin B receptor-mediated airway contractions in a murine in vitro model of asthma: roles ofendothelin converting enzyme and mitogen-activated protein kinase pathways. Clin Exp Allergy. 2004,34(9):1480-1487.
21. Zhai W, Eynott PR, Oltmanns U, et al. Mitogen-activated protein kinase signalling pathways in IL-1{beta}-dependent rat airway smooth muscle proliferation. Br J Pharmacol. 2004,143(8) :1042-1049
22. Karpova, AK, Abe MK, Li J, et al. MEK1 is required for PDGF-induced ERK activation and DNA synthesis in tracheal monocytes. Am J Physiol Lung Cell Mol Physiol 1997,272: L558-L565.
23. Lee JH, Johnson PR, Roth M, et al. ERK activation and mitogenesis in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2001 ,280(5):L1019-1029.
24. Huang CD, Chen HH, Wang CH, et al. Human neutrophil-derived elastase induces airway smooth muscle cell proliferation. Life Sci. 2004,74(20):2479-2492.
25. Song R, Mahidhara RS, Liu F, et al. Carbon monoxide inhibits human airway smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Am J Respir Cell Mol Biol. 2002 ,27(5):603-610.
26. Kazi AS, Lotfi S, Goncharova EA, et al. Vascular endothelial growth factor-induced secretion of fibronectin is ERK dependent. Am J Physiol Lung Cell Mol Physiol. 2004,286(3):L539-545.
27. Chwieralski CE, Schnurra I, Thim L, et al. Epidermal Growth Factor and Trefoil Factor Family 2 Synergistically Trigger Chemotaxis on BEAS-2B Cells via Different Signaling Cascades. Am J Respir Cell Mol Biol. 2004 ,31(5):528-537.