肺微血管内皮细胞功能表型变化与博莱霉素大鼠肺纤维化相关性研究
|
摘要
目的:
肺纤维化(pulmonary fibrosis,PF)是机体对肺组织损伤的过度修复和重塑的病理结果,而肌成纤维细胞(myofibroblasts, MFbs)正是导致胶原大量分泌、组织过度修复的主要效应靶细胞,其在间质中数量增加并持续活化被认为是病程向纤维化进展的重要标志。MFbs主要由间质中的成纤维细胞(fibroblasts, Fbs)转化而来,后者在缺氧、促纤维化细胞因子等因素的诱导下表达MFbs的特征性蛋白分子——α-SMA,从而转化为MFbs,发挥更强的致纤维化作用,因此,大量活化的Fbs转化为致纤维化能力更强的MFbs的病理过程是PF进程的关键环节。回顾文献发现,肺微血管内皮细胞(pulmonary microvascular endothelial cells, PMVECs)作为血管壁基本的结构和功能单位,是血管屏障的重要组成部分,它不仅在生理状态下调节血管内外的物质交换、稳定机体的内环境;还在病理状态下超早期的发生应激反应,促进组织修复。然而,它在消除致病因子对机体损伤的同时也可能由于某种原因而过度地发挥了介导免疫、炎症反应,加重组织缺氧,分泌过量细胞因子等生物学作用,从而促进了组织的纤维性修复。文献显示,上述病态的PMVECs功能可能在Fbs向MFbs转化的病理过程发挥着重要作用,本实验将采用ELISA、Western Blot、RT-PCR等方法检测PMVECs中相关细胞因子的合成、分泌水平,并使用millicell细胞共培养体系,结合抗体中和试验,研究体外共培养条件下,BLM大鼠PMVECs对Fbs的生物学作用及其机制,进一步揭示PMVECs及其功能表型变化在PF早期病程中的作用。
方法:
SD大鼠,体重100±20 g,雄性,以博莱霉素(Bleomycin,BLM)-A5溶液气管内灌注的方法诱导大鼠PF模型,并在相同条件下向正常大鼠气管内灌注等体积生理盐水作为对照。分别于给药后第3,7,14,21和28天处死大鼠,取外周肺组织留作原代培养PMVECs和Fbs,其余肺组织用10 g/L多聚甲醛固定后石蜡包埋、切片、VG染色。在各时间点原代培养PMVECs和Fbs后,利用ELISA、Western Blot、RT-PCR等方法检测各组大鼠PMVECs合成、分泌细胞因子TGF-β1及CTGF的水平;并将各组大鼠PMVECs分别与预先培养、传代的对照组大鼠Fbs共培养,采用细胞生长曲线测定、PCNA免疫组化染色、流式细胞染色、Western Blot等方法,检测共培养后的Fbs的增殖、转化及胶原合成能力,并以单培养的各组大鼠Fbs的相应功能作为阳性对照,进行比较分析;结合细胞因子抗体中和试验检测PMVECs细胞因子分泌功能的变化与其促Fbs增殖、转化功能的相关关系。
结果:
1、BLM大鼠PMVECs的对数生长期较对照组大鼠PMVECs提前。
2、免疫荧光染色及Western Blot检测证实BLM诱导大鼠PF过程中PMVECs上调TGF-β1和CTGF蛋白的表达,且高峰出现在BLM气管内灌注后7天组PMVECs。经RT-PCR鉴定,BLM气管内灌注后7天组PMVECs中TGF-β1和CTGF的转录显著升高。ELISA实验证实,各组PMVECs培养上清中TGF-β1和CTGF的分泌水平与Western Blot检测的细胞中相应蛋白的表达水平基本一致。
3、细胞免疫荧光染色及Western Blot检测证实BLM大鼠PMVECs中出现α-SMA蛋白的表达,其高峰亦位于BLM气管内灌注后7天组。4、生长曲线及PCNA染色显示与BLM气管内灌注后7、14、21、28天组PMVECs共培养的Fbs的对数生长期提前,核增殖能力明显高于对照组。流式细胞染色及Western Blot结果显示与BLM气管内灌注后7天组PMVECs共培养的Fbs群中,MFbs数量显著增加,α-SMA蛋白的表达亦明显上调;与BLM气管内灌注后7、14天组PMVECs共培养的Fbs中ColⅠA1的表达显著上调。
5、抗体中和试验显示,单独使用TGF-β1抗体使共培养上清中TGF-β1的浓度下降约53.15±8.91%,可使共培养的Fbs数量减少约23.39±2.12%,Fbs群中MFbs百分比下降约4.68±0.86%(降幅约22.48%);单独使用CTGF抗体使共培养上清中CTGF的浓度下降约54.65±10.24%,可使共培养的Fbs数量减少约45.16±5.79%,Fbs群中MFbs百分比下降约8.06±1.31%(降幅约38.71%);而联合使用TGF-β1和CTGF抗体使共培养上清中TGF-β1和CTGF浓度同比下降约50%,可使共培养的Fbs数量减少约73.39±11.89%,Fbs群中MFbs百分比下降约10.15±1.37%(降幅约48.75%)。
结论:
1、BLM诱导的大鼠PF过程中,PMVECs合成、分泌促纤维化细胞因子TGF-β1及CTGF的功能上调,尤其在病程早期,PMVECs合成、分泌细胞因子功能旺盛,细胞以分泌功能表型为主。
2、在体外共培养条件下,BLM大鼠PMVECs可促进正常鼠Fbs的增殖、转化及胶原合成,并以BLM气管内灌注后7天大鼠PMVECs的促Fbs增殖作用最强。
3、以TGF-β1及CTGF高表达为代表的PMVECs表型异常是促进Fbs活化、增殖并转化为MFbs,进而导致细胞外基质过度分泌的重要原因;也可能是生理状态下早期激活间质中静止的Fbs,并促进其发挥致纤维化作用的关键因素。
Purpose:
Pulmonary fibrosis is results from abnormal repair and reconstruction of lung tissue after injury. Myofibroblasts (MFbs) marked by increased expression of smooth muscle alpha-actin (alpha-SMA) stress fibers (a contractile phenotype) is one of the primary effective cells involved in the repair and reconstruction of lung tissue. Therefore, accumulation and activation of MFbs are regarded as the hallmark of progressive pulmonary fibrosis. In general, MFbs are mainly derived from transformation of resident lung fibroblasts (Fbs) which will transform to MFbs to play a stronger role in fibrosis by the induction of hypoxia, profibrotic growth factor and so on. Pulmonary microvascular endothelial cells (PMVECs), one of pivotal effective cells against pathopoiesis factor in early stage of disease, are proved to play an important role in mediating inflammatory response, aggravating tissue hypoxia, and secreting cytokines and matrix to regulate the migration, proliferation and differentiation of mesenchymal cells. Many experiments indicated the injury of PMVECs facilitated the progress of pulmonary fibrosis and the accumulation and transformation of fibroblasts was closed correlated with the biological activity of PMVECs in the process of pulmonary fibrosis, so we established a coculture system of PMVECs and Fbs, which can be useful to engineer a more in vivo-like microenvironment for both cells sharing the same culture medium, applying in order to study the phenotype and function of pulmonary microvascular endothelial cell in early stage of progressive pulmonary fibrosis.
Methods:
SD rats, male, weighing 100±20g (provided by the experimental animal center of the Fourth Military Medical University). The BLM rats were injected intrathecally with 0.125 ml BLM-A5 solution (4 g/L in sterile water, dosage 5mg/kg weight) to induce pulmonary fibrosis, and the control animals were injected intrathecally with 0.125 ml sterile saline. After rats were euthanized at 3, 7, 14, 21and 28 days post-instillation, the peripheral lung tissue was cut for primary cell culture of PMVECs and Fbs, and the remanent lung tissue was used for histological analysis by VG stain.
PMVECs and Fbs were isolated from lung tissue of each group rats, and were cultured. PMVECs from each group and Fbs from control group were co-cultured respectively. Immunofluorescence, ELISA, Western Blot(WB), reverse transcription-PCR (RT-PCR), FCM and neutralization test of cytokines were performed to detect the synthesis and secretion of connective tissue growth factor(CTGF) and transformation growth factor-beta1 (TGF-β1) in PMVECs, and to analyze the role of PMVECs in process of pulmonary fibrosis.
Results:
1、The logarithmic growth phase of PMVECs isolated from BLM-induced rats were ahead of control group.
2、Immunofluorescence, Western blot and ELISA analysis revealed a peak of synthesis and secretion of CTGF and TGF-β1 protein in PMVECs at 7-day post-instillation group. RT-PCR analysis revealed that the transcription of TGF-β1 and CTGF were prominently up-regulated in PMVECs of 7-day post-instillation group.
3、α-SMA protein was detected in PMVECs of BLM-induced rats by immunofluorescence and western blot analysis.
4、MTT, PCNA immunohistologic stain, FCM and western blot analysis revealed the proliferation, the transformation and the function of synthesizing and secreting collagenⅠwere prominently up-regulated in Fbs cocultured with PMVECs of 7, 14, 21, 28-day post-instillation groups, especially in Fbs cocultured with PMVECs of 7-day post-instillation groups.
5、Neutralization test of cytokines displayed, about 23.39±2.12% drop in quantity of cocultured Fbs and 4.68±0.86% drop in percent of MFbs in cocultured Fbs were caused by neutralizing of 53.15±8.91% TGF-β1; about 45.16±5.79% drop in quantity of cocultured Fbs and 8.06±1.31% drop in percent of MFbs in cocultured Fbs were caused by neutralizing of 54.65±10.24% CTGF; 73.39±11.89% drop in quantity of cocultured Fbs and 10.15±1.37% drop in percent of MFbs in cocultured Fbs were caused by neutralizing of both TGF-β1 and CTGF.
