Chinese Journal of Tissue Engineering Research ›› 2024, Vol. 28 ›› Issue (11): 1743-1748.doi: 10.12307/2024.237
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Zeng Jiaxu1, He Qi1, Chen Bohao1, Li Miao1, Li Shaocong1, Yang Junzheng1, Pan Zhaofeng1, Wang Haibin1, 2
Received:
2023-03-02
Accepted:
2023-04-06
Online:
2024-04-18
Published:
2023-07-27
Contact:
Wang Haibin, MD, Chief physician, First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China; First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
About author:
Zeng Jiaxu, First Clinical Medicine School, Guangzhou University of Chinese Medicine, Guangzhou 510405, Guangdong Province, China
Supported by:
CLC Number:
Zeng Jiaxu, He Qi, Chen Bohao, Li Miao, Li Shaocong, Yang Junzheng, Pan Zhaofeng, Wang Haibin. An insight into the mechanism of iron overload in knee osteoarthritis under the theory of blood stasis[J]. Chinese Journal of Tissue Engineering Research, 2024, 28(11): 1743-1748.
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2.1 膝骨关节炎的中医认识 膝骨关节炎在现代中医学中多以“痹症”或“骨痹”论治。广义的痹,多指病邪侵袭机体,阻滞机体气血运行,使其运行不畅、脏腑气机不利而导致的各种病证,如喉痹、五体痹、食痹等;狭义的痹,则强调人体的肢体、关节的疼痛及屈伸不利等病变[15]。对于痹症,《素问·痹论》曰:“风寒湿三气杂至,合而为痹也”,认为风、寒、湿三气的外邪是痹症发生的根本原因。所谓痹症,就是“各以其时重感于风寒湿之气也”,西汉《中藏经·论痹》则提出:“痹者,闭也。五脏六腑,感于邪气,乱于真气,闭而不仁,故曰痹。”认为痹症与外感之邪气、内伤之脏腑虚衰均有关联[16-17]。又见《灵枢·本脏》曰:“经脉者,所以行血气而营阴阳,濡筋骨,利关节者也……血和则经脉流行,利关节者也……血和则经脉流行、营复阴阳、筋骨劲强、关节清利矣”,指出关节的痹症还与气血运行的状态有关,气血运行流畅则关节清利[18]。基于以上认识,现代学界大致将膝骨关节炎分为气滞血瘀、风寒湿痹、肝肾亏虚、湿热蕴结、脾阳亏虚等证[19-20]。并且气血运行的流畅不仅在经典古籍的论述中至关重要,临床上,气滞血瘀型的膝骨关节炎在诸多证型的膝骨关节炎中发病率最高[21]。这昭示着在膝骨关节炎的临床诊断以及治疗方案的选择上,有必要以气血的运行作为出发点。 气血运行的异常与脏腑的虚损有关。脾为气血生化之源、统摄血脉、脾胃虚弱、则气血生化乏源、推动统摄无力[22],“血瘀”与痰湿搏结,进而导致膝骨关节炎的发生,脾虚致瘀是膝骨关节炎发病的重要原因;风寒湿邪气乘虚侵袭人体后,痹阻脉络,影响血行,血滞停留为瘀,与痰浊相结,留滞于筋骨关节也可发生膝骨关节炎[23]。而现代医学理论则发现:寒冷潮湿环境、过度疲劳及各种原因导致的局部血液循环障碍等都是膝骨关节炎的危险因素,提示风寒湿凝滞脉络,或过劳而气虚无力推动血行等因素也是膝骨关节炎的重要影响因素[24],而气滞血瘀型的膝骨关节炎在诸多证型的膝骨关节炎中发病率最高[21]。进一步证明瘀血是膝骨关节炎中重要的致病因素[25]。因此文章认为,“血瘀”是致痹的重要因素,与膝骨关节炎具有密切关系。 