修回日期: 2013-02-17
接受日期: 2013-02-20
在线出版日期: 2013-03-28
肝纤维化是多种慢性肝病向肝硬化发展的必经阶段, 是所有慢性肝病的共同病理基础. 血小板衍生生长因子(platelet-derived growth factors, PDGFs)是由4个亚基同型或异型两两相互聚合形成的二聚体, 现已证实其与肝纤维化的形成、发展密切相关. 本文就PDGFs及其受体在肝纤维化的发生、治疗及其研究进展作一综述.
引文著录: 黄雯, 朱萱. PDGF及其受体与肝纤维化的相关性. 世界华人消化杂志 2013; 21(9): 773-778
Revised: February 17, 2013
Accepted: February 20, 2013
Published online: March 28, 2013
Liver fibrosis occurs as a result of various injurious processes and is the common pathologic basis for all chronic hepatic diseases. Platelet-derived growth factors (PDGFs) are homodimers or heterodimers consisting of two polypeptide chains. Previous studies have proved that PDGFs are closely related to the occurrence and development of liver fibrosis. In this article, we review the advances in research on the role of PDGFs and their receptor in pathogenesis and therapy of liver fibrosis.
- Citation: Huang W, Zhu X. Correlation between PDGFs and their receptor and liver fibrosis. Shijie Huaren Xiaohua Zazhi 2013; 21(9): 773-778
- URL: https://www.wjgnet.com/1009-3079/full/v21/i9/773.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i9.773
肝纤维化, 作为慢性肝病的共同晚期阶段, 主要由慢性肝损诱导的肝星状细胞(hepatic stellate cells, HSCs)的活化、增殖引起, 以形成细胞外基质蛋白的沉积物、高发病率和死亡率为主要特点[1]. 而在多种促纤维化因子中, 血小板衍生生长因子和转化生长因子在调节肝星状细胞的活化、增殖、迁移和细胞外基质的产生方面发挥至关重要的作用[1,2]. 在肝纤维化时, 各种不同的细胞包括肝星状细胞, 在肝损阶段即可自分泌生长因子以及许多促炎症细胞因子, 并受这些因子的影响而调节自身的促有丝分裂作用, 而血小板源性生长因子信号通路是促进HSC的活化、分裂、增殖的最有效通路之一[3].
血小板衍生生长因子家族包括4个生长因子成员(PDGF-A、PDGF-B、PDGF-C和PDGF-D), 在炎症微环境的刺激下, 由血小板和Kupffer细胞等分泌[4], 并参与调控纤维母细胞和平滑肌细胞等结缔组织细胞的生长. PDGFs是两条多肽链通过二硫键连接而成的同型或异型二聚体, 具有多种形式的二聚体结构, 即PDGF-AA、PDGF-BB、PDGF-AB、PDGF-CC以及PDGF-DD[5]. PDGFs必须与细胞膜上的相应受体结合后才能发挥其生物学效应. PDGFs有PDGFRα和PDGFRβ两种受体, 他们都属于酪氨酸激酶受体(receptor tyrosine kinases, RTKs), 并有不同的表达模式和生理作用. PDGFRα信号调控原肠胚形式及一些诸如肺、肠、皮肤、睾丸、肾、骨和神经组织等的发育; PDGFRβ信号被认为是早期造血系统和血管形成的必要调节者[6]. PDGFRα与PDGF-A、-B和-C链具有较高的结合亲和力, 而PDGFRβ对PDGF-B和PDGF-D的亲和力更高[7], 可见PDGFRα和β两种受体对PDGF-B链具有较高的敏感性, 相比于PDGF其他亚基, PDGF-AB、PDGF-BB的刺激信号在同时具有PDGFRα和β两种受体的组织中的传播效率可能更高, PDGF-BB和PDGF-DD较其他亚基在PDGFRβ信号传播效率也可能更高.