Conclusion:
1、The synthesis and secretion of TGF-β1 and CTGF protein were prominently up-regulated in PMVECs in process of BLM-induced rats pulmonary fibrosis, and PMVEC showed secretion phenotype.
2、PMVECs isolated from BLM-induced rats can improve the proliferation, the transformation and the function in synthesizing and secreting collagenⅠprotein of control Fbs in vitro, especially in PMVECs of 7-day post-instillation groups.
3、Abnormal phenotype in PMVECs, displaying up-regulation of TGF-β1 and CTGF protein expression is the important reason for activation, proliferation and transformation of Fbs, even for excess secretion of extracellular matrix,which is probably the key factor to activate the static Fbs in lung interstitium and stimulate Fb to play its profibrotic role in early stage of disease in vivo.
肺纤维化(pulmonary fibrosis,PF)是机体对肺组织损伤的过度修复和重塑的病理结果,而肌成纤维细胞(myofibroblasts, MFbs)正是导致胶原大量分泌、组织过度修复的主要效应靶细胞,其在间质中数量增加并持续活化被认为是病程向纤维化进展的重要标志。MFbs主要由间质中的成纤维细胞(fibroblasts, Fbs)转化而来,后者在缺氧、促纤维化细胞因子等因素的诱导下表达MFbs的特征性蛋白分子——α-SMA,从而转化为MFbs,发挥更强的致纤维化作用,因此,大量活化的Fbs转化为致纤维化能力更强的MFbs的病理过程是PF进程的关键环节。回顾文献发现,肺微血管内皮细胞(pulmonary microvascular endothelial cells, PMVECs)作为血管壁基本的结构和功能单位,是血管屏障的重要组成部分,它不仅在生理状态下调节血管内外的物质交换、稳定机体的内环境;还在病理状态下超早期的发生应激反应,促进组织修复。然而,它在消除致病因子对机体损伤的同时也可能由于某种原因而过度地发挥了介导免疫、炎症反应,加重组织缺氧,分泌过量细胞因子等生物学作用,从而促进了组织的纤维性修复。文献显示,上述病态的PMVECs功能可能在Fbs向MFbs转化的病理过程发挥着重要作用,本实验将采用ELISA、Western Blot、RT-PCR等方法检测PMVECs中相关细胞因子的合成、分泌水平,并使用millicell细胞共培养体系,结合抗体中和试验,研究体外共培养条件下,BLM大鼠PMVECs对Fbs的生物学作用及其机制,进一步揭示PMVECs及其功能表型变化在PF早期病程中的作用。
方法:
SD大鼠,体重100±20 g,雄性,以博莱霉素(Bleomycin,BLM)-A5溶液气管内灌注的方法诱导大鼠PF模型,并在相同条件下向正常大鼠气管内灌注等体积生理盐水作为对照。分别于给药后第3,7,14,21和28天处死大鼠,取外周肺组织留作原代培养PMVECs和Fbs,其余肺组织用10 g/L多聚甲醛固定后石蜡包埋、切片、VG染色。在各时间点原代培养PMVECs和Fbs后,利用ELISA、Western Blot、RT-PCR等方法检测各组大鼠PMVECs合成、分泌细胞因子TGF-β1及CTGF的水平;并将各组大鼠PMVECs分别与预先培养、传代的对照组大鼠Fbs共培养,采用细胞生长曲线测定、PCNA免疫组化染色、流式细胞染色、Western Blot等方法,检测共培养后的Fbs的增殖、转化及胶原合成能力,并以单培养的各组大鼠Fbs的相应功能作为阳性对照,进行比较分析;结合细胞因子抗体中和试验检测PMVECs细胞因子分泌功能的变化与其促Fbs增殖、转化功能的相关关系。
结果:
1、BLM大鼠PMVECs的对数生长期较对照组大鼠PMVECs提前。
2、免疫荧光染色及Western Blot检测证实BLM诱导大鼠PF过程中PMVECs上调TGF-β1和CTGF蛋白的表达,且高峰出现在BLM气管内灌注后7天组PMVECs。经RT-PCR鉴定,BLM气管内灌注后7天组PMVECs中TGF-β1和CTGF的转录显著升高。ELISA实验证实,各组PMVECs培养上清中TGF-β1和CTGF的分泌水平与Western Blot检测的细胞中相应蛋白的表达水平基本一致。
3、细胞免疫荧光染色及Western Blot检测证实BLM大鼠PMVECs中出现α-SMA蛋白的表达,其高峰亦位于BLM气管内灌注后7天组。4、生长曲线及PCNA染色显示与BLM气管内灌注后7、14、21、28天组PMVECs共培养的Fbs的对数生长期提前,核增殖能力明显高于对照组。流式细胞染色及Western Blot结果显示与BLM气管内灌注后7天组PMVECs共培养的Fbs群中,MFbs数量显著增加,α-SMA蛋白的表达亦明显上调;与BLM气管内灌注后7、14天组PMVECs共培养的Fbs中ColⅠA1的表达显著上调。
5、抗体中和试验显示,单独使用TGF-β1抗体使共培养上清中TGF-β1的浓度下降约53.15±8.91%,可使共培养的Fbs数量减少约23.39±2.12%,Fbs群中MFbs百分比下降约4.68±0.86%(降幅约22.48%);单独使用CTGF抗体使共培养上清中CTGF的浓度下降约54.65±10.24%,可使共培养的Fbs数量减少约45.16±5.79%,Fbs群中MFbs百分比下降约8.06±1.31%(降幅约38.71%);而联合使用TGF-β1和CTGF抗体使共培养上清中TGF-β1和CTGF浓度同比下降约50%,可使共培养的Fbs数量减少约73.39±11.89%,Fbs群中MFbs百分比下降约10.15±1.37%(降幅约48.75%)。
结论:
1、BLM诱导的大鼠PF过程中,PMVECs合成、分泌促纤维化细胞因子TGF-β1及CTGF的功能上调,尤其在病程早期,PMVECs合成、分泌细胞因子功能旺盛,细胞以分泌功能表型为主。
2、在体外共培养条件下,BLM大鼠PMVECs可促进正常鼠Fbs的增殖、转化及胶原合成,并以BLM气管内灌注后7天大鼠PMVECs的促Fbs增殖作用最强。
3、以TGF-β1及CTGF高表达为代表的PMVECs表型异常是促进Fbs活化、增殖并转化为MFbs,进而导致细胞外基质过度分泌的重要原因;也可能是生理状态下早期激活间质中静止的Fbs,并促进其发挥致纤维化作用的关键因素。
Purpose:
Pulmonary fibrosis is results from abnormal repair and reconstruction of lung tissue after injury. Myofibroblasts (MFbs) marked by increased expression of smooth muscle alpha-actin (alpha-SMA) stress fibers (a contractile phenotype) is one of the primary effective cells involved in the repair and reconstruction of lung tissue. Therefore, accumulation and activation of MFbs are regarded as the hallmark of progressive pulmonary fibrosis. In general, MFbs are mainly derived from transformation of resident lung fibroblasts (Fbs) which will transform to MFbs to play a stronger role in fibrosis by the induction of hypoxia, profibrotic growth factor and so on. Pulmonary microvascular endothelial cells (PMVECs), one of pivotal effective cells against pathopoiesis factor in early stage of disease, are proved to play an important role in mediating inflammatory response, aggravating tissue hypoxia, and secreting cytokines and matrix to regulate the migration, proliferation and differentiation of mesenchymal cells. Many experiments indicated the injury of PMVECs facilitated the progress of pulmonary fibrosis and the accumulation and transformation of fibroblasts was closed correlated with the biological activity of PMVECs in the process of pulmonary fibrosis, so we established a coculture system of PMVECs and Fbs, which can be useful to engineer a more in vivo-like microenvironment for both cells sharing the same culture medium, applying in order to study the phenotype and function of pulmonary microvascular endothelial cell in early stage of progressive pulmonary fibrosis.
Methods:
SD rats, male, weighing 100±20g (provided by the experimental animal center of the Fourth Military Medical University). The BLM rats were injected intrathecally with 0.125 ml BLM-A5 solution (4 g/L in sterile water, dosage 5mg/kg weight) to induce pulmonary fibrosis, and the control animals were injected intrathecally with 0.125 ml sterile saline. After rats were euthanized at 3, 7, 14, 21and 28 days post-instillation, the peripheral lung tissue was cut for primary cell culture of PMVECs and Fbs, and the remanent lung tissue was used for histological analysis by VG stain.
PMVECs and Fbs were isolated from lung tissue of each group rats, and were cultured. PMVECs from each group and Fbs from control group were co-cultured respectively. Immunofluorescence, ELISA, Western Blot(WB), reverse transcription-PCR (RT-PCR), FCM and neutralization test of cytokines were performed to detect the synthesis and secretion of connective tissue growth factor(CTGF) and transformation growth factor-beta1 (TGF-β1) in PMVECs, and to analyze the role of PMVECs in process of pulmonary fibrosis.
Results:
1、The logarithmic growth phase of PMVECs isolated from BLM-induced rats were ahead of control group.
2、Immunofluorescence, Western blot and ELISA analysis revealed a peak of synthesis and secretion of CTGF and TGF-β1 protein in PMVECs at 7-day post-instillation group. RT-PCR analysis revealed that the transcription of TGF-β1 and CTGF were prominently up-regulated in PMVECs of 7-day post-instillation group.
3、α-SMA protein was detected in PMVECs of BLM-induced rats by immunofluorescence and western blot analysis.
4、MTT, PCNA immunohistologic stain, FCM and western blot analysis revealed the proliferation, the transformation and the function of synthesizing and secreting collagenⅠwere prominently up-regulated in Fbs cocultured with PMVECs of 7, 14, 21, 28-day post-instillation groups, especially in Fbs cocultured with PMVECs of 7-day post-instillation groups.