2.2 铁超载与“血瘀”具有密切的联系 2.2.1 “血瘀”的理论基础 血瘀理论起源于《黄帝内经》,《素问·痈疽》曰:“寒邪客于经络之中则血泣,血泣则不通”,《素问·调经论》曰:“血气未并,五藏安定,孙络水溢,则经有留血”,《灵枢·天年》曰:“六十岁,心气始衰,苦忧悲,血气懈惰,故好卧”,提出外感的邪气,人体的衰老,心气的虚衰均是导致血留而不行的原因。东汉张仲景在《金匮要略》中提出:“病人胸满……但欲漱水不欲咽,无寒热,脉微大来迟。腹不满,其人言我满,为有瘀血。”“病者如热状……此为阴伏,是瘀血也”,则首次提出了瘀血概念。而“瘀血”与“血瘀”,又有一定区别,瘀血即“瘀之血”,指的是狭义之瘀,是血液停留于体内,不能及时排出消散形成的“有形之瘀”;血瘀即“血之瘀”,指的是广义之瘀,是痰浊、食滞等各种因素导致血行动力不足,血行不畅而形成的“无形之瘀”[26-27]。王道明[28]则认为,“血瘀”与“瘀血”分别代表着疾病在发生发展过程中不同的病变程度,人体气虚无力推动血液运行、气滞不能行血、阴虚煎熬血液等会导致血行缓慢以及血液黏稠等一系列血液流变学改变,即是“血瘀”的病理状态;当病情由浅入深,瘀结凝滞,留滞于脉道中,则发为“瘀血”。综上,“血瘀”是一类逐渐发展的病理状态,内外因素导致的“血瘀”状态若无法及时治疗,便会导致瘀血等一系列病理产物的生成。 在诸多医家研究者共同的研究下,血瘀理论获得了长足的发展,活血化瘀类的方剂如桃红四物汤在加减后也能广泛地运用于骨关节炎、骨质疏松、股骨头坏死等骨科疾病[29-31];但是由于人体“血瘀”状态以及活血化瘀类药物影响骨病进程的相关机制仍不明确。因此,进一步探究中医药影响人体“血瘀”状态的机制,为临床提供进一步的指导是十分重要的。 2.2.2 “血瘀”与铁超载的关系 铁超载与骨骼系统、心血管等多系统疾病相关,并与“血瘀”状态呈强烈的关联。铁在生理状态下常保持平衡,膳食中的铁主要经过肠道吸收,并形成铁-转铁蛋白复合物被细胞利用,多余的铁则排出体外,此平衡受到肝细胞产生的铁调素调节[32]。然而,当患者患有遗传性的血色素沉着相关基因突变或血幼素、铁调素抗菌肽、转铁蛋白受体2突变和铁转运蛋白SLC40A1等基因突变时,铁代谢的异常常会引起肝脏、心脏、骨骼等多处组织的铁超载[33-34];而外源性的铁摄入过量如血液疾病如骨髓增生异常综合征、地中海贫血、血红蛋白病等引起的频繁输血或膳食铁过量,则会引起继发性的铁超载[35]。 当人体内铁代谢紊乱,铁过多积累时,会催化有毒自由基的形成,引起细胞氧化应激损伤,引起细胞的异常凋亡。当血铁含量超过转铁蛋白的铁结合能力,便会形成“非转铁蛋白结合铁”。非转铁蛋白结合铁的一小部分称为不稳定血浆铁。不稳定血浆铁具有氧化还原活性和螯合性。它可以穿过质膜,特别容易被各种细胞吸收,例如通过电压门控钙通道被心肌细胞吸收[36]。而当心肌细胞发生铁超载时,心肌细胞的功能受损,便会导致心力衰竭,引起人体血行动力的不足,提示着铁超载发生与血液的病理状态改变有着并行不悖的关系。 “血瘀”是人体生理、生化和免疫等各系统共同作用导致的病理状态,与各类疾病都有密切的关系。铁超载症状中:面部紫黑、肌肤甲错、肢体麻木及舌质紫暗等特点与中医“血瘀证”的临床症状相类似[37],提示着两者在症状上的关联。血液是向人体各组织输送营养物质的载体,对人体的新陈代谢,损伤修复等功能起重要作用,“血瘀”表现出的血液流变学失常、凝血-纤溶系统失衡、血管内皮功能障碍等方面的病理性表现极大地影响了人体各组织细胞的生长凋亡[38],其中,血液流变学涵盖了如红细胞流变性、血小板流变性、白细胞流变性以及血液血浆内微观分子间相互作用的微观上的血液流变性质[39]。铁超载时,通过血清铁蛋白检测可发现,人体内的铁蛋白含量上升,血液黏度也随之上升[14], 血液流变学与“血瘀”类似,进一步印证了两者的强相关性。基于以上理论依据指出的关联性,SAEIDNIA等[40]利用破血行气药物姜黄的提取物姜黄素进行了临床随机对照试验,发现姜黄素可有效减轻中间型 β-地中海贫血患者的铁过载,提示了“血瘀”理论治疗铁超载在临床的可用性。无独有偶,益母草作为一味活血调经的要药,其主要提取物益母草碱也被发现能够抑制炎症转录因子核转录因子κB的核转位并下调其下游促炎细胞因子——肿瘤坏死因子α 和白细胞介素1 β,进一步缓解核转录因子E2相关因子2(nuclear factor E2-related factor 2,NRF2)和核转录因子 B信号介导的铁超载肝毒性[41],也能够通过激活Nrf2核转位抵抗氧化应激损伤和抑制Toll 样受体 4(Toll-like receptor 4,TLR4)/核转录因子κB通路介导的炎症基因表达,对大鼠缺血性急性肾损伤起保护作用[42]。