PDGF不仅是强有力的促有丝分裂原, 而且与TGF-β具有协同促纤维化作用的生长因子[4]. PDGF传导的信号由刺激跨膜酪氨酸激酶受体开始, 已经证实有该受体启动多条信号通路, 主要包括Ras-MAPK、PI3K/Akt、PLC-γ、钙通道、Na+/H+、JAK/STAT途径等[8,9], 他们都参与细胞的生长发育过程. PDGFRs主要通过生长因子受体结合蛋白2(Grb2)和包含SH2结构域蛋白(Shc)与Ras-MAPK通路链接. Grb2与活化的PDGFR的蛋白结合域SH2结合, 参与PDGF介导的信号转导[10], 或是Grb2同时与Shc、Sos结合形成Shc-Grb2-Sos复合物, 并将Sos激活, 激活的Sos与质膜上的Ras蛋白结合, 激活Ras, 引起下游Raf-1和MAPK级联的活化, 进而刺激基因的转录, 促进细胞生长、分化及迁移活动[11]. PI3K是一种胞内磷脂酰肌醇激酶, 其信号感受器为丝氨酸/苏氨酸激酶, 包括Akt/PKB[12]、p70S6激酶[13]、JNK[14]以及Rho家族的小GTP酶类[15]等. PDGFRs激活的PI3K/Akt通路促进肌动蛋白重组、增加细胞的迁移、刺激细胞的生长并抑制其凋亡[12,16]. PLC-γ与PDGFR结合, 发生磷酸化后被激活, 导致细胞内钙离子的流动和蛋白激酶C(protein kinase C, PKC)的活化, 刺激细胞的生长和迁移. PDGF诱导复制的能力主要依赖于胞外内流方式引起的细胞内持续的钙离子升高, 而非细胞内储存钙离子的释放, 而且PDGF刺激可提高大鼠或人HSCs的Na+/H+交换泵活力, 而Na+/H+的交换又可调节PDGF诱导的HSCs增生反应[17]. Ping等[18]发现, 降低钙调蛋白依赖性蛋白激酶Ⅱ水平, 不仅可削弱PDGF诱导的HSC增生, 还减弱ERK1/2的磷酸化作用, 但对于c-Jun氨基末端激酶(c-Jun N-terminal kinase, JNK)的磷酸化并无影响. PDGFRs还可激活与一些信号分子, 包括酶类、适配器和转录因子. PDGF激活的多条信号通路中, 丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)家族成员调控的信号通路占主导作用, 包括细胞外信号调节激酶(extracellular signal-regulated protein kinase, ERK)通路以及两条应激活化蛋白激酶通路(stress activated protein kinase, SAPK): JNK和p38信号通路[19,20]. MAPKs能够磷酸化激活多种转录因子, 这对于启动细胞的增殖和迁移非常重要.
关于PDGF与肝纤维化的关系已经有许多相关研究, 尽管已经证明PDGF的4种亚基都可能参与肝纤维化过程[21,22], 但他们在肝纤维化的发生、发展过程中所发挥的作用并不相同. Breitkopf等[23]研究了体外促肝纤维化模型, 首先发现静息的HSC向肌成纤维细胞转化过程中PDGF的4个亚型的表达情况: PDGF-A mRNA仅出现微量的波动, PDGF-B在HSC激活的第3天表达已经明显下降, 而C型、D型mRNA水平在此过程中表达分别升高5倍和8倍, 且持续较长时间, 表明在HSC激活的早期主要通过PDGF-B介导信号转导, 后期则通过C型、D型介导, 且比起PDGFRα的轻微变化, PDGFRβ出现早期持续的高表达. Campbell等[24]研究发现PDGF-C可能作为肝纤维化发生的起始作用因子, 其作用机制可能是通过诱导大量促肝纤维化途径的激活而发挥作用. 