ACM  >> Vol. 8 No. 2 (April 2018)

作者:  

冯爱然,于文成:青岛大学附属医院,山东 青岛

关键词:
肺纤维化炎症氧化应激促凝机制Pulmonary Fibrosis Inflammation Oxidative Stress Coagulation

摘要:

肺纤维化为慢性肺部疾病,特发性肺纤维化(IPF)为其主要类型,也是最严重的纤维化类型,其中位生存期仅为3年。目前肺纤维化发生机制尚不明确,主要研究炎症和免疫学机制、氧化应激和氧化信号通路、促凝机制等领域。本文就三项主要研究领域做一简要综述。

Pulmonary fibrosis is a chronic lung disease. Idiopathic pulmonary fibrosis (IPF) is the most common and severe form of the disease, with a median survival of three years. Despite the fact that the precise mechanisms that drive fibrosis in patients remain incompletely understood. Three broad areas have been explored: inflammation and immune mechanisms, oxidative stress and procoagulant mechanisms. This paper gives a brief overview of three major research areas.

1. 引言

纤维化是机体针对慢性损害的免疫反应,若损害因素持续存在,过量的纤维化会导致固有免疫的激活、成纤维细胞的募集、增殖与活化,促进细胞外基质的合成与相互交联,导致大量瘢痕组织形成,最后可引起器官功能衰竭。

肺纤维化为慢性肺部疾病,以细胞外基质沉积、肺重构为特点。特发性肺纤维化(IPF)为最严重的肺纤维化类型,中期生存时间仅为3年,没有有效的治疗方法,肺移植为终末期患者唯一的治疗方法 [1] 。病理学发现肺纤维化的病理改变(细胞外基质过度沉积与肺重构)由于两种生理过程的失衡造成的:成纤维细胞的增殖与凋亡、细胞外基质的沉积与降解失衡。当细胞外基质的平衡被打破,造成成纤维细胞增殖增加或者成纤维细胞凋亡减少,则造成细胞外基质的积累。肺纤维化中,造成成纤维细胞改变、肺泡上皮细胞的丧失、细胞外基质的过度沉积的原因主要提到以下三个主要的领域:炎症和免疫学机制、氧化应激及促凝机制 [2] 。本文就三个主要研究领域做简要综述。

2. 炎症免疫学机制

最早关于肺纤维化的描述中,认为肺纤维化患者肺实质中持续存在炎症细胞,而且组织学分析,许多患者肺间质可见淋巴细胞、巨噬细胞、浆细胞、嗜酸性粒细胞、中心粒细胞以及淋巴细胞的聚集 [3] [4] [5] 。但是,在最近的20年,炎症机制被质疑,认为炎症机制并不是IPF发生的必要条件 [6] ,但是,糖皮质激素或联合免疫抑制剂在治疗以炎症改变为主的间质性肺疾病(如非特异性间质性肺炎)时有临床效果。但是,由于IPF是以纤维化改变为主的间质性肺疾病,激素联合免疫抑制剂治疗缺乏理论依据。有较多临床试验将糖皮质激素联合免疫抑制剂用于肺纤维化的治疗,但与安慰剂比较均未取得疗效。2013年开展的一项随机双盲的Ⅲ期临床试验,拟通过比较干预组[泼尼松(强的松)+环磷酰胺]与对照组在早期生存率、全因死亡率、高分辨率CT表现及呼吸性疾病病死率间的差异,判断免疫抑制剂的疗效,目前尚未公布结果。但是,虽然糖皮质激素治疗肺纤维化效果不佳,但是仍不能完全除外炎性机制对肺纤维化的影响,因为有些炎性疾病糖皮质激素治疗效果不佳 [7] 。基于对炎性细胞、细胞因子、趋化因子以及表面分子的研究,肺纤维化疾病的炎性假设占据了40余年,目前仍有许多学者认为IPF是一种慢性炎性肺部疾病 [7] [8] [9] 。

3. 炎症潜在的作用

最近人们强调IPF是由于上皮细胞、间充质细胞和细胞外基质异常所致,不再强调炎症机制对疾病的影响。虽然大部分IPF患者表现为轻到中度的慢性炎症细胞浸润,但是,一些终末期患者和严重的IPF的患者,肺实质内炎性细胞浸润证据不足。虽然,一般来说慢性炎症表现为炎性细胞的浸润,但是,不同的组织,炎性细胞浸润的程度不同。例如肌腱组织,判断炎性病变主要根据细胞因子、生长因子、前列腺素和神经肽的存在,而非炎性细胞的浸润 [10] [11] 。同样,大脑受到损伤或者自身免疫反应时,炎性细胞浸润少见,但是大脑却能激活炎症反应,细胞因子起重要作用 [11] 。