5、Neutralization test of cytokines displayed, about 23.39±2.12% drop in quantity of cocultured Fbs and 4.68±0.86% drop in percent of MFbs in cocultured Fbs were caused by neutralizing of 53.15±8.91% TGF-β1; about 45.16±5.79% drop in quantity of cocultured Fbs and 8.06±1.31% drop in percent of MFbs in cocultured Fbs were caused by neutralizing of 54.65±10.24% CTGF; 73.39±11.89% drop in quantity of cocultured Fbs and 10.15±1.37% drop in percent of MFbs in cocultured Fbs were caused by neutralizing of both TGF-β1 and CTGF.
Conclusion:
1、The synthesis and secretion of TGF-β1 and CTGF protein were prominently up-regulated in PMVECs in process of BLM-induced rats pulmonary fibrosis, and PMVEC showed secretion phenotype.
2、PMVECs isolated from BLM-induced rats can improve the proliferation, the transformation and the function in synthesizing and secreting collagenⅠprotein of control Fbs in vitro, especially in PMVECs of 7-day post-instillation groups.
3、Abnormal phenotype in PMVECs, displaying up-regulation of TGF-β1 and CTGF protein expression is the important reason for activation, proliferation and transformation of Fbs, even for excess secretion of extracellular matrix,which is probably the key factor to activate the static Fbs in lung interstitium and stimulate Fb to play its profibrotic role in early stage of disease in vivo.
引文
1. Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW, Schwartz DA, King TE, Jr. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med, 2004, 350(2):125-133.
2. Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest, 2007, 132(4):1311-1321.
3. Teles-Grilo ML, Leite-Almeida H, Martins dos Santos J, Oliveira C, Boaventura P, Grande NR. Differential expression of collagens type I and type IV in lymphangiogenesis during the angiogenic process associated with bleomycin-induced pulmonary fibrosis in rat. Lymphology, 2005, 38(3):130-135.
4. Beon M, Harley RA, Wessels A, Silver RM, Ludwicka-Bradley A. Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. Clin Exp Rheumatol, 2004, 22(6):733-742.
5. Verma S, Slutsky AS. Idiopathic pulmonary fibrosis--new insights. N Engl J Med, 2007, 356(13):1370-1372.
6.侯显明.特发性肺纤维化:病理和临床的界定、认知、共识和借鉴.中华内科杂志, 2000, 39(8 ):511-512.
7. Green FH. Overview of pulmonary fibrosis. Chest, 2002, 122(6 Suppl):334S-339S.
8. Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med, 1999, 341(17):1264-1269.
9. Dekan G. [Histological classification of interstitial lung diseases]. Z Rheumatol, 2003, 62(1):16-20.
10. Buhl R, Meier-Sydow J, Vogelmeier C. [Pathogenesis of idiopathic pulmonary fibrosis]. Immun Infekt, 1995, 23(3):92-96.
11.崔光彬,魏经国,王耀程,潘爱国,邬秋珍,黄梅,张晓楠.博莱霉素损伤后肺表面活性物质测定的实验研究.中华劳动卫生职业病杂志, 2002 20 (1 ):35-37.
12.殷茜,黄晓峰,崔光彬,魏经国.博莱霉素及肺炎双球菌性肺损伤毛细血管内皮细胞间紧密连接的变化及其意义.实用放射学杂志, 2008, 24(2):261-263,286.
13.崔光彬,魏经国,王玮,殷茜,王春梅,魏龙晓,杨浩.博莱霉素对大鼠肺微血管内皮细胞紧密连接改变及Cx43表达变化的影响.中华劳动卫生职业病杂志, 2006 24(2):99-102.
14. Costabel U, Guzman J. [Pulmonary fibrosis. Classification, diagnosis, therapy]. Internist (Berl), 2003, 44 Suppl 1:S35-43.
15. Calabrese F, Giacometti C, Rea F, Loy M, Valente M. Idiopathic interstitial pneumonias: Primum movens: epithelial, endothelial or whatever. Sarcoidosis Vasc Diffuse Lung Dis, 2005, 22 Suppl 1:S15-23.
16. Johansson J, Curstedt T, Robertson B. The proteins of the surfactant system. Eur Respir J, 1994, 7(2):372-391.
17. Elssner A, Mazur G, Vogelmeier C. Inhibition of factor XIIIa-mediated incorporation of fibronectin into fibrin by pulmonary surfactant. Am J Physiol, 1999, 276(4 Pt 1):L625-630.
18. Maniscalco WM, Sinkin RA, Watkins RH, Campbell MH. Transforming growth factor-beta 1 modulates type II cell fibronectin and surfactant protein C expression. Am J Physiol, 1994, 267(5 Pt 1):L569-577.
19. Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, Borok Z. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol, 2005, 166(5):1321-1332.
20.吕长俊,赵洪文,侯显明,于润江.肺间质巨噬细胞的致纤维化研究.中华结核和呼吸杂志, 1998, 21(1):686-688.
21. Huaux F, Liu T, McGarry B, Ullenbruch M, Xing Z, Phan SH. Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. J Immunol, 2003, 171(10):5470-5481.
22. Lympany PA, Southcott AM, Welsh KI, Black CM, Boylston AW, du Bois RM. T-cell receptor gene usage in patients with fibrosing alveolitis and control subjects. Eur J Clin Invest, 1999, 29(2):173-181.
23. Sasaki M, Kashima M, Ito T, Watanabe A, Sano M, Kagaya M, Shioya T, Miura M. Effect of heparin and related glycosaminoglycan on PDGF-induced lung fibroblast proliferation, chemotactic response and matrix metalloproteinases activity. Mediators Inflamm, 2000, 9(2):85-91.
24. Gabbiani G. The biology of the myofibroblast. Kidney Int, 1992, 41(3):530-532.
25. Abraham DJ, Eckes B, Rajkumar V, Krieg T. New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma. Curr Rheumatol Rep, 2007, 9(2):136-143.
26. Carnevale E, Fogel E, Aplin AC, Gelati M, Howson KM, Zhu WH, Nicosia RF. Regulation of postangiogenic neovessel survival by beta1 and beta3 integrins in collagen and fibrin matrices. J Vasc Res, 2007, 44(1):40-50.
27.柴文戌,李永春,刘玉玲,包翠芬.博莱霉素致肺纤维化大鼠形态学变化的实验研究.中国实验动物学报, 2003, 11(2):77-79.
28. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol, 2002, 3(5):349-363.
29. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev, 2003, 83(3):835-870.
30. Horowitz JC, Rogers DS, Sharma V, Vittal R, White ES, Cui Z, Thannickal VJ. Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts. Cell Signal, 2007, 19(4):761-771.
31. Darby IA, Hewitson TD. Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol, 2007, 257:143-179.
32. Oberringer M, Meins C, Bubel M, Pohlemann T. In vitro wounding: effects of hypoxia and transforming growth factor beta1 on proliferation, migration and myofibroblastic differentiation in an endothelial cell-fibroblast co-culture model. J Mol Histol, 2008, 39(1):37-47.
33. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol, 2007, 170(6):1807-1816.
34. Phan SH. The myofibroblast in pulmonary fibrosis. Chest, 2002, 122(6 Suppl):286S-289S.
35. Derk CT, Jimenez SA. Statins and the vasculopathy of systemic sclerosis: potential therapeutic agents? Autoimmun Rev, 2006, 5(1):25-32.
36. Waghray M, Cui Z, Horowitz JC, Subramanian IM, Martinez FJ, Toews GB, Thannickal VJ. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J, 2005, 19(7):854-856.
37. Buhling F, Wille A, Rocken C, Wiesner O, Baier A, Meinecke I, Welte T, Pap T.Altered expression of membrane-bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis. Respir Res, 2005, 6:37.
38. Moodley YP, Caterina P, Scaffidi AK, Misso NL, Papadimitriou JM, McAnulty RJ, Laurent GJ, Thompson PJ, Knight DA. Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis. J Pathol, 2004, 202(4):486-495.
39. Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell, 2001, 12(9):2730-2741.
40.杨雪梅,王兴胜.肌成纤维细胞在肺纤维化中的来源和作用.国际病理科学与临床杂志, 2008, 28(1):54-58.
41. Leask A, Sa S, Holmes A, Shiwen X, Black CM, Abraham DJ. The control of ccn2 (ctgf) gene expression in normal and scleroderma fibroblasts. Mol Pathol, 2001, 54(3):180-183.
42. Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res, 2005, 6:56.
43. Dhainaut JF, Charpentier J, Chiche JD. Transforming growth factor-beta: a mediator of cell regulation in acute respiratory distress syndrome. Crit Care Med, 2003, 31(4 Suppl):S258-264.
44. Kolb M, Margetts PJ, Sime PJ, Gauldie J. Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J Physiol Lung Cell Mol Physiol, 2001, 280(6):L1327-1334.
45. Grotendorst GR, Duncan MR. Individual domains of connective tissue growth factor regulate fibroblast proliferation and myofibroblast differentiation. FASEB J, 2005, 19(7):729-738.
46. Bork P. The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett, 1993, 327(2):125-130.
47. Okada H, Kikuta T, Kobayashi T, Inoue T, Kanno Y, Takigawa M, Sugaya T, Kopp JB, Suzuki H. Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. J Am Soc Nephrol, 2005, 16(1):133-143.
48. Chen CC, Chen N, Lau LF. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts. J BiolChem, 2001, 276(13):10443-10452.
49. Chen Y, Segarini P, Raoufi F, Bradham D, Leask A. Connective tissue growth factor is secreted through the Golgi and is degraded in the endosome. Exp Cell Res, 2001, 271(1):109-117.
50. Chang CC, Shih JY, Jeng YM, Su JL, Lin BZ, Chen ST, Chau YP, Yang PC, Kuo ML. Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis. J Natl Cancer Inst, 2004, 96(5):364-375.
51.王艳,刘新民.转化生长因子β_1对人胚肺成纤维细胞结缔组织生长因子及低密度脂蛋白受体相关蛋白表达的影响.北京大学学报(医学版), 2006, 38(5):506-509.