最近的研究表明, PDGF-B和PDGF-D经PDGFRβ传递的信号与肝纤维化的关系最紧密. Borkham-Kamphorst等[21]研究发现, 胆总管结扎引起纤维化的大鼠肝脏中PDGF配体和受体的转录水平被上调, 其中PDGF-B、PDGF-D和PDGFRβ的转录水平比PDGF-A、PDGF-C和PDGFRα更高, 他们还发现, 经PDGF-B或PDGF-D刺激的肝星状细胞或肌成纤维母细胞发生显著的增殖表现, 而经PDGF-A或PDGF-C处理的却没有明显的改变. 说明只有PDGF-D与PDGF-B对肝脏具有明显的促有丝分裂和纤维化的作用, 而PDGF-A和PDGF-C对肝纤维化的影响甚微[25]. Li等[26]用PDGF-BB加入HSCs的培养基中培养15 min后, 对比未加药处理的HSCs小而圆的形态, 加药处理后的呈现出扁平、纤薄、体型延长、出现类似伪足的形态, 表明PDGF-BB对HSCs的激活作用还是比较显著的. 最近的一项研究表明, 胆总管结扎引起的小鼠肝纤维化程度不如经PDGF-B抗体处理后的肝纤维化程度严重[27]. 此前Czochra等[28]通过研究过表达PDGF-B的转基因老鼠, 就已经发现其肝脏的纤维化水平明显提高, 由PDGF-B的高表达及其引发的α平滑肌肌动蛋白(α-smooth muscle actin, α-SMA)和PDGFRβ的表达升高, 提示肝星状细胞和肌成纤维母细胞的显著激活, 可见PDGF-B是体内促增殖和纤维化的刺激物, 也是促进肝星状细胞进入分化阶段的有效诱导物. 因此, 在PDGF家族中以PDGF-B、PDGF-D和PDGFRβ在肝纤维化过程中的作用尤为突出, HSCs表面的PDGF受体以β受体为主, 并与PDGF-B和-D具有较强的亲和力[29,30].
肝纤维化的发生主要是因为HSCs的活动引起, 而PDGF作为促分裂和纤维化的最有力生长因子, 参与调节HSCs活化、增生、迁移等过程. PDGF主要在慢性肝损早期间质细胞增生和细胞外基质产生的时候高表达, 而非肝细胞再生时期[25], 且静止期的HSCs无PDGF受体表达, 只有活化的HSCs高表达PDGF受体, 促进肝纤维化的发生和进展[31]. 已知NADPH氧化酶(NAPDH oxidase, NOX)一直被公认为ROS的主要来源并专职控制细胞内ROS的水平, 参与调节细胞的再生、凋亡等生理活动[32,33]. Adachi等[34]发现NOX在PDGF调控的离体HSCs的增生及肝纤维化活体模型中发挥关键性作用, NOX是PDGF-BB诱导的HSC内产ROS的主要来源, PDGF-BB可促使HSC中NOX的表达并产生ROS, ROS又经p38MAPK的磷酸化途径促进HSCs的增生, 他们还发现, 经NOX抑制剂DPI处理后, PDGF-BB引起的HSC增生和MAPKs的磷酸化程度显著受到抑制, 进一步说明了PDHG-BB是通过激活NOX/产生ROS的过程以诱导的p38MAPK磷酸化, 将信号传至细胞核内, 调节基因的表达. 肝纤维化形成过程中, PDGF-B、PDGF-D与其敏感受体PDGFRβ结合, 受体发生自身磷酸化并激活Ras系统, 相继通过Raf-1、MEK和ERK(MAPKs通路)的磷酸化激活过程传播信号, 激活的ERK不仅可促进胞质靶蛋白的磷酸化、调节其他蛋白激酶活性, 还可进入细胞核内, 促进多种转录因子(如AP-1、NF-κB)的磷酸化, 使其与相应反应元件的靶基因启动子结合, 增强转录活性, 参与靶基因产物Ⅰ型胶原、TIMP-1、MMP1、Bcl-2、XIAP等的表达, 调控细胞的分裂、增殖和凋亡[29,35]. TIMP-1、MMP1、Ⅰ型胶原等在肝纤维化过程中是不可或缺的, 活化的HSCs可上调TIMPs的表达, 降低MMPs的表达, 促进胶原的产生, 增加细胞外基质的沉积, 形成瘢痕组织, 破坏肝脏的组织结构和器官功能[36,37].