4. 糖皮质激素治疗无效不能说明不存在炎症

有些疾病确定认为炎症反应的存在,但是给予传统抗炎治疗效果差或者完全无效 [7] 。慢性阻塞性肺病(COPD)为炎性肺部疾病,促炎性细胞及细胞因子,但是大部分研究表明,吸入或者全身糖皮质激素治疗并不能明显减少炎性细胞及炎性介质,也不能长期改善肺功能及预后 [12] [13] 。支气管哮喘为典型的气道炎性反应性疾病,虽然大部分病人对糖皮质激素反应良好,但还有一部分患者出现糖皮质激素抵抗,治疗反应差,且尽管给予糖皮质激素的治疗,但是肺泡巨噬细胞与T细胞持续表达促炎和促纤维化细胞因子 [14] [15] [16] [17] 。类风湿关节炎、系统性红斑狼疮属于自身免疫性炎症反应性疾病,但是仍有部分患者对糖皮质激素反应差,糖皮质激素并不能抑制单核细胞以及T淋巴细胞的增殖也不能促进他们的凋亡 [18] ,同样,部分炎症性肠病(IBD)患者应用糖皮质激素后反应较差或者无反应,虽然应用糖皮质激素,但并不能抑制周围血T细胞的增殖 [19] [20] 。最近关于老鼠肺损伤模型提示,炎症反应在IPF病理中仍发挥一定的作用。研究表明,IPF患者肺内尿酸水平较肺纤维化患者肺内的尿酸高 [21] ,博来霉素诱导动物模型中,肺损伤造成尿酸的积累,积累的尿酸形成尿酸结晶,反过来激活NLRP3炎症小体,造成IL-1β的产生和造成肺纤维化的形成 [22] 。尽管在IPF患者中并未发现急性炎症途径的编码基因过表达,但是,编码趋化因子和细胞因子的基因表达上调 [23] ,因此,有人已经提出进行精确的抗炎治疗,例如选择性的调节关键炎症反映途径,减少纤维化的发生。

组织损伤修复是一种基本的生物机制,在机体受伤后机体进行替换死亡或受损的细胞,这一过程对生存至关重要 [24] 。然而,如果损伤与修复机制受损,细胞外基质过度积累,形成“疤痕”。所以,肺纤维化常认为是一种损伤修复机制受损导致的疾病。组织的损伤修复包括4个不同的阶段:1.血小板聚集,2.炎症反应阶段,3.成纤维细胞的迁移与增殖,4.组织重构。组织损伤早期阶段,上皮细胞或者内皮细胞释放炎症调节因子,使得血小板聚集,血小板聚集后脱颗粒,促使血管扩张,渗透性增加,促进炎症细胞聚集至受损伤部位(例如:中性粒细胞、巨噬细胞、淋巴细胞和嗜酸性粒细胞)。中性粒细胞是伤口愈合早期最丰富的炎症细胞,但在中性粒细胞减少后很快被巨噬细胞取代。最初白细胞迁移阶段,激活的巨噬细胞和中性粒细胞释放大量的细胞因子,会扩大炎症反应,促进成纤维细胞增殖。

目前的研究显示,肺纤维化过程中肌成纤维细胞募集的来源主要有三个 [25] :①肺组织成纤维细胞转化为肌成纤维细胞,TGF-β是成纤维细胞转化为肌成纤维细胞的主要活化因子,通过激活成纤维细胞内c-Jun氨基末端激酶(c-Jun-NH2-terminal kinase, JNK)通路,时间–剂量依赖性地诱导人类肺成纤维细胞向肌成纤维细胞的转化,表现为平滑肌肌动蛋白(smooth muscle actin II, SMA)的表达大量增加;②骨髓源性纤维细胞转化为肌成纤维细胞,骨髓源性纤维细胞,这是一种具有成纤维细胞特性的白细胞亚群,可以由外周血迁移到损伤组织处并转化为肌成纤维细胞,促进胶原分泌和组织纤维化;③肺泡上皮细胞转化为肌成纤维细胞,即为上皮–间质细胞转化(epithelial mesenchymal transformation, EMT)。EMT主要表现为E钙黏蛋白、角蛋白、闭锁小带1(ZO-1)蛋白水平等上皮细胞的标志丢失,并获得a-SMA、纤维连接蛋白等间质细胞标志。TGF-b可以诱导肺泡上皮细胞出现成纤维样细胞的形态,且a-SMA、I型胶原和波形蛋白表达增加;同时,还测得IPF患者肺组织标本中肺泡上皮细胞亦表达a-SMA。