52.颜林枫,南海燕,崔光彬,殷茜,魏经国.肺微血管内皮细胞表型改变与博菜霉素所致大鼠肺纤维化的关系.第四军医大学学报, 2008, 29(16):1458-1461.
53. Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med, 1997, 156(2 Pt 1):600-608.
54. Hocher B, Schwarz A, Fagan KA, Thone-Reineke C, El-Hag K, Kusserow H, Elitok S, Bauer C, Neumayer HH, Rodman DM. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol, 2000, 23(1):19-26.
55.凌伟.细胞因子在肺纤维化中的信号转导通路.四川医学, 2007, 28(4):369-371.
56. Li J, Poovey HG, Rodriguez JF, Brody A, Hoyle GW. Effect of platelet-derived growth factor on the development and persistence of asbestos-induced fibroproliferative lung disease. J Environ Pathol Toxicol Oncol, 2004, 23(4):253-266.
57. Cao B, Guo Z, Zhu Y, Xu W. The potential role of PDGF, IGF-1, TGF-beta expression in idiopathic pulmonary fibrosis. Chin Med J (Engl), 2000, 113(9):776-782.
58. Krein PM, Winston BW. Roles for insulin-like growth factor I and transforming growth factor-beta in fibrotic lung disease. Chest, 2002, 122(6 Suppl):289S-293S.
59. Currie AE, Kelly M, Vyas JR, Pandya H, Field D, Kotecha S. Fibroblast mitogenic activity of lung lavage fluid from infants with chronic lung disease of prematurity. Arch Dis Child Fetal Neonatal Ed, 2002, 86(3):F193-197.
60. Daian T, Ohtsuru A, Rogounovitch T, Ishihara H, Hirano A, Akiyama-Uchida Y, Saenko V, Fujii T, Yamashita S. Insulin-like growth factor-I enhances transforminggrowth factor-beta-induced extracellular matrix protein production through the P38/activating transcription factor-2 signaling pathway in keloid fibroblasts. J Invest Dermatol, 2003, 120(6):956-962.
61. Khalil N, Xu YD, O'Connor R, Duronio V. Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-beta1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK. J Biol Chem, 2005, 280(52):43000-43009.
62. Pantelidis P, McGrath DS, Southcott AM, Black CM, du Bois RM. Tumour necrosis factor-alpha production in fibrosing alveolitis is macrophage subset specific. Respir Res, 2001, 2(6):365-372.
63. Piguet PF, Kaufman S, Barazzone C, Muller M, Ryffel B, Eugster HP. Resistance of TNF/LT alpha double deficient mice to bleomycin-induced fibrosis. Int J Exp Pathol, 1997, 78(1):43-48.
64. Kenyon NJ, Ward RW, McGrew G, Last JA. TGF-beta1 causes airway fibrosis and increased collagen I and III mRNA in mice. Thorax, 2003, 58(9):772-777.
65. Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest, 2001, 107(12):1529-1536.
66. Vasakova M, Striz I, Slavcev A, Jandova S, Dutka J, Terl M, Kolesar L, Sulc J. Correlation of IL-1alpha and IL-4 gene polymorphisms and clinical parameters in idiopathic pulmonary fibrosis. Scand J Immunol, 2007, 65(3):265-270.
67. Millar AB. IL-10: Another therapeutic target in idiopathic pulmonary fibrosis? Thorax, 2006, 61(10):835-836.
68.卫张蕊,周国锋.炎症细胞和细胞因子在肺纤维化中作用的研究进展.细胞与分子免疫学杂志, 2005, 21(suppl):S85-S87.
69. Gharaee-Kermani M, McCullumsmith RE, Charo IF, Kunkel SL, Phan SH. CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis. Cytokine, 2003, 24(6):266-276.
70. Friedman SL. Cytokines and fibrogenesis. Semin Liver Dis, 1999, 19(2):129-140.
71. Swiderski RE, Dencoff JE, Floerchinger CS, Shapiro SD, Hunninghake GW. Differential expression of extracellular matrix remodeling genes in a murine model of bleomycin-induced pulmonary fibrosis. Am J Pathol, 1998, 152(3):821-828.
72.吴浩,许祖德,张月娥,刘学松,张秀荣,查锡良.纤维连接蛋白在大鼠肺纤维化中的作用.中华结核和呼吸杂志, 2001, 24(1):40-42.
73. Fukuda Y, Ishizaki M, Kudoh S, Kitaichi M, Yamanaka N. Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases. Lab Invest, 1998, 78(6):687-698.
74. Selman M, Ruiz V, Cabrera S, Segura L, Ramirez R, Barrios R, Pardo A. TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? Am J Physiol Lung Cell Mol Physiol, 2000, 279(3):L562-574.
75. Sheppard D. Functions of pulmonary epithelial integrins: from development to disease. Physiol Rev, 2003, 83(3):673-686.
76. White ES, Thannickal VJ, Carskadon SL, Dickie EG, Livant DL, Markwart S, Toews GB, Arenberg DA. Integrin alpha4beta1 regulates migration across basement membranes by lung fibroblasts: a role for phosphatase and tensin homologue deleted on chromosome 10. Am J Respir Crit Care Med, 2003, 168(4):436-442.
77.佟振月.粘附分子与肺纤维化.国外医学呼吸系统分册, 1998, 18(1 ):14-17
78. Xia H, Diebold D, Nho R, Perlman D, Kleidon J, Kahm J, Avdulov S, Peterson M, Nerva J, Bitterman P. Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J Exp Med, 2008, 205(7):1659-1672.
79. Borok Z. Role for alpha3 integrin in EMT and pulmonary fibrosis. J Clin Invest, 2009, 119(1):7-10.
80. Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, Frank JA, Brumwell AN, Wheeler SE, Kreidberg JA. Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest, 2009, 119(1):213-224.
81. Puthawala K, Hadjiangelis N, Jacoby SC, Bayongan E, Zhao Z, Yang Z, Devitt ML, Horan GS, Weinreb PH, Lukashev ME. Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. Am J Respir Crit Care Med, 2008, 177(1):82-90.
82. Sheppard D. Integrin-mediated activation of transforming growth factor-beta(1) in pulmonary fibrosis. Chest, 2001, 120(1 Suppl):49S-53S.
83. Adamson IY, Hedgecock C, Bowden DH. Epithelial cell-fibroblast interactions in lung injury and repair. Am J Pathol, 1990, 137(2):385-392.
84. Plataki M, Koutsopoulos AV, Darivianaki K, Delides G, Siafakas NM, Bouros D. Expression of apoptotic and antiapoptotic markers in epithelial cells in idiopathicpulmonary fibrosis. Chest, 2005, 127(1):266-274.
85. Kuwano K. Involvement of epithelial cell apoptosis in interstitial lung diseases. Intern Med, 2008, 47(5):345-353.
86. Oshitari T, Polewski P, Chadda M, Li AF, Sato T, Roy S. Effect of combined antisense oligonucleotides against high-glucose- and diabetes-induced overexpression of extracellular matrix components and increased vascular permeability. Diabetes, 2006, 55(1):86-92.
87. Chaudhuri V, Karasek MA. Mechanisms of microvascular wound repair II. Injury induces transformation of endothelial cells into myofibroblasts and the synthesis of matrix proteins. In Vitro Cell Dev Biol Anim, 2006, 42(10):314-319.
88. Rosenbloom J, Jimenez SA. Molecular ablation of transforming growth factor beta signaling pathways by tyrosine kinase inhibition: the coming of a promising new era in the treatment of tissue fibrosis. Arthritis Rheum, 2008, 58(8):2219-2224.
89. Venkatesan N, Pini L, Ludwig MS. Changes in Smad expression and subcellular localization in bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2004, 287(6):L1342-1347.
90. Gauldie J, Kolb M, Ask K, Martin G, Bonniaud P, Warburton D. Smad3 signaling involved in pulmonary fibrosis and emphysema. Proc Am Thorac Soc, 2006, 3(8):696-702.
91. Xu SW, Howat SL, Renzoni EA, Holmes A, Pearson JD, Dashwood MR, Bou-Gharios G, Denton CP, du Bois RM, Black CM. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem, 2004, 279(22):23098-23103.
92. Horstmeyer A, Licht C, Scherr G, Eckes B, Krieg T. Signalling and regulation of collagen I synthesis by ET-1 and TGF-beta1. FEBS J, 2005, 272(24):6297-6309.
93. Holmes A, Abraham DJ, Sa S, Shiwen X, Black CM, Leask A. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem, 2001, 276(14):10594-10601.
94. Chen Y, Shi-wen X, Eastwood M, Black CM, Denton CP, Leask A, Abraham DJ. Contribution of activin receptor-like kinase 5 (transforming growth factor beta receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts. Arthritis Rheum, 2006, 54(4):1309-1316.
95. Shi-Wen X, Leask A, Abraham D. Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis. Cytokine Growth FactorRev, 2008, 19(2):133-144.
96.孔琪,秦川.肺纤维化的发病机制及关键靶点.国外医学呼吸系统分册, 2005, 25(5):331-333,336.
97.姜莉,陈佰义,侯显明.肺纤维化大鼠细胞外基质蛋白的变化.中国医科大学学报, 1998, 27(1):26-29.
98. Kennedy L, Shi-Wen X, Carter DE, Abraham DJ, Leask A. Fibroblast adhesion results in the induction of a matrix remodeling gene expression program. Matrix Biol, 2008, 27(4):274-281.
99. King J, Hamil T, Creighton J, Wu S, Bhat P, McDonald F, Stevens T. Structural and functional characteristics of lung macro- and microvascular endothelial cell phenotypes. Microvasc Res, 2004, 67(2):139-151.