慢性纤维化改变可发生在多个不同器官和系统, PDGF信号通路参与形成纤维化的过程, 并在促进肌成纤维细胞的复制, 存活, 和迁移等方面发挥重要作用. 而PDGF的活动与肌成纤维细胞表面表达的PDGFRα和βPDGF相关, 在纤维化发展过程中, 这些受体被激活继而放大PDGF传递的信号刺激. PDGF参与多个器官的纤维化过程, 包括肺[38]、肾[39]、肝[40,41]、真皮[42]和心脏[43]等. Nagaoka等[44]曾报道称正常人肺泡巨噬细胞中含有PDGF-A和PDGF-B的mRNA, 但PDGF-B比PDGF-A的mRNA多10倍的量, 他们还发现特发性肺纤维化病人的巨噬细胞中, PDGF-A和PDGF-B的mRNA水平都显著提高. 这说明PDGF在特发性肺纤维化病人肺泡巨噬细胞中的大量分泌是由于加快的转录速率, 并且被巨噬细胞释放的PDGF亚基主要是PDGF-B链构成的二聚体[45]. Kimani等[38]也发现PDGFRα受体的表达可促进肺肌成纤维细胞的增生, 而PDGF-A对其却有抑制作用. 当然, 在其他的肺疾病中也可发现PDGF的过表达, 例如闭塞性细支气管炎[46]、石棉肺[47]、尘肺[48]等, 且都以PDGF-B链发挥关键作用. PDGF-C缺乏或有其中和抗体的老鼠可削弱经单侧输尿管结扎引起的肾纤维化的程度, 相反的是, PDGF-C对肝脏的纤维化进程影响不明显, 而以PDGF-B、PDGF-D对肝纤维化的影响更显著[49]. Liu等[50]从硬皮病患者病变处检测到PDGFRα的表达升高, 受体结合的PDGF-AA配体也相应增加, 促进纤维母细胞的增生及向肌成纤维母细胞的转化. M2巨噬细胞分泌PDGF-CC可诱导口腔和牙龈纤维母细胞表达α-SMA, 促进该细胞的分化[51]. 在心脏受损时, 可检测到PDGF的表达是提高的, PDGF促进中性粒细胞、巨噬细胞、纤维母细胞和平滑肌细胞等增生和迁移至伤处, 刺激肉芽组织的形成, 组织结构的纤维化改变[43].
近年来, 有一些关于经抗PDGFs、PDGFRs的抗体[27,52]或阻断PDGFs、PDGFRs信号通路[53]的方法对抗肝纤维化的研究, 研究发现注射抗PDGF-B疫苗的小鼠, 可抵制CCl4药物作用导致的肝纤维化发生, 并抑制已发生纤维化的肝脏HSCs的活化、增殖[54]. 川芎嗪具有削弱纤维化标志基因表达的作用, 减少PDGFRβ受体的表达, 从而阻断PDGFRβ下游ERK和p38的磷酸化作用, 抑制过氧化物H2O2引起的HSCs的活化, 并诱导其凋亡[55]. 苜蓿素、花青素等植物提取物有类似酪氨酸激酶抑制剂活性, 通过减少PDGFRβ和ERK1/2和Akt的磷酸化作用, 抑制PDGF-BB导致的HSCs的活化、增生等[56,57]. 索拉非尼, 作为多重酪氨酸激酶受体抑制剂, 针对PDGF受体及Raf/ERK信号通路, 能有效治疗肝细胞癌患者, 并且在纤维化动物模型中可发挥抗纤维的作用[58]. 尼洛替尼, 也具有酪氨酸受体抑制作用, 阻断PDGF和TGF-β诱导的ERK和Akt磷酸化, 抑制HSCs的增生、迁移及α-SMA、胶原蛋白丝的合成[59]. 实际上, PDGFR抑制剂在疾病的临床前期的运用研究, 为抗纤维化的治疗提供了一个新的前景, PDGF受体抑制剂或抗PDGF疫苗很可能是有效预防和减缓肝纤维化的有效制剂.