5. 细胞因子在肺纤维化中的作用

成纤维的激活、迁移和增殖促进细胞外基质的产生,促进了纤维化疾病的进展 [26] [27] 。纤维化疾病中表现为成纤维细胞和肌成纤维细胞的增生,相对于成纤维细胞而言,肌成纤维细胞α-SMA表达上调,且细胞外基质产生增加,包括I、III、V和VI型胶原蛋白。而且肌成纤维细胞表达组织抑制剂金属蛋白酶(TIMPs),导致细胞外基质降解酶活性下降 [28] [29] ,而成纤维细胞增殖分化为肌成纤维细胞的来源之一,而TGF-β可抑制肌成纤维细胞的凋亡 [12] ,TGF-β诱导EndMT发生,促进了纤维化的发展 [30] 。有试验证实 [31] TGF-β与Ras共同诱导肺微血管发生EntMT,而guan, R [32] 等人的试验与该实验结果一致。血小板衍生因子(PDGF)与血小板衍生因子受体(PDGFR)结合,通过影响多条通路的因子或蛋白的表达及改变蛋白的磷酸化状态来传递信号。成纤维细胞体外实验及博来霉素诱导小鼠体内实验发现PDGF对成纤维细胞具有较强的趋化作用 [33] ,且PDGF调节细胞外基质的代谢,介导胶原的合成。白IL-4,由Th2亚群细胞产生,体外实验表明,IL-4刺激纤维细胞的增殖以及细胞外基质的产生 [8] [9] [34] 。IL-4调节肌成纤维细胞表达α-SMA,且IL-4的表达可以判断患者的预后 [35] 。TNF-α有助于成纤维细胞的消除,促进肌成纤维细胞凋亡 [36] [37] ,TNF-α抑制抑制成纤维细胞的增殖,抑制TGF-β1诱导的成纤维细胞向肌成纤维细胞转化以及促进细胞外基质的收缩 [38] 。而且TNF-α诱导金属蛋白酶2和9的产生 [39] ,从而促进胶原的溶解。最近的研究提出,TNF-α可以缓解已有肺纤维化小鼠的纤维化程度,认为TNF-α减少巨噬细胞的数量或者减少其功能状态 [40] 。Thanh-Thuy T. Le [41] 等人的研究发现,IPF患者及小鼠肺纤维化启动及进展时期,sIL-6Rα表达增加,考虑在肺纤维化的发展过程中,成纤维细胞通过加强IL-6反式信号通路,促进肺成纤维细胞的增殖及细胞外基质的沉积。

6. 表面分子在肺纤维化中的作用

CD40-CD40L系统

免疫介质CD40是CD40L的经典受体,属于肿瘤坏死因子受体(TNFR)超家族,也属于与T淋巴细胞和B淋巴细胞相关的表面抗原。编码基因位于20q12q13.2,有277个氨基酸,相对分子量为45000,50000。CD40为I型跨膜糖蛋白,包括胞外区和跨膜区三部分,分别由193、62和22个氨基酸组成。激活的抗原呈递细胞表达CD40,主要表达在B淋巴细胞上,但同时成纤维细胞、表皮树突状细胞、血管内皮细胞、平滑肌细胞和单核巨噬细胞、上皮细胞和血小板等也有表达 [42] [43] 。CD40L又称为CD154,属于肿瘤坏死因子家族成员。CD40L相关基因位于Xq26.3q27.1,有261个氨基酸,相对分子量为32000,33000。激活的CD4+T细胞表达CD40L。CD40L是II型跨膜蛋白, 通常以膜结合型CD40配体(mCD40L)和可溶性CD40L(sCD40L)两种形式存在。sCD40L主要来源于活化的血小板及T淋巴细胞,是由CD40L水解,以游离形式存在于血浆中,具有生物活性的、可溶性的三聚体片段,可与CD40结合,可由mCD40L在蛋白水解酶的作用下裂解而成,可通过与血管细胞(内皮细胞)表面的CD40结合而导致粘附分子的表达及炎症因子、促凝血递质/组织因子的释放,如白细胞介素6(interleukin-6,IL-6)。CD40L与SCD40L均以三聚体形式与相应受体结合,在启动免疫、调节炎症反应中发挥重要作用。因为成纤维细胞表达CD40,因此CD40/CD40L可能影响着成纤维细胞的功能。眼眶成纤维细胞表面表达CD40,CD40-CD40L结合促进透明质酸的产生,而且CD40-CD40L相互作用,促进炎性细胞因子的产生,包括IL-8和IL-6 [44] [45] 。