100. Lum H, Malik AB. Regulation of vascular endothelial barrier function. Am J Physiol, 1994, 267(3 Pt 1):L223-241.
101. Csortos C, Kolosova I, Verin AD. Regulation of vascular endothelial cell barrier function and cytoskeleton structure by protein phosphatases of the PPP family. Am J Physiol Lung Cell Mol Physiol, 2007, 293(4):L843-854.
102. Massaro D, Massaro GD. Pulmonary alveolus formation: critical period, retinoid regulation and plasticity. Novartis Found Symp, 2001, 234:229-236; discussion 236-241.
103. Massaro D, Massaro GD. Invited Review: pulmonary alveoli: formation, the "call for oxygen," and other regulators. Am J Physiol Lung Cell Mol Physiol, 2002, 282(3):L345-358.
104. Sato Y. Current understanding of the biology of vascular endothelium. Cell Struct Funct, 2001, 26(1):9-10.
105. Van Rijen H, van Kempen MJ, Analbers LJ, Rook MB, van Ginneken AC, Gros D, Jongsma HJ. Gap junctions in human umbilical cord endothelial cells contain multiple connexins. Am J Physiol, 1997, 272(1 Pt 1):C117-130.
106. Chetham PM, Babal P, Bridges JP, Moore TM, Stevens T. Segmental regulation of pulmonary vascular permeability by store-operated Ca2+ entry. Am J Physiol, 1999, 276(1 Pt 1):L41-50.
107. Parker JC, Yoshikawa S. Vascular segmental permeabilities at high peak inflation pressure in isolated rat lungs. Am J Physiol Lung Cell Mol Physiol, 2002, 283(6):L1203-1209.
108. Takabatake N, Arao T, Sata M, Abe S, Inoue S, Shibata Y, Takeishi Y, Kubota I.Involvement of pulmonary endothelial cell injury in the pathogenesis of pulmonary fibrosis: clinical assessment by 123I-MIBG lung scintigraphy. Eur J Nucl Med Mol Imaging, 2005, 32(2):221-228.
109. Takabatake N, Arao T, Sata M, Abe S, Inoue S, Shibata Y, Takeishi Y, Kubota I. Involvement of pulmonary endothelial cell injury in the pathogenesis of pulmonary fibrosis: clinical assessment by 123I-MIBG lung scintigraphy. Eur J Nucl Med Mol Imaging(4101), 2005, 32(2):221-228.
110. Das SK, Mukherjee S, Banerjee DK. Beta-adrenoreceptors of multiple affinities in a clonal capillary endothelial cell line and its functional implication. Mol Cell Biochem, 1994, 140(1):49-54.
111. Schneeberger EE, Lynch RD. Structure, function, and regulation of cellular tight junctions. Am J Physiol, 1992, 262(6 Pt 1):L647-661.
112. Kevil CG, Okayama N, Trocha SD, Kalogeris TJ, Coe LL, Specian RD, Davis CP, Alexander JS. Expression of zonula occludens and adherens junctional proteins in human venous and arterial endothelial cells: role of occludin in endothelial solute barriers. Microcirculation, 1998, 5(2-3):197-210.
113. Matter K, Balda MS. Functional analysis of tight junctions. Methods, 2003, 30(3):228-234.
114.陆洲,魏经国,王玮,崔光彬.博莱霉素损伤肺TGF-β1与VEGF表达特征与血管新生的关系.实用放射学杂志, 2003, 19 (9):769-773.
115. Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science, 2001, 293(5539):2449-2452.
116. Wang XM, Zhang Y, Kim HP, Zhou Z, Feghali-Bostwick CA, Liu F, Ifedigbo E, Xu X, Oury TD, Kaminski N. Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med, 2006, 203(13):2895-2906.
117. Pries AR, Kuebler WM. Normal endothelium. Handb Exp Pharmacol, 2006(176 Pt 1):1-40.
118. Mauro M, Kim J, Costello C, Laurence J. Role of transforming growth factor beta1 in microvascular endothelial cell apoptosis associated with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. Am J Hematol, 2001, 66(1):12-22.
119. Sakao S, Taraseviciene-Stewart L, Wood K, Cool CD, Voelkel NF. Apoptosis ofpulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth. Am J Physiol Lung Cell Mol Physiol(4214), 2006, 291(3):L362-368.
120. Mutsaers SE, Foster ML, Chambers RC, Laurent GJ, McAnulty RJ. Increased endothelin-1 and its localization during the development of bleomycin-induced pulmonary fibrosis in rats. Am J Respir Cell Mol Biol, 1998, 18(5):611-619.
121. Okada M, Ekimoto H, Ito J, Takahashi K. [Effects of anti-platelet aggregating agents on peplomycin induced pulmonary toxicity in mice]. Nippon Gan Chiryo Gakkai Shi, 1989, 24(4):793-797.
122. Dussaubat N, Capetillo M, Lathrop ME, Mendoza R, Oyarzun M. The effects of imidazole on pulmonary damage induced by bleomycin. Biol Res, 1995, 28(4):261-266.
123. Cox RH, Haas KS, Moisey DM, Tulenko TN. Effects of endothelium regeneration on canine coronary artery function. Am J Physiol, 1989, 257(5 Pt 2):H1681-1692.
124. Tashiro M, Izumikawa K, Yoshioka D, Nakamura S, Kurihara S, Sakamoto N, Seki M, Kakeya H, Yamamoto Y, Yanagihara K. Lung fibrosis 10 years after cessation of bleomycin therapy. Tohoku J Exp Med, 2008, 216(1):77-80.
125.曾庆富,牛海艳.肺纤维化机制的研究进展.中华病理学杂志, 2001, 30(5 ):371-373.
126. Chen SF, Fei X, Li SH. A new simple method for isolation of microvascular endothelial cells avoiding both chemical and mechanical injuries. Microvasc Res, 1995, 50(1):119-128.
127.姜明,金岩,刘源,赵宇,刘鹏,董蕊.大鼠肺微血管内皮细胞培养方法的研究.实用口腔医学杂志, 2004, 20(1):24-26.
128.谢崧,杨晓静,钱桂生,王关嵩.大鼠肺微血管内皮细胞培养及鉴定.中国应用生理学杂志, 1997, 13(2):189-190.
129.黄明,罗卓荆,肖伟,张强.免疫磁珠法分离和提纯雪旺细胞的实验研究.中国矫形外科杂志, 2008, 16(8):599-601,612.
130. Chaudhuri V, Zhou L, Karasek M. Inflammatory cytokines induce the transformation of human dermal microvascular endothelial cells into myofibroblasts: a potential role in skin fibrogenesis. J Cutan Pathol, 2007, 34(2):146-153.
131. Pan LH, Yamauchi K, Uzuki M, Nakanishi T, Takigawa M, Inoue H, Sawai T. Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF. Eur Respir, J 2001, 17(6):1220-1227.
132. Marinelli WA. Idiopathic pulmonary fibrosis. Progress and challenge. Chest, 1995, 108(2):297-298.
133. Knight D. Epithelium-fibroblast interactions in response to airway inflammation. Immunol Cell Biol, 2001, 79(2):160-164.
134. Bischoff J. Cell adhesion and angiogenesis. J Clin Invest, 1997, 99(3):373-376.
135. Moussad EE, Brigstock DR. Connective tissue growth factor: what's in a name? Mol Genet Metab, 2000, 71(1-2):276-292.
136. Sohn M, Tan Y, Wang B, Klein RL, Trojanowska M, Jaffa AA. Mechanisms of low-density lipoprotein-induced expression of connective tissue growth factor in human aortic endothelial cells. Am J Physiol Heart Circ Physiol, 2006, 290(4):H1624-1634.
137. Muehlich S, Cicha I, Garlichs CD, Krueger B, Posern G, Goppelt-Struebe M. Actin-dependent regulation of connective tissue growth factor. Am J Physiol Cell Physiol, 2007, 292(5):C1732-1738.
138. Karasek MA. Does transformation of microvascular endothelial cells into myofibroblasts play a key role in the etiology and pathology of fibrotic disease? Med Hypotheses, 2007, 68(3):650-655.
139. Hinz B, Gabbiani G, Chaponnier C. The NH2-terminal peptide of alpha-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J Cell Biol, 2002, 157(4):657-663.
140. Wang J, Zohar R, McCulloch CA. Multiple roles of alpha-smooth muscle actin in mechanotransduction. Exp Cell Res, 2006, 312(3):205-214.
141. Chaqour B, Yang R, Sha Q. Mechanical stretch modulates the promoter activity of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation. J Biol Chem, 2006, 281(29):20608-20622.
142. Grotendorst GR. Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev, 1997, 8(3):171-179.
143. Bonniaud P, Margetts PJ, Kolb M, Haberberger T, Kelly M, Robertson J, Gauldie J. Adenoviral gene transfer of connective tissue growth factor in the lung induces transient fibrosis. Am J Respir Crit Care Med, 2003, 168(7):770-778.
144. Grotendorst GR, Okochi H, Hayashi N. A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene. Cell Growth Differ, 1996, 7(4):469-480.
145.黄山英,宋良文.效应细胞、细胞因子及相关基因调控在肺纤维化发生中的作用研究进展.国外医学呼吸系统分册, 2005, 25(5):328-330.
146. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J, 1999, 13(13):1774-1786.
147. Yokoi H, Sugawara A, Mukoyama M, Mori K, Makino H, Suganami T, Nagae T, Yahata K, Fujinaga Y, Tanaka I. Role of connective tissue growth factor in profibrotic action of transforming growth factor-beta: a potential target for preventing renal fibrosis. Am J Kidney Dis, 2001, 38(4 Suppl 1):S134-138.
2. Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest, 2007, 132(4):1311-1321.
3. Teles-Grilo ML, Leite-Almeida H, Martins dos Santos J, Oliveira C, Boaventura P, Grande NR. Differential expression of collagens type I and type IV in lymphangiogenesis during the angiogenic process associated with bleomycin-induced pulmonary fibrosis in rat. Lymphology, 2005, 38(3):130-135.