许多不同的疾病和毒素都可导致肝损害, 长期慢性肝损常常会进展为肝纤维化、肝硬化甚至肝癌, 而治疗肝纤维化是非常困难的, 如何阻止或逆转肝纤维化的发生、发展成为肝病治疗的重大课题. 通过阐述PDGF在肝纤维化中的作用, 对PDGF及其受体进行中和或抑制, 就可能达到抗纤维化的目的, 为抗肝纤维化的治疗提供了一个新的研究方向.
肝纤维化是所有慢性肝病的共同病理基础, 是多种慢性肝病向肝 硬化发展的必经阶段, 如何阻止或逆转肝纤维化的发生、发展成为肝病治疗的重大课题. 近年研究发现, 阻断血小板衍生生长因子(PDGFs)家族参与的信号通路可能达到治疗纤维化的目的. 因此本文就PDGFs及其受体与肝纤维化的密切关系做一综述.
刘绍能, 主任医师, 中国中医科学院广安门医院消化科
本文全面专一的介绍PDGFs及其受体在结构、亚基、激活的信号通路、机制等方面与肝纤维化的密切关系, 强调PDGF-B、PDGF-D、PDGFR-β在肝纤维化过程中的突出作用, 概括PDGF家族与其他组织器官纤维化的关系, 总结了PDGF家族参与的抗肝纤维化的多方研究成果.
血小板源性生长因子(PDGF): 在生理状态下, 主要储存于血小板中, 肝脏受损时,巨噬细胞、血小板、浸润的炎症细胞、受损的内皮细胞及激活的肝星形细胞均可以分泌PDGF, 成为促进有丝分裂因子, 刺激特定细胞群的分裂、增殖.
本文对PDGF及其受体在肝纤维化的发生、治疗及其研究进展进行综述, 资料详细, 内容丰富, 条理清晰, 可读性强.
编辑:李军亮 电编: 鲁亚静
| 1. | Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol. 2011;6:425-456. [PubMed] [DOI] |
| 2. | Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655-1669. [PubMed] [DOI] |
| 3. | Heldin CH. Autocrine PDGF stimulation in malignancies. Ups J Med Sci. 2012;117:83-91. [PubMed] [DOI] |
| 4. | Pinzani M, Macias-Barragan J. Update on the pathophysiology of liver fibrosis. Expert Rev Gastroenterol Hepatol. 2010;4:459-472. [PubMed] [DOI] |
| 5. | Chen PH, Chen X, He X. Platelet-derived growth factors and their receptors: Structural and functional perspectives. Biochim Biophys Acta. 2012; Nov 5. [Epub ahead of print]. [PubMed] [DOI] |
| 6. | Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22:1276-1312. [PubMed] [DOI] |
| 7. | Yang Y, Yuzawa S, Schlessinger J. Contacts between membrane proximal regions of the PDGF receptor ectodomain are required for receptor activation but not for receptor dimerization. Proc Natl Acad Sci U S A. 2008;105:7681-7686. [PubMed] [DOI] |
| 8. | Donovan J, Abraham D, Norman J. Platelet-derived growth factor signaling in mesenchymal cells. Front Biosci. 2013;18:106-119. [PubMed] [DOI] |
| 9. | Clement DL, Mally S, Stock C, Lethan M, Satir P, Schwab A, Pedersen SF, Christensen ST. PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2-ERK1/2-p90RSK and AKT signaling pathways. J Cell Sci. 2012; Dec 21. [Epub ahead of print]. [PubMed] [DOI] |
| 10. | Kawada K, Upadhyay G, Ferandon S, Janarthanan S, Hall M, Vilardaga JP, Yajnik V. Cell migration is regulated by platelet-derived growth factor receptor endocytosis. Mol Cell Biol. 2009;29:4508-4518. [PubMed] [DOI] |
| 11. | Fey D, Croucher DR, Kolch W, Kholodenko BN. Crosstalk and signaling switches in mitogen-activated protein kinase cascades. Front Physiol. 2012;3:355. [PubMed] [DOI] |
| 12. | Wang Y, Jiang XY, Liu L, Jiang HQ. Phosphatidylinositol 3-kinase/Akt pathway regulates hepatic stellate cell apoptosis. World J Gastroenterol. 2008;14:5186-5191. [PubMed] [DOI] |
| 13. | Gäbele E, Reif S, Tsukada S, Bataller R, Yata Y, Morris T, Schrum LW, Brenner DA, Rippe RA. The role of p70S6K in hepatic stellate cell collagen gene expression and cell proliferation. J Biol Chem. 2005;280:13374-13382. [PubMed] [DOI] |
| 14. | Tu CT, Li J, Wang FP, Li L, Wang JY, Jiang W. Glycyrrhizin regulates CD4+T cell response during liver fibrogenesis via JNK, ERK and PI3K/AKT pathway. Int Immunopharmacol. 2012;14:410-421. [PubMed] [DOI] |