7. 氧化应激机制

氧化应激是指过多的活性氧(ROS)和/或抗氧化防御系统耗尽,造成分子、细胞和组织异常 [46] [47] [48] 。相对于其他器官而言,肺更容易受到氧化应激的影响,因为肺内氧分压为体内最高,吸入空气的氧分压为150 mmHg,肺泡内的氧分压为100 mmHg,而静脉血或者其他其器官的氧分压为1~45 mmHg之间。生物系统不断地暴露在外部因素(如:烟草、石棉/二氧化硅、辐射、博来霉素和其他药物等),以及由炎性细胞以及组织上皮细胞、间质细胞和内皮细胞产生内在因素 [49] 。体内常见的ROS包括:超氧离子自由基 ( O 2 ) 、NO自由基、羟自基(-OH)和过氧化氢(H2O2)、脂质过氧化物、髓过氧化物、单线态氧、过氧亚硝酸盐等。抗氧化剂主要包括:人体必需营养物资(维生素A、E等)、小分子抗氧化物、粘单白、金属蛋白、超氧化物歧化酶(SODs)等。氧化应激促进炎性介质的释放、诱导肺泡上皮细胞损伤、促进成纤维细胞增殖、促进上皮细胞间质转化、破坏蛋白酶/抗蛋白酶平衡、调节细胞因子表达、激活NF-κB活化等途径促进细胞外基质沉积,从而促进肺纤维化的发生 [50] [51] 。通常低水平的ROS可以促进细胞的增殖,激活抗氧化反应系统,但是高水平的ROS会造成DNA损伤,P53激活,阻断细胞周期,造成细胞坏死或者凋亡 [49] [52] [53] ,以上这些因素对于纤维化的形成起重要作用。

8. 促凝血机制

凝血机制异常似乎与肺纤维化的发生有密不可分的关系。一项丹麦的研究发现,凝血因子V基因突变的患者较未突变的患者呼吸功能差,主要表现在基因突变患者有严重的呼吸困难、第一秒用力呼气容积(FEV1)及用力肺活量(FVC)更低,以及FEV1与FVC每年下降的幅度更大 [54] 。且另有试验证明,既往有深静脉血栓或者肺栓塞病史的患者,发生间质性肺部疾病或者特发性间质性肺炎的发生率高 [55] 。有实验证实,IPF患者肺泡灌洗液(BAL)中TF增加,且免疫组化显示TF高表达于立方上皮细胞中,以及IPF、系统性硬化症、隐源性机化性肺炎患者的II型肺泡上皮细胞中 [56] [57] 。也有试验证实,IPF患者BAL中第VII凝血因子表达较正常人高 [58] 。不仅凝血因子表达异常,IPF患者抗凝血机制激活也有变化,特别是纤溶酶原激活抑制剂1(PAI-1)和纤溶酶原激活抑制剂2(PAI-2),IPF患者两种PAI肺泡灌洗液较正常人升高,提示IPF患者抗纤溶活性失调 [56] 。

9. 结语

肺纤维化形成机制目前尚无明确定论,目前主要于炎症机制、氧化应激机制以及促凝血机制三方面进行研究。仍需要继续探索肺纤维化形成机制,以便寻找治疗靶点,控制疾病进展以及改善预后等。

参考文献

文章引用:
冯爱然, 于文成. 肺纤维化形成分子机制研究[J]. 临床医学进展, 2018, 8(2): 93-100. https://doi.org/10.12677/ACM.2018.82017