4. Beon M, Harley RA, Wessels A, Silver RM, Ludwicka-Bradley A. Myofibroblast induction and microvascular alteration in scleroderma lung fibrosis. Clin Exp Rheumatol, 2004, 22(6):733-742.
5. Verma S, Slutsky AS. Idiopathic pulmonary fibrosis--new insights. N Engl J Med, 2007, 356(13):1370-1372.
6.侯显明.特发性肺纤维化:病理和临床的界定、认知、共识和借鉴.中华内科杂志, 2000, 39(8 ):511-512.
7. Green FH. Overview of pulmonary fibrosis. Chest, 2002, 122(6 Suppl):334S-339S.
8. Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis. N Engl J Med, 1999, 341(17):1264-1269.
9. Dekan G. [Histological classification of interstitial lung diseases]. Z Rheumatol, 2003, 62(1):16-20.
10. Buhl R, Meier-Sydow J, Vogelmeier C. [Pathogenesis of idiopathic pulmonary fibrosis]. Immun Infekt, 1995, 23(3):92-96.
11.崔光彬,魏经国,王耀程,潘爱国,邬秋珍,黄梅,张晓楠.博莱霉素损伤后肺表面活性物质测定的实验研究.中华劳动卫生职业病杂志, 2002 20 (1 ):35-37.
12.殷茜,黄晓峰,崔光彬,魏经国.博莱霉素及肺炎双球菌性肺损伤毛细血管内皮细胞间紧密连接的变化及其意义.实用放射学杂志, 2008, 24(2):261-263,286.
13.崔光彬,魏经国,王玮,殷茜,王春梅,魏龙晓,杨浩.博莱霉素对大鼠肺微血管内皮细胞紧密连接改变及Cx43表达变化的影响.中华劳动卫生职业病杂志, 2006 24(2):99-102.
14. Costabel U, Guzman J. [Pulmonary fibrosis. Classification, diagnosis, therapy]. Internist (Berl), 2003, 44 Suppl 1:S35-43.
15. Calabrese F, Giacometti C, Rea F, Loy M, Valente M. Idiopathic interstitial pneumonias: Primum movens: epithelial, endothelial or whatever. Sarcoidosis Vasc Diffuse Lung Dis, 2005, 22 Suppl 1:S15-23.
16. Johansson J, Curstedt T, Robertson B. The proteins of the surfactant system. Eur Respir J, 1994, 7(2):372-391.
17. Elssner A, Mazur G, Vogelmeier C. Inhibition of factor XIIIa-mediated incorporation of fibronectin into fibrin by pulmonary surfactant. Am J Physiol, 1999, 276(4 Pt 1):L625-630.
18. Maniscalco WM, Sinkin RA, Watkins RH, Campbell MH. Transforming growth factor-beta 1 modulates type II cell fibronectin and surfactant protein C expression. Am J Physiol, 1994, 267(5 Pt 1):L569-577.
19. Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, Borok Z. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol, 2005, 166(5):1321-1332.
20.吕长俊,赵洪文,侯显明,于润江.肺间质巨噬细胞的致纤维化研究.中华结核和呼吸杂志, 1998, 21(1):686-688.
21. Huaux F, Liu T, McGarry B, Ullenbruch M, Xing Z, Phan SH. Eosinophils and T lymphocytes possess distinct roles in bleomycin-induced lung injury and fibrosis. J Immunol, 2003, 171(10):5470-5481.
22. Lympany PA, Southcott AM, Welsh KI, Black CM, Boylston AW, du Bois RM. T-cell receptor gene usage in patients with fibrosing alveolitis and control subjects. Eur J Clin Invest, 1999, 29(2):173-181.
23. Sasaki M, Kashima M, Ito T, Watanabe A, Sano M, Kagaya M, Shioya T, Miura M. Effect of heparin and related glycosaminoglycan on PDGF-induced lung fibroblast proliferation, chemotactic response and matrix metalloproteinases activity. Mediators Inflamm, 2000, 9(2):85-91.
24. Gabbiani G. The biology of the myofibroblast. Kidney Int, 1992, 41(3):530-532.
25. Abraham DJ, Eckes B, Rajkumar V, Krieg T. New developments in fibroblast and myofibroblast biology: implications for fibrosis and scleroderma. Curr Rheumatol Rep, 2007, 9(2):136-143.
26. Carnevale E, Fogel E, Aplin AC, Gelati M, Howson KM, Zhu WH, Nicosia RF. Regulation of postangiogenic neovessel survival by beta1 and beta3 integrins in collagen and fibrin matrices. J Vasc Res, 2007, 44(1):40-50.
27.柴文戌,李永春,刘玉玲,包翠芬.博莱霉素致肺纤维化大鼠形态学变化的实验研究.中国实验动物学报, 2003, 11(2):77-79.
28. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol, 2002, 3(5):349-363.
29. Werner S, Grose R. Regulation of wound healing by growth factors and cytokines. Physiol Rev, 2003, 83(3):835-870.
30. Horowitz JC, Rogers DS, Sharma V, Vittal R, White ES, Cui Z, Thannickal VJ. Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts. Cell Signal, 2007, 19(4):761-771.
31. Darby IA, Hewitson TD. Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol, 2007, 257:143-179.
32. Oberringer M, Meins C, Bubel M, Pohlemann T. In vitro wounding: effects of hypoxia and transforming growth factor beta1 on proliferation, migration and myofibroblastic differentiation in an endothelial cell-fibroblast co-culture model. J Mol Histol, 2008, 39(1):37-47.
33. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol, 2007, 170(6):1807-1816.
34. Phan SH. The myofibroblast in pulmonary fibrosis. Chest, 2002, 122(6 Suppl):286S-289S.
35. Derk CT, Jimenez SA. Statins and the vasculopathy of systemic sclerosis: potential therapeutic agents? Autoimmun Rev, 2006, 5(1):25-32.
36. Waghray M, Cui Z, Horowitz JC, Subramanian IM, Martinez FJ, Toews GB, Thannickal VJ. Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J, 2005, 19(7):854-856.
37. Buhling F, Wille A, Rocken C, Wiesner O, Baier A, Meinecke I, Welte T, Pap T.Altered expression of membrane-bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis. Respir Res, 2005, 6:37.
38. Moodley YP, Caterina P, Scaffidi AK, Misso NL, Papadimitriou JM, McAnulty RJ, Laurent GJ, Thompson PJ, Knight DA. Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis. J Pathol, 2004, 202(4):486-495.
39. Hinz B, Celetta G, Tomasek JJ, Gabbiani G, Chaponnier C. Alpha-smooth muscle actin expression upregulates fibroblast contractile activity. Mol Biol Cell, 2001, 12(9):2730-2741.
40.杨雪梅,王兴胜.肌成纤维细胞在肺纤维化中的来源和作用.国际病理科学与临床杂志, 2008, 28(1):54-58.
41. Leask A, Sa S, Holmes A, Shiwen X, Black CM, Abraham DJ. The control of ccn2 (ctgf) gene expression in normal and scleroderma fibroblasts. Mol Pathol, 2001, 54(3):180-183.
42. Kasai H, Allen JT, Mason RM, Kamimura T, Zhang Z. TGF-beta1 induces human alveolar epithelial to mesenchymal cell transition (EMT). Respir Res, 2005, 6:56.
43. Dhainaut JF, Charpentier J, Chiche JD. Transforming growth factor-beta: a mediator of cell regulation in acute respiratory distress syndrome. Crit Care Med, 2003, 31(4 Suppl):S258-264.
44. Kolb M, Margetts PJ, Sime PJ, Gauldie J. Proteoglycans decorin and biglycan differentially modulate TGF-beta-mediated fibrotic responses in the lung. Am J Physiol Lung Cell Mol Physiol, 2001, 280(6):L1327-1334.
45. Grotendorst GR, Duncan MR. Individual domains of connective tissue growth factor regulate fibroblast proliferation and myofibroblast differentiation. FASEB J, 2005, 19(7):729-738.
46. Bork P. The modular architecture of a new family of growth regulators related to connective tissue growth factor. FEBS Lett, 1993, 327(2):125-130.
47. Okada H, Kikuta T, Kobayashi T, Inoue T, Kanno Y, Takigawa M, Sugaya T, Kopp JB, Suzuki H. Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis. J Am Soc Nephrol, 2005, 16(1):133-143.
48. Chen CC, Chen N, Lau LF. The angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblasts. J BiolChem, 2001, 276(13):10443-10452.
49. Chen Y, Segarini P, Raoufi F, Bradham D, Leask A. Connective tissue growth factor is secreted through the Golgi and is degraded in the endosome. Exp Cell Res, 2001, 271(1):109-117.
50. Chang CC, Shih JY, Jeng YM, Su JL, Lin BZ, Chen ST, Chau YP, Yang PC, Kuo ML. Connective tissue growth factor and its role in lung adenocarcinoma invasion and metastasis. J Natl Cancer Inst, 2004, 96(5):364-375.
51.王艳,刘新民.转化生长因子β_1对人胚肺成纤维细胞结缔组织生长因子及低密度脂蛋白受体相关蛋白表达的影响.北京大学学报(医学版), 2006, 38(5):506-509.
52.颜林枫,南海燕,崔光彬,殷茜,魏经国.肺微血管内皮细胞表型改变与博菜霉素所致大鼠肺纤维化的关系.第四军医大学学报, 2008, 29(16):1458-1461.
53. Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med, 1997, 156(2 Pt 1):600-608.
54. Hocher B, Schwarz A, Fagan KA, Thone-Reineke C, El-Hag K, Kusserow H, Elitok S, Bauer C, Neumayer HH, Rodman DM. Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol, 2000, 23(1):19-26.
55.凌伟.细胞因子在肺纤维化中的信号转导通路.四川医学, 2007, 28(4):369-371.