| 15. | Błajecka K, Marinov M, Leitner L, Uth K, Posern G, Arcaro A. Phosphoinositide 3-kinase C2β regulates RhoA and the actin cytoskeleton through an interaction with Dbl. PLoS One. 2012;7:e44945. [PubMed] [DOI] |
| 16. | Glass DJ. PI3 kinase regulation of skeletal muscle hypertrophy and atrophy. Curr Top Microbiol Immunol. 2010;346:267-278. [PubMed] [DOI] |
| 17. | Pinzani M. PDGF and signal transduction in hepatic stellate cells. Front Biosci. 2002;7:d1720-d1726. [PubMed] |
| 18. | Ping A, Yihao T, Jingxing D, Minkai C, Hesheng L. Ca2+/calmodulin-dependent protein kinase II mediates platelet-derived growth factor-induced human hepatic stellate cell proliferation. Dig Dis Sci. 2012;57:935-942. [PubMed] [DOI] |
| 19. | Samajová O, Komis G, Samaj J. Emerging topics in the cell biology of mitogen-activated protein kinases. Trends Plant Sci. 2013; Jan 3. [Epub ahead of print]. [PubMed] [DOI] |
| 20. | Chye SM, Tiong YL, Yip WK, Koh RY, Len YW, Seow HF, Ng KY, Ranjit DA, Chen SC. Apoptosis induced by para-phenylenediamine involves formation of ROS and activation of p38 and JNK in chang liver cells. Environ Toxicol. 2012; Nov 22. [Epub ahead of print]. [PubMed] [DOI] |
| 21. | Borkham-Kamphorst E, van Roeyen CR, Ostendorf T, Floege J, Gressner AM, Weiskirchen R. Pro-fibrogenic potential of PDGF-D in liver fibrosis. J Hepatol. 2007;46:1064-1074. [PubMed] [DOI] |
| 22. | Thieringer F, Maass T, Czochra P, Klopcic B, Conrad I, Friebe D, Schirmacher P, Lohse AW, Blessing M, Galle PR. Spontaneous hepatic fibrosis in transgenic mice overexpressing PDGF-A. Gene. 2008;423:23-28. [PubMed] [DOI] |
| 23. | Breitkopf K, Roeyen Cv, Sawitza I, Wickert L, Floege J, Gressner AM. Expression patterns of PDGF-A, -B, -C and -D and the PDGF-receptors alpha and beta in activated rat hepatic stellate cells (HSC). Cytokine. 2005;31:349-357. [PubMed] [DOI] |
| 24. | Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC, Odell MM, Bauer RL, Ren HP, Haugen HS. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2005;102:3389-3394. [PubMed] [DOI] |
| 25. | Borkham-Kamphorst E, Kovalenko E, van Roeyen CR, Gassler N, Bomble M, Ostendorf T, Floege J, Gressner AM, Weiskirchen R. Platelet-derived growth factor isoform expression in carbon tetrachloride-induced chronic liver injury. Lab. Invest. 2008;88:1090-1100. [PubMed] [DOI] |
| 26. | Li L, Li J, Wang JY, Yang CQ, Jia ML, Jiang W. Role of RhoA in platelet-derived growth factor-BB-induced migration of rat hepatic stellate cells. Chin Med J (Engl). 2010;123:2502-2509. [PubMed] |
| 27. | Ogawa S, Ochi T, Shimada H, Inagaki K, Fujita I, Nii A, Moffat MA, Katragadda M, Violand BN, Arch RH. Anti-PDGF-B monoclonal antibody reduces liver fibrosis development. Hepatol Res. 2010;40:1128-1141. [PubMed] [DOI] |
| 28. | Czochra P, Klopcic B, Meyer E, Herkel J, Garcia-Lazaro JF, Thieringer F, Schirmacher P, Biesterfeld S, Galle PR, Lohse AW. Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. J Hepatol. 2006;45:419-428. [PubMed] [DOI] |