参考文献

[1] Raghu, G., Collard, H.R., Egan, J.J., et al. (2011) An Official ATS/ERS/JRS/ALAT Statement: Idiopathic Pulmonary Fibrosis: Evidence-Based Guidelines for Diagnosis and Management. American Journal of Respiratory and Critical Care Medicine, 183, 788-824.
https://doi.org/10.1164/rccm.2009-040GL
[2] Todd, N.W., Luzina, I.G. and Atamas, S.P. (2012) Molecular and Cellular Mechanisms of Pulmonary Fibrosis. Fibrogenesis & Tissue Repair, 5, 11.
https://doi.org/10.1186/1755-1536-5-11
[3] Crystal, R.G., Fulmer, J.D., Roberts, W.C., et al. (1976) Idiopathic Pulmonary Fibrosis. Clinical, Histologic, Radiographic, Physiologic, Scintigraphic, Cytologic, and Biochemical Aspects. Annals of Internal Medicine, 85, 769-788.
https://doi.org/10.7326/0003-4819-85-6-769
[4] Hamman, L. and Rich, A.R. (1935) Fulminating Diffuse Inter-stitial Fibrosis of the Lungs. Transactions of the American Clinical and Climatological Association, 51, 154-163.
[5] Scadding, J.G. and Hinson, K.F. (1967) Diffuse Fibrosing Alveolitis (Diffuse Interstitial Fibrosis of the Lungs). Correlation of Histology at Biopsy with Prognosis. Thorax, 22, 291-304.
https://doi.org/10.1136/thx.22.4.291
[6] Selman, M., King, T.E. and Pardo, A. (2001) Idiopathic Pulmonary Fi-brosis: Prevailing and Evolving Hypotheses about Its Pathogenesis and Implications for Therapy. Annals of Internal Medicine, 134, 136-151.
https://doi.org/10.7326/0003-4819-134-2-200101160-00015
[7] Barnes, P.J. and Adcock, I.M. (2009) Gluco-corticoid Resistance in Inflammatory Diseases. Lancet, 373, 1905-1917.
https://doi.org/10.1016/S0140-6736(09)60326-3
[8] Homer, R.J., Elias, J.A., Lee, C.G., et al. (2011) Modern Concepts on the Role of Inflammation in Pulmonary Fibrosis. Archives of Pathology & Laboratory Medicine, 135, 780-788.
[9] Wynn, T.A. (2011) Integrating Mechanisms of Pulmonary Fibrosis. Journal of Experimental Medicine, 208, 1339-1350.
https://doi.org/10.1084/jem.20110551
[10] Fredberg, U. and Stengaard-Pedersen, K. (2008) Chronic Tendinopathy Tissue Pathology, Pain Mechanisms, and Etiology with a Special Focus on Inflammation. Scan-dinavian Journal of Medicine & Science in Sports, 18, 3-15.
https://doi.org/10.1111/j.1600-0838.2007.00746.x
[11] Schulze-Tanzil, G., Al-Sadi, O., Wiegand, E., et al. (2011) The Role of Pro-Inflammatory and Immunoregulatory Cytokines in Tendon Healing and Rupture: New Insights. Scandinavian Journal of Medicine & Science in Sports, 21, 337-351.
https://doi.org/10.1111/j.1600-0838.2010.01265.x
[12] Zhang, H.Y. and Phan, S.H. (1999) Inhibition of Myofi-broblast Apoptosis by Transforming Growth Factor β1. American Journal of Respiratory Cell and Molecular Biology, 21, 658-665.
https://doi.org/10.1165/ajrcmb.21.6.3720
[13] Loppow, D., Schleiss, M.B., Kanniess, F., et al. (2001) In Patients with Chronic Bronchitis a Four Week Trial with Inhaled Steroids Does Not Attenuate Airway Inflammation. Respiratory Medicine, 95, 115-121.
https://doi.org/10.1053/rmed.2000.0960
[14] Leung, D.Y., Martin, R.J., Szefler, S.J., et al. (1995) Dysregulation of Interleukin 4, Interleukin 5, and Interferon Gamma Gene Expression in Steroid-Resistant Asthma. Journal of Ex-perimental Medicine, 181, 33-40.
https://doi.org/10.1084/jem.181.1.33
[15] Kay, A.B., Diaz, P., Carmicheal, J., et al. (1981) Corticoster-oid-Resistant Chronic Asthma and Monocyte Complement Receptors. Clinical & Experimental Immunology, 44, 576-580.