56. Li J, Poovey HG, Rodriguez JF, Brody A, Hoyle GW. Effect of platelet-derived growth factor on the development and persistence of asbestos-induced fibroproliferative lung disease. J Environ Pathol Toxicol Oncol, 2004, 23(4):253-266.
57. Cao B, Guo Z, Zhu Y, Xu W. The potential role of PDGF, IGF-1, TGF-beta expression in idiopathic pulmonary fibrosis. Chin Med J (Engl), 2000, 113(9):776-782.
58. Krein PM, Winston BW. Roles for insulin-like growth factor I and transforming growth factor-beta in fibrotic lung disease. Chest, 2002, 122(6 Suppl):289S-293S.
59. Currie AE, Kelly M, Vyas JR, Pandya H, Field D, Kotecha S. Fibroblast mitogenic activity of lung lavage fluid from infants with chronic lung disease of prematurity. Arch Dis Child Fetal Neonatal Ed, 2002, 86(3):F193-197.
60. Daian T, Ohtsuru A, Rogounovitch T, Ishihara H, Hirano A, Akiyama-Uchida Y, Saenko V, Fujii T, Yamashita S. Insulin-like growth factor-I enhances transforminggrowth factor-beta-induced extracellular matrix protein production through the P38/activating transcription factor-2 signaling pathway in keloid fibroblasts. J Invest Dermatol, 2003, 120(6):956-962.
61. Khalil N, Xu YD, O'Connor R, Duronio V. Proliferation of pulmonary interstitial fibroblasts is mediated by transforming growth factor-beta1-induced release of extracellular fibroblast growth factor-2 and phosphorylation of p38 MAPK and JNK. J Biol Chem, 2005, 280(52):43000-43009.
62. Pantelidis P, McGrath DS, Southcott AM, Black CM, du Bois RM. Tumour necrosis factor-alpha production in fibrosing alveolitis is macrophage subset specific. Respir Res, 2001, 2(6):365-372.
63. Piguet PF, Kaufman S, Barazzone C, Muller M, Ryffel B, Eugster HP. Resistance of TNF/LT alpha double deficient mice to bleomycin-induced fibrosis. Int J Exp Pathol, 1997, 78(1):43-48.
64. Kenyon NJ, Ward RW, McGrew G, Last JA. TGF-beta1 causes airway fibrosis and increased collagen I and III mRNA in mice. Thorax, 2003, 58(9):772-777.
65. Kolb M, Margetts PJ, Anthony DC, Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis. J Clin Invest, 2001, 107(12):1529-1536.
66. Vasakova M, Striz I, Slavcev A, Jandova S, Dutka J, Terl M, Kolesar L, Sulc J. Correlation of IL-1alpha and IL-4 gene polymorphisms and clinical parameters in idiopathic pulmonary fibrosis. Scand J Immunol, 2007, 65(3):265-270.
67. Millar AB. IL-10: Another therapeutic target in idiopathic pulmonary fibrosis? Thorax, 2006, 61(10):835-836.
68.卫张蕊,周国锋.炎症细胞和细胞因子在肺纤维化中作用的研究进展.细胞与分子免疫学杂志, 2005, 21(suppl):S85-S87.
69. Gharaee-Kermani M, McCullumsmith RE, Charo IF, Kunkel SL, Phan SH. CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis. Cytokine, 2003, 24(6):266-276.
70. Friedman SL. Cytokines and fibrogenesis. Semin Liver Dis, 1999, 19(2):129-140.
71. Swiderski RE, Dencoff JE, Floerchinger CS, Shapiro SD, Hunninghake GW. Differential expression of extracellular matrix remodeling genes in a murine model of bleomycin-induced pulmonary fibrosis. Am J Pathol, 1998, 152(3):821-828.
72.吴浩,许祖德,张月娥,刘学松,张秀荣,查锡良.纤维连接蛋白在大鼠肺纤维化中的作用.中华结核和呼吸杂志, 2001, 24(1):40-42.
73. Fukuda Y, Ishizaki M, Kudoh S, Kitaichi M, Yamanaka N. Localization of matrix metalloproteinases-1, -2, and -9 and tissue inhibitor of metalloproteinase-2 in interstitial lung diseases. Lab Invest, 1998, 78(6):687-698.
74. Selman M, Ruiz V, Cabrera S, Segura L, Ramirez R, Barrios R, Pardo A. TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? Am J Physiol Lung Cell Mol Physiol, 2000, 279(3):L562-574.
75. Sheppard D. Functions of pulmonary epithelial integrins: from development to disease. Physiol Rev, 2003, 83(3):673-686.
76. White ES, Thannickal VJ, Carskadon SL, Dickie EG, Livant DL, Markwart S, Toews GB, Arenberg DA. Integrin alpha4beta1 regulates migration across basement membranes by lung fibroblasts: a role for phosphatase and tensin homologue deleted on chromosome 10. Am J Respir Crit Care Med, 2003, 168(4):436-442.
77.佟振月.粘附分子与肺纤维化.国外医学呼吸系统分册, 1998, 18(1 ):14-17
78. Xia H, Diebold D, Nho R, Perlman D, Kleidon J, Kahm J, Avdulov S, Peterson M, Nerva J, Bitterman P. Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J Exp Med, 2008, 205(7):1659-1672.
79. Borok Z. Role for alpha3 integrin in EMT and pulmonary fibrosis. J Clin Invest, 2009, 119(1):7-10.
80. Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, Frank JA, Brumwell AN, Wheeler SE, Kreidberg JA. Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest, 2009, 119(1):213-224.
81. Puthawala K, Hadjiangelis N, Jacoby SC, Bayongan E, Zhao Z, Yang Z, Devitt ML, Horan GS, Weinreb PH, Lukashev ME. Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis. Am J Respir Crit Care Med, 2008, 177(1):82-90.
82. Sheppard D. Integrin-mediated activation of transforming growth factor-beta(1) in pulmonary fibrosis. Chest, 2001, 120(1 Suppl):49S-53S.
83. Adamson IY, Hedgecock C, Bowden DH. Epithelial cell-fibroblast interactions in lung injury and repair. Am J Pathol, 1990, 137(2):385-392.
84. Plataki M, Koutsopoulos AV, Darivianaki K, Delides G, Siafakas NM, Bouros D. Expression of apoptotic and antiapoptotic markers in epithelial cells in idiopathicpulmonary fibrosis. Chest, 2005, 127(1):266-274.
85. Kuwano K. Involvement of epithelial cell apoptosis in interstitial lung diseases. Intern Med, 2008, 47(5):345-353.
86. Oshitari T, Polewski P, Chadda M, Li AF, Sato T, Roy S. Effect of combined antisense oligonucleotides against high-glucose- and diabetes-induced overexpression of extracellular matrix components and increased vascular permeability. Diabetes, 2006, 55(1):86-92.
87. Chaudhuri V, Karasek MA. Mechanisms of microvascular wound repair II. Injury induces transformation of endothelial cells into myofibroblasts and the synthesis of matrix proteins. In Vitro Cell Dev Biol Anim, 2006, 42(10):314-319.
88. Rosenbloom J, Jimenez SA. Molecular ablation of transforming growth factor beta signaling pathways by tyrosine kinase inhibition: the coming of a promising new era in the treatment of tissue fibrosis. Arthritis Rheum, 2008, 58(8):2219-2224.
89. Venkatesan N, Pini L, Ludwig MS. Changes in Smad expression and subcellular localization in bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2004, 287(6):L1342-1347.
90. Gauldie J, Kolb M, Ask K, Martin G, Bonniaud P, Warburton D. Smad3 signaling involved in pulmonary fibrosis and emphysema. Proc Am Thorac Soc, 2006, 3(8):696-702.
91. Xu SW, Howat SL, Renzoni EA, Holmes A, Pearson JD, Dashwood MR, Bou-Gharios G, Denton CP, du Bois RM, Black CM. Endothelin-1 induces expression of matrix-associated genes in lung fibroblasts through MEK/ERK. J Biol Chem, 2004, 279(22):23098-23103.
92. Horstmeyer A, Licht C, Scherr G, Eckes B, Krieg T. Signalling and regulation of collagen I synthesis by ET-1 and TGF-beta1. FEBS J, 2005, 272(24):6297-6309.
93. Holmes A, Abraham DJ, Sa S, Shiwen X, Black CM, Leask A. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J Biol Chem, 2001, 276(14):10594-10601.
94. Chen Y, Shi-wen X, Eastwood M, Black CM, Denton CP, Leask A, Abraham DJ. Contribution of activin receptor-like kinase 5 (transforming growth factor beta receptor type I) signaling to the fibrotic phenotype of scleroderma fibroblasts. Arthritis Rheum, 2006, 54(4):1309-1316.
95. Shi-Wen X, Leask A, Abraham D. Regulation and function of connective tissue growth factor/CCN2 in tissue repair, scarring and fibrosis. Cytokine Growth FactorRev, 2008, 19(2):133-144.
96.孔琪,秦川.肺纤维化的发病机制及关键靶点.国外医学呼吸系统分册, 2005, 25(5):331-333,336.
97.姜莉,陈佰义,侯显明.肺纤维化大鼠细胞外基质蛋白的变化.中国医科大学学报, 1998, 27(1):26-29.
98. Kennedy L, Shi-Wen X, Carter DE, Abraham DJ, Leask A. Fibroblast adhesion results in the induction of a matrix remodeling gene expression program. Matrix Biol, 2008, 27(4):274-281.
99. King J, Hamil T, Creighton J, Wu S, Bhat P, McDonald F, Stevens T. Structural and functional characteristics of lung macro- and microvascular endothelial cell phenotypes. Microvasc Res, 2004, 67(2):139-151.
100. Lum H, Malik AB. Regulation of vascular endothelial barrier function. Am J Physiol, 1994, 267(3 Pt 1):L223-241.
101. Csortos C, Kolosova I, Verin AD. Regulation of vascular endothelial cell barrier function and cytoskeleton structure by protein phosphatases of the PPP family. Am J Physiol Lung Cell Mol Physiol, 2007, 293(4):L843-854.