| 29. | Borkham-Kamphorst E, Herrmann J, Stoll D, Treptau J, Gressner AM, Weiskirchen R. Dominant-negative soluble PDGF-beta receptor inhibits hepatic stellate cell activation and attenuates liver fibrosis. Lab Invest. 2004;84:766-777. [PubMed] [DOI] |
| 30. | Borkham-Kamphorst E, Stoll D, Gressner AM, Weiskirchen R. Antisense strategy against PDGF B-chain proves effective in preventing experimental liver fibrogenesis. Biochem Biophys Res Commun. 2004;321:413-423. [PubMed] [DOI] |
| 31. | Bonner JC. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004;15:255-273. [PubMed] |
| 32. | Daiber A. Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim Biophys Acta. 2010;1797:897-906. [PubMed] [DOI] |
| 33. | Jiang F, Zhang Y, Dusting GJ. NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev. 2011;63:218-242. [PubMed] [DOI] |
| 34. | Adachi T, Togashi H, Suzuki A, Kasai S, Ito J, Sugahara K, Kawata S. NAD(P)H oxidase plays a crucial role in PDGF-induced proliferation of hepatic stellate cells. Hepatology. 2005;41:1272-1281. [PubMed] |
| 35. | Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802:396-405. [PubMed] [DOI] |
| 36. | Mann DA, Marra F. Fibrogenic signalling in hepatic stellate cells. J Hepatol. 2010;52:949-950. [PubMed] [DOI] |
| 37. | Pellicoro A, Ramachandran P, Iredale JP. Reversibility of liver fibrosis. Fibrogenesis Tissue Repair. 2012; Jun 6; 5 Suppl 1: S26. [Epub ahead of print]. [PubMed] |
| 38. | Kimani PW, Holmes AJ, Grossmann RE, McGowan SE. PDGF-Ralpha gene expression predicts proliferation, but PDGF-A suppresses transdifferentiation of neonatal mouse lung myofibroblasts. Respir Res. 2009;10:119. [PubMed] [DOI] |
| 39. | Farris AB, Colvin RB. Renal interstitial fibrosis: mechanisms and evaluation. Curr Opin Nephrol Hypertens. 2012;21:289-300. [PubMed] [DOI] |
| 40. | Thoen LF, Guimarães EL, Dollé L, Mannaerts I, Najimi M, Sokal E, van Grunsven LA. A role for autophagy during hepatic stellate cell activation. J Hepatol. 2011;55:1353-1360. [PubMed] [DOI] |
| 41. | Guyot C, Lepreux S, Combe C, Sarrazy V, Billet F, Balabaud C, Bioulac-Sage P, Desmoulière A. Fibrogenic cell phenotype modifications during remodelling of normal and pathological human liver in cultured slices. Liver Int. 2010;30:1529-1540. [PubMed] [DOI] |
| 42. | Reich N, Maurer B, Akhmetshina A, Venalis P, Dees C, Zerr P, Palumbo K, Zwerina J, Nevskaya T, Gay S. The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis Rheum. 2010;62:280-290. [PubMed] [DOI] |
| 43. | Leask A. Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res. 2010;106:1675-1680. [PubMed] [DOI] |
| 44. | Nagaoka I, Trapnell BC, Crystal RG. Upregulation of platelet-derived growth factor-A and -B gene expression in alveolar macrophages of individuals with idiopathic pulmonary fibrosis. J Clin Invest. 1990;85:2023-2027. [PubMed] |
| 45. | Kogan EA, Tyong FV, Demura SA. [The mechanism of lung tissue remodeling in the progression of idiopathic pulmonary fibrosis]. Arkh Patol. 2010;72:30-36. [PubMed] |