[16] Corrigan, C.J., Brown, P.H., Barnes, N.C., et al. (1991) Glucocorticoid Resistance in Chronic Asthma. Peripheral Blood T Lymphocyte Activation and Comparison of the T Lymphocyte Inhibitory Effects of Glucocorticoids and Cyclosporin A. The American Review of Respiratory Disease, 144, 1026-1032.
https://doi.org/10.1164/ajrccm/144.5.page
[17] Yang, M., Kumar, R.K., Hansbro, P.M., et al. (2012) Emerging Roles of Pulmonary Macrophages in Driving the Development of Severe Asthma. Journal of Leukocyte Biology, 91, 557-569.
https://doi.org/10.1189/jlb.0711357
[18] Sliwinska-Stanczyk, P., Pazdur, J., Ziolkowska, M., et al. (2007) The Effect of Methylprednisolone on Proliferation of PBMCs Obtained from Steroid-Sensitive and Ster-oid-Resistant Rheumatoid Arthritis Patients. Scandinavian Journal of Rheumatology, 36, 167-171.
https://doi.org/10.1080/03009740601154111
[19] Farrell, R.J. and Kelleher, D. (2003) Glucocorticoid Resistance in Inflammatory Bowel Disease. Journal of Endocrinology, 178, 339-346.
https://doi.org/10.1677/joe.0.1780339
[20] Hearing, S.D., Norman, M., Probert, C.S., et al. (1999) Predicting Therapeutic Outcome in Severe Ulcerative Colitis by Measuring in Vitro Steroid Sensitivity of Proliferating Peripheral Blood Lymphocytes. Gut, 45, 382-388.
https://doi.org/10.1136/gut.45.3.382
[21] Markart, P., Luboeinski, T., Korfei, M., et al. (2009) Alveolar Oxidative Stress Is Associated with Elevated Levels of Nonenzymatic Low-Molecular-Weight Antioxidants in Patients with Different Forms of Chronic Fibrosing Interstitial Lung Diseases. Antioxidants & Redox Signaling, 11, 227-240.
https://doi.org/10.1089/ars.2008.2105
[22] De Nardo, D., De Nardo, C.M. and Latz, E. (2014) New Insights into Mechanisms Controlling the NLRP3 Inflammasome and Its Role in Lung Disease. American Journal of Pathology, 184, 42-54.
https://doi.org/10.1016/j.ajpath.2013.09.007
[23] Zuo, F.R., Kaminski, N., Eugui, E., et al. (2002) Gene Expres-sion Analysis Reveals Matrilysin as a Key Regulator of Pulmonary Fibrosis in Mice and Humans. Proceedings of the National Academy of Sciences of the United States of America, 99, 6292-6297.
https://doi.org/10.1073/pnas.092134099
[24] Wynn, T.A. (2007) Common and Unique Mechanisms Regulate Fibrosis in Various Fibroproliferative Diseases. Journal of Clinical Investigation, 117, 524-529.
https://doi.org/10.1172/JCI31487
[25] Hinz, B., Phan, S.H., Thannickal, V.J., et al. (2007) The Myofibroblast: One Function, Multiple Origins. American Journal of Pathology, 170, 1807-1816.
https://doi.org/10.2353/ajpath.2007.070112
[26] Yin, Q., Wang, W., Cui, G., et al. (2018) Potential Role of the Jagged1/Notch1 Signaling Pathway in the Endothelial-Myofibroblast Transition during BLM-Induced Pulmonary Fi-brosis. Journal of Cellular Physiology, 233, 2451-2463.
https://doi.org/10.1002/jcp.26122
[27] Bolanos, A.L., Milla, C.M., Lira, J.C., et al. (2012) Role of Sonic Hedgehog in Idiopathic Pulmonary Fibrosis. American Journal of Physiology-Lung Cellular and Molecular Physiology, 303, L978-L990.
https://doi.org/10.1152/ajplung.00184.2012
[28] Ho, Y.Y., Lagares, D., Tager, A.M., et al. (2014) Fibrosis—A Lethal Component of Systemic Sclerosis. Nature Reviews Rheumatology, 10, 390-402.
https://doi.org/10.1038/nrrheum.2014.53
[29] Hinz, B., Phan, S.H., Thannickal, V.J., et al. (2012) Recent De-velopments in Myofibroblast Biology: Paradigms for Connective Tissue Remodeling. American Journal of Pathology, 180, 1340-1355.