102. Massaro D, Massaro GD. Pulmonary alveolus formation: critical period, retinoid regulation and plasticity. Novartis Found Symp, 2001, 234:229-236; discussion 236-241.
103. Massaro D, Massaro GD. Invited Review: pulmonary alveoli: formation, the "call for oxygen," and other regulators. Am J Physiol Lung Cell Mol Physiol, 2002, 282(3):L345-358.
104. Sato Y. Current understanding of the biology of vascular endothelium. Cell Struct Funct, 2001, 26(1):9-10.
105. Van Rijen H, van Kempen MJ, Analbers LJ, Rook MB, van Ginneken AC, Gros D, Jongsma HJ. Gap junctions in human umbilical cord endothelial cells contain multiple connexins. Am J Physiol, 1997, 272(1 Pt 1):C117-130.
106. Chetham PM, Babal P, Bridges JP, Moore TM, Stevens T. Segmental regulation of pulmonary vascular permeability by store-operated Ca2+ entry. Am J Physiol, 1999, 276(1 Pt 1):L41-50.
107. Parker JC, Yoshikawa S. Vascular segmental permeabilities at high peak inflation pressure in isolated rat lungs. Am J Physiol Lung Cell Mol Physiol, 2002, 283(6):L1203-1209.
108. Takabatake N, Arao T, Sata M, Abe S, Inoue S, Shibata Y, Takeishi Y, Kubota I.Involvement of pulmonary endothelial cell injury in the pathogenesis of pulmonary fibrosis: clinical assessment by 123I-MIBG lung scintigraphy. Eur J Nucl Med Mol Imaging, 2005, 32(2):221-228.
109. Takabatake N, Arao T, Sata M, Abe S, Inoue S, Shibata Y, Takeishi Y, Kubota I. Involvement of pulmonary endothelial cell injury in the pathogenesis of pulmonary fibrosis: clinical assessment by 123I-MIBG lung scintigraphy. Eur J Nucl Med Mol Imaging(4101), 2005, 32(2):221-228.
110. Das SK, Mukherjee S, Banerjee DK. Beta-adrenoreceptors of multiple affinities in a clonal capillary endothelial cell line and its functional implication. Mol Cell Biochem, 1994, 140(1):49-54.
111. Schneeberger EE, Lynch RD. Structure, function, and regulation of cellular tight junctions. Am J Physiol, 1992, 262(6 Pt 1):L647-661.
112. Kevil CG, Okayama N, Trocha SD, Kalogeris TJ, Coe LL, Specian RD, Davis CP, Alexander JS. Expression of zonula occludens and adherens junctional proteins in human venous and arterial endothelial cells: role of occludin in endothelial solute barriers. Microcirculation, 1998, 5(2-3):197-210.
113. Matter K, Balda MS. Functional analysis of tight junctions. Methods, 2003, 30(3):228-234.
114.陆洲,魏经国,王玮,崔光彬.博莱霉素损伤肺TGF-β1与VEGF表达特征与血管新生的关系.实用放射学杂志, 2003, 19 (9):769-773.
115. Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC. Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science, 2001, 293(5539):2449-2452.
116. Wang XM, Zhang Y, Kim HP, Zhou Z, Feghali-Bostwick CA, Liu F, Ifedigbo E, Xu X, Oury TD, Kaminski N. Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med, 2006, 203(13):2895-2906.
117. Pries AR, Kuebler WM. Normal endothelium. Handb Exp Pharmacol, 2006(176 Pt 1):1-40.
118. Mauro M, Kim J, Costello C, Laurence J. Role of transforming growth factor beta1 in microvascular endothelial cell apoptosis associated with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome. Am J Hematol, 2001, 66(1):12-22.
119. Sakao S, Taraseviciene-Stewart L, Wood K, Cool CD, Voelkel NF. Apoptosis ofpulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth. Am J Physiol Lung Cell Mol Physiol(4214), 2006, 291(3):L362-368.
120. Mutsaers SE, Foster ML, Chambers RC, Laurent GJ, McAnulty RJ. Increased endothelin-1 and its localization during the development of bleomycin-induced pulmonary fibrosis in rats. Am J Respir Cell Mol Biol, 1998, 18(5):611-619.
121. Okada M, Ekimoto H, Ito J, Takahashi K. [Effects of anti-platelet aggregating agents on peplomycin induced pulmonary toxicity in mice]. Nippon Gan Chiryo Gakkai Shi, 1989, 24(4):793-797.
122. Dussaubat N, Capetillo M, Lathrop ME, Mendoza R, Oyarzun M. The effects of imidazole on pulmonary damage induced by bleomycin. Biol Res, 1995, 28(4):261-266.
123. Cox RH, Haas KS, Moisey DM, Tulenko TN. Effects of endothelium regeneration on canine coronary artery function. Am J Physiol, 1989, 257(5 Pt 2):H1681-1692.
124. Tashiro M, Izumikawa K, Yoshioka D, Nakamura S, Kurihara S, Sakamoto N, Seki M, Kakeya H, Yamamoto Y, Yanagihara K. Lung fibrosis 10 years after cessation of bleomycin therapy. Tohoku J Exp Med, 2008, 216(1):77-80.
125.曾庆富,牛海艳.肺纤维化机制的研究进展.中华病理学杂志, 2001, 30(5 ):371-373.
126. Chen SF, Fei X, Li SH. A new simple method for isolation of microvascular endothelial cells avoiding both chemical and mechanical injuries. Microvasc Res, 1995, 50(1):119-128.
127.姜明,金岩,刘源,赵宇,刘鹏,董蕊.大鼠肺微血管内皮细胞培养方法的研究.实用口腔医学杂志, 2004, 20(1):24-26.
128.谢崧,杨晓静,钱桂生,王关嵩.大鼠肺微血管内皮细胞培养及鉴定.中国应用生理学杂志, 1997, 13(2):189-190.
129.黄明,罗卓荆,肖伟,张强.免疫磁珠法分离和提纯雪旺细胞的实验研究.中国矫形外科杂志, 2008, 16(8):599-601,612.
130. Chaudhuri V, Zhou L, Karasek M. Inflammatory cytokines induce the transformation of human dermal microvascular endothelial cells into myofibroblasts: a potential role in skin fibrogenesis. J Cutan Pathol, 2007, 34(2):146-153.
131. Pan LH, Yamauchi K, Uzuki M, Nakanishi T, Takigawa M, Inoue H, Sawai T. Type II alveolar epithelial cells and interstitial fibroblasts express connective tissue growth factor in IPF. Eur Respir, J 2001, 17(6):1220-1227.
132. Marinelli WA. Idiopathic pulmonary fibrosis. Progress and challenge. Chest, 1995, 108(2):297-298.
133. Knight D. Epithelium-fibroblast interactions in response to airway inflammation. Immunol Cell Biol, 2001, 79(2):160-164.
134. Bischoff J. Cell adhesion and angiogenesis. J Clin Invest, 1997, 99(3):373-376.
135. Moussad EE, Brigstock DR. Connective tissue growth factor: what's in a name? Mol Genet Metab, 2000, 71(1-2):276-292.
136. Sohn M, Tan Y, Wang B, Klein RL, Trojanowska M, Jaffa AA. Mechanisms of low-density lipoprotein-induced expression of connective tissue growth factor in human aortic endothelial cells. Am J Physiol Heart Circ Physiol, 2006, 290(4):H1624-1634.
137. Muehlich S, Cicha I, Garlichs CD, Krueger B, Posern G, Goppelt-Struebe M. Actin-dependent regulation of connective tissue growth factor. Am J Physiol Cell Physiol, 2007, 292(5):C1732-1738.
138. Karasek MA. Does transformation of microvascular endothelial cells into myofibroblasts play a key role in the etiology and pathology of fibrotic disease? Med Hypotheses, 2007, 68(3):650-655.
139. Hinz B, Gabbiani G, Chaponnier C. The NH2-terminal peptide of alpha-smooth muscle actin inhibits force generation by the myofibroblast in vitro and in vivo. J Cell Biol, 2002, 157(4):657-663.
140. Wang J, Zohar R, McCulloch CA. Multiple roles of alpha-smooth muscle actin in mechanotransduction. Exp Cell Res, 2006, 312(3):205-214.
141. Chaqour B, Yang R, Sha Q. Mechanical stretch modulates the promoter activity of the profibrotic factor CCN2 through increased actin polymerization and NF-kappaB activation. J Biol Chem, 2006, 281(29):20608-20622.
142. Grotendorst GR. Connective tissue growth factor: a mediator of TGF-beta action on fibroblasts. Cytokine Growth Factor Rev, 1997, 8(3):171-179.
143. Bonniaud P, Margetts PJ, Kolb M, Haberberger T, Kelly M, Robertson J, Gauldie J. Adenoviral gene transfer of connective tissue growth factor in the lung induces transient fibrosis. Am J Respir Crit Care Med, 2003, 168(7):770-778.
144. Grotendorst GR, Okochi H, Hayashi N. A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene. Cell Growth Differ, 1996, 7(4):469-480.
145.黄山英,宋良文.效应细胞、细胞因子及相关基因调控在肺纤维化发生中的作用研究进展.国外医学呼吸系统分册, 2005, 25(5):328-330.
146. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR. Connective tissue growth factor mediates transforming growth factor beta-induced collagen synthesis: down-regulation by cAMP. FASEB J, 1999, 13(13):1774-1786.
147. Yokoi H, Sugawara A, Mukoyama M, Mori K, Makino H, Suganami T, Nagae T, Yahata K, Fujinaga Y, Tanaka I. Role of connective tissue growth factor in profibrotic action of transforming growth factor-beta: a potential target for preventing renal fibrosis. Am J Kidney Dis, 2001, 38(4 Suppl 1):S134-138.