| 46. | Alho HS, Maasilta PK, Vainikka T, Salminen US. Platelet-derived growth factor, transforming growth factor-beta, and connective tissue growth factor in a porcine bronchial model of obliterative bronchiolitis. Exp Lung Res. 2007;33:303-320. [PubMed] |
| 47. | Li Y, Karjalainen A, Koskinen H, Vainio H, Pukkala E, Hemminki K, Brandt-Rauf PW. Serum growth factors in asbestosis patients. Biomarkers. 2009;14:61-66. [PubMed] [DOI] |
| 48. | Wang GZ, Wang MJ, Liu LH, Wang JH, Qin WH, Liu Y, He JF. [The surface biomarkers of sputum cells in coal mine workers and patients with pneumoconiosis]. Zhonghua Laodong Weisheng Zhiyebing Zazhi. 2011;29:837-840. [PubMed] |
| 49. | Martin IV, Borkham-Kamphorst E, Zok S, van Roeyen CR, Eriksson U, Boor P, Hittatiya K, Fischer HP, Wasmuth HE, Weiskirchen R. Platelet-derived growth factor (PDGF)-C neutralization reveals differential roles of PDGF receptors in liver and kidney fibrosis. Am J Pathol. 2013;182:107-117. [PubMed] [DOI] |
| 50. | Liu T, Zhang J. [Role of PDGF-A/PDGFR-α in proliferation and transdifferentiation of fibroblasts from skin lesions of patients with systemic sclerosis]. Nanfang Yike Daxue Xuebao. 2012;32:496-501. [PubMed] |
| 51. | Glim JE, Niessen FB, Everts V, van Egmond M, Beelen RH. Platelet derived growth factor-CC secreted by M2 macrophages induces alpha-smooth muscle actin expression by dermal and gingival fibroblasts. Immunobiology. 2012; Oct 26. [Epub ahead of print]. [PubMed] [DOI] |
| 52. | Mahlknecht P, Stemberger S, Sprenger F, Rainer J, Hametner E, Kirchmair R, Grabmer C, Scherfler C, Wenning GK, Seppi K. An antibody microarray analysis of serum cytokines in neurodegenerative Parkinsonian syndromes. Proteome Sci. 2012;10:71. [PubMed] [DOI] |
| 53. | Hou X, Kumar A, Lee C, Wang B, Arjunan P, Dong L, Maminishkis A, Tang Z, Li Y, Zhang F. PDGF-CC blockade inhibits pathological angiogenesis by acting on multiple cellular and molecular targets. Proc Natl Acad Sci U S A. 2010;107:12216-12221. [PubMed] [DOI] |
| 54. | Hao ZM, Fan XB, Li S, Lv YF, Su HQ, Jiang HP, Li HH. Vaccination with platelet-derived growth factor B kinoids inhibits CCl4-induced hepatic fibrosis in mice. J Pharmacol Exp Ther. 2012;342:835-842. [PubMed] [DOI] |
| 55. | Zhang F, Ni C, Kong D, Zhang X, Zhu X, Chen L, Lu Y, Zheng S. Ligustrazine attenuates oxidative stress-induced activation of hepatic stellate cells by interrupting platelet-derived growth factor-β receptor-mediated ERK and p38 pathways. Toxicol Appl Pharmacol. 2012;265:51-60. [PubMed] [DOI] |
| 56. | Seki N, Toh U, Kawaguchi K, Ninomiya M, Koketsu M, Watanabe K, Aoki M, Fujii T, Nakamura A, Akagi Y. Tricin inhibits proliferation of human hepatic stellate cells in vitro by blocking tyrosine phosphorylation of PDGF receptor and its signaling pathways. J Cell Biochem. 2012;113:2346-2355. [PubMed] [DOI] |
| 57. | Choi JH, Hwang YP, Park BH, Choi CY, Chung YC, Jeong HG. Anthocyanins isolated from the purple-fleshed sweet potato attenuate the proliferation of hepatic stellate cells by blocking the PDGF receptor. Environ Toxicol Pharmacol. 2011;31:212-219. [PubMed] [DOI] |