https://doi.org/10.1016/j.ajpath.2012.02.004
[30] Van Meeteren, L.A. and Ten Dijke, P. (2012) Regulation of Endothelial Cell Plasticity by TGF-Beta. Cell and Tissue Research, 347, 177-186.
https://doi.org/10.1007/s00441-011-1222-6
[31] Hashimoto, N., Phan, S.H., Imaizumi, K., et al. (2010) Endo-thelial-Mesenchymal Transition in Bleomycin-Induced Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology, 43, 161-172.
https://doi.org/10.1165/rcmb.2009-0031OC
[32] Guan, R., Wang, X., Zhao, X., et al. (2016) Emodin Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats by Suppressing Epithelial-Mesenchymal Transition and Fibroblast Activation. Scientific Reports, 6, Article No. 35696.
https://doi.org/10.1038/srep35696
[33] Aono, Y., Kishi, M., Yokota, Y., et al. (2014) Role of Platelet-Derived Growth Factor/Platelet-Derived Growth Factor Receptor Axis in the Trafficking of Circulating Fibrocytes in Pulmonary Fibrosis. American Journal of Respiratory Cell and Molecular Biology, 51, 793-801.
https://doi.org/10.1165/rcmb.2013-0455OC
[34] Gordon, S. and Martinez, F.O. (2010) Alternative Activation of Macrophages: Mechanism and Functions. Immunity, 32, 593-604.
https://doi.org/10.1016/j.immuni.2010.05.007
[35] Waisberg, D.R., Parra, E.R., Barbas-Filho, J.V., et al. (2012) Increased Fibroblast Telomerase Expression Precedes Myofibroblast Alpha-Smooth Muscle Actin Expression in Idio-pathic Pulmonary Fibrosis. Clinics (Sao Paulo), 67, 1039-1046.
https://doi.org/10.6061/clinics/2012(09)10
[36] Wynes, M.W., Edelman, B.L., Kostyk, A.G., et al. (2011) In-creased Cell Surface Fas Expression Is Necessary and Sufficient to Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis. Journal of Immunology, 187, 527-537.
https://doi.org/10.4049/jimmunol.1100447
[37] Frankel, S.K., Cosgrove, G.P., Cha, S.I., et al. (2006) TNF-Alpha Sensitizes Normal and Fibrotic Human Lung Fibroblasts to Fas-Induced Apoptosis. American Journal of Respiratory Cell and Molecular Biology, 34, 293-304.
https://doi.org/10.1165/rcmb.2005-0155OC
[38] Goldberg, M.T., Han, Y.P., Yan, C., et al. (2007) TNF-Alpha Suppresses Alpha-Smooth Muscle Actin Expression in Human Dermal Fibroblasts: An Implication for Abnormal Wound Healing. Journal of Investigative Dermatology, 127, 2645-2655.
https://doi.org/10.1038/sj.jid.5700890
[39] Zhang, H.S. and Wang, S.Q. (2006) Salvianolic Acid B from Salvia miltiorrhiza Inhibits Tumor Necrosis Factor-Alpha (TNF-Alpha)-Induced MMP-2 Upregulation in Human Aortic Smooth Muscle Cells via Suppression of NAD(P)H Oxidase-Derived Reactive Oxygen Species. Journal of Molecular and Cellular Cardiology, 41, 138-148.
https://doi.org/10.1016/j.yjmcc.2006.03.007
[40] Redente, E.F., Keith, R.C., Janssen, W., et al. (2014) Tumor Necrosis Factor-Alpha Accelerates the Resolution of Established Pulmonary Fibrosis in Mice by Targeting Profibrotic Lung Macrophages. American Journal of Respiratory Cell and Molecular Biology, 50, 825-837.
https://doi.org/10.1165/rcmb.2013-0386OC
[41] Le, T.T., Karmouty-Quintana, H., Melicoff, E., et al. (2014) Blockade of IL-6 Trans Signaling Attenuates Pulmonary Fibrosis. The Journal of Immunology, 193, 3755-3768.
https://doi.org/10.4049/jimmunol.1302470
[42] Borcherding, F., Nitschke, M., Hundorfean, G., et al. (2010) The CD40-CD40L Pathway Contributes to the Proinflammatory Function of Intestinal Epithelial Cells in Inflammatory Bowel Disease. American Journal of Pathology, 176, 1816-1827.
https://doi.org/10.2353/ajpath.2010.090461
[43] Santilli, F., Basili, S., Ferroni, P., et al. (2007) CD40/CD40L System and Vascular Disease. Internal and Emergency Medicine, 2, 256-268.
https://doi.org/10.1007/s11739-007-0076-0
[44] Gillespie, E.F., Raychaudhuri, N., Papageorgiou, K.I., et al. (2012) Interleukin-6 Production in CD40-Engaged Fibrocytes in Thyroid-Associated Ophthalmopathy: Involvement of Akt and NF-kappaB. Investigative Ophthalmology & Visual Science, 53, 7746-7753.
https://doi.org/10.1167/iovs.12-9861
[45] Douglas, R.S., Mester, T., Ginter, A., et al. (2014) Thyrotropin Re-ceptor and CD40 Mediate Interleukin-8 Expression in Fibrocytes: Implications for Thyroid-Associated Ophthalmopathy (An American Ophthalmological Society thesis). Transactions of the American Ophthalmological Society, 112, 26-37.
[46] Faner, R., Rojas, M., Macnee, W., et al. (2012) Abnormal Lung Aging in Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine, 186, 306-313.
https://doi.org/10.1164/rccm.201202-0282PP
[47] Kinnula, V.L. and Crapo, J.D. (2003) Superoxide Dismutases in the Lung and Human Lung Diseases. American Journal of Respiratory and Critical Care Medicine, 167, 1600-1619.
https://doi.org/10.1164/rccm.200212-1479SO
[48] Jones, D.P. (2006) Extracellular Redox State: Refining the Definition of Oxidative Stress in Aging. Rejuvenation Research, 9, 169-181.
https://doi.org/10.1089/rej.2006.9.169
[49] Winterbourn, C.C. (2008) Reconciling the Chemistry and Biology of Reactive Oxygen Species. Nature Chemical Biology, 4, 278-286.
https://doi.org/10.1038/nchembio.85
[50] 胡玉洁, 董文杰. 氧化应激促进肺间质纤维化的机制[J]. 国际呼吸杂志, 2012, 8(32): 605-607.
[51] 杨丽, 吕晓东, 刘勇明, 等. 中医药防治肺纤维化氧化应激作用机制研究进展[J]. 世界中西医结合杂志, 2017, 12(3): 297-300.
[52] Kliment, C.R. and Oury, T.D. (2010) Oxidative Stress, Extracellular Matrix Targets, and Idiopathic Pulmonary Fibrosis. Free Radical Biology & Medicine, 49, 707-717.
https://doi.org/10.1016/j.freeradbiomed.2010.04.036
[53] Kamp, D.W., Graceffa, P., Pryor, W.A., et al. (1992) The Role of Free Radicals in Asbestos-Induced Diseases. Free Radical Biology & Medicine, 12, 293-315.
https://doi.org/10.1016/0891-5849(92)90117-Y
[54] Juul, K., Tybjaerg-Hansen, A., Mortensen, J., et al. (2005) Factor V Leiden Homozygosity, Dyspnea, and Reduced Pulmonary Function. Archives of Internal Medicine, 165, 2032-2036.
https://doi.org/10.1001/archinte.165.17.2032
[55] Sode, B.F., Dahl, M., Nielsen, S.F., et al. (2010) Venous Thromboembolism and Risk of Idiopathic Interstitial Pneumonia: A Nationwide Study. American Journal of Respiratory and Critical Care Medicine, 181, 1085-1092.
https://doi.org/10.1164/rccm.200912-1951OC
[56] Kotani, I., Sato, A., Hayakawa, H., et al. (1995) Increased Procoagulant and Antifibrinolytic Activities in the Lungs with Idiopathic Pulmonary Fibrosis. Thrombosis Research, 77, 493-504.
https://doi.org/10.1016/0049-3848(95)00025-9
[57] Imokawa, S., Sato, A., Hayakawa, H., et al. (1997) Tissue Factor Expression and Fibrin Deposition in the Lungs of Patients with Idiopathic Pulmonary Fibrosis and Systemic Sclerosis. American Journal of Respiratory and Critical Care Medicine, 156, 631-636.
https://doi.org/10.1164/ajrccm.156.2.9608094
[58] Wygrecka, M., Kwapiszewska, G., Jablonska, E., et al. (2011) Role of Protease-Activated Receptor-2 in Idiopathic Pulmonary Fibrosis. American Journal of Respiratory and Critical Care Medicine, 183, 1703-1714.
https://doi.org/10.1164/rccm.201009-1479OC