有研究在利用白藜芦醇协同姜黄素治疗接受血液透析的慢性肾病铁超载患者的肌肉以及骨量流失时,发现患者的铁蛋白含量呈降低表现,而白藜芦醇以及姜黄素分别在活血中药虎杖以及郁金中具有丰富的含量[43]。赵朋敏等[44]使用三七制剂血塞通治疗继发性铁超载患者,发现血塞通也能够有效降低铁蛋白的含量。“活血法”及“补肾活血法”治疗慢性再生性贫血合并输血性铁超载的患者,也取得了良好的效果[45]。马娟娟[46]使用活血祛瘀的丹参注射液治疗铁超载小鼠,发现丹参能够显著降低铁超载小鼠肝脏内的铁沉积,同时铁超载导致的脂质过氧化也受到抑制,均提示着“血瘀”理论治疗铁超载的优越性。 综上所述,铁超载是血液疾病的重要因素,在生物学上是“血瘀”状态出现的原因之一,“血瘀”与铁超载具有强烈的相似性及关联性,活血化瘀类药物也对铁超载具有一定的治疗作用,提示着“血瘀”理论治疗铁超载相关疾病的可行性。 2.3 铁超载在膝骨关节炎发展中占重要地位 2.3.1 膝骨关节炎的发病常伴随铁超载的发生 铁超载是因机体内铁代谢调节紊乱,导致体内铁离子异常堆积,进而导致体内脏器的结构和功能损害的病理状态。临床多通过血清铁蛋白检测进行诊断,一般情况下,当血清铁蛋白多次检测均高于1 000 μg/L时,能够认为患者确诊铁超载[47]。当人体细胞发生铁超载时,则易发生芬顿(fenton)反应,造成人体的过氧化损伤。且铁的代谢紊乱也与炎症因子的增加乃至炎症的发生息息相关[48],如体内免疫调节因子如白细胞介素1,5,6,7等促炎性因子的含量上升。其中,白细胞介素1,6能够通过诱导铁调素的生成从而调节铁的转运[49];铁超载也会导致膝骨关节炎豚鼠体内白细胞介素6基因相对增加,而白细胞介素6蛋白可调节铁调素的表达,铁调素又会促进转铁蛋白的降解,加重了细胞的铁负载[50]。因此,从细胞分子层面,分别探究铁超载对关节软骨及软骨下骨的相关机制是至关重要的。 2.3.2 铁超载在膝骨关节炎进展中对骨组织的影响 膝骨关节炎中膝关节创伤或机械超载导致微出血或滑膜炎下的滑膜液渗出会导致关节的铁积累[51],影响人体关节内的骨组织如软骨、软骨下骨及骨髓间充质干细胞等。 人体关节中的软骨是一类以支持作用为主的结缔组织,主要支架由Ⅱ型胶原蛋白构成[4]。研究发现,白细胞介素1β和枸橼酸铁铵(Ferric ammonium citrate,FAC)干预软骨细胞时,两者均可诱导软骨细胞中活性氧、脂质过氧化物的积累和铁死亡相关蛋白的水平上升,且铁死亡诱导剂能够促进软骨细胞基质金属蛋白酶13(matrix metalloproteinase 13,MMP13)的表达,抑制Ⅱ型胶原的表达 [52]。而活性氧上升也能够影响BCL2关联X蛋白(Bcl2 Associated X ,Bax)、B淋巴细胞瘤-2(B-cell lymphoma-2,Bcl-2)等的表达,进而影响线粒体的活性,引起软骨细胞凋亡[53]。这些发现提示了铁超载对膝骨关节炎发展中软骨的退行性改变起重要作用,这些改变主要与炎症因子增加导致的金属离子转运蛋白异常引起。 软骨下骨的骨小梁在正常关节中起着减震、支持和为关节软骨提供营养和新陈代谢的作用[54]。铁超载能够促进破骨细胞的分化、激活以及骨吸收效应。转铁蛋白受体1(transferrin receptor protein 1,TFR1)介导的铁摄取能够促进破骨细胞分化和骨吸收活性,这一效应与诱导线粒体呼吸、活性氧的产生和过氧化物酶体增殖物激活受体 γ辅激活因子1β(peroxisome proliferator-activated receptor-gamma coactivator 1β,Ppargc1b)转录有关[55];铁离子也能够催化活性氧的形成,并通过影响RAW264.7细胞和骨髓源性巨噬细胞中的核转录因子κB受体活化因子配体(receptor activator of nuclear factor-κB ligand,RANKL)诱导的破骨细胞的形成[56]。除此之外,外源性引起的铁超载阻断了Runt相关转录因子2(Runt related transcription factor 2,Runx2)、骨钙素和碱性磷酸酶的上调,选择性地抑制骨髓间充质干细胞的成骨分化[57];对于成骨细胞,过量铁下调了成熟人成骨细胞Runx2及其靶蛋白骨钙素和碱性磷酸酶的表达,这种作用伴随着成骨细胞细胞外基质矿化的减少,且铁介导的成骨细胞活性的降低和以及细胞外基质矿化的抑制是由铁诱导的铁蛋白及其铁氧化物酶活性上调导致的[58]。总而言之,以上研究表明,铁超载可以通过促进破骨细胞的化生和增加破骨细胞的活性来促进骨吸收,提示铁超载加速了膝骨关节炎早期骨质的流失,促进了膝骨关节炎的发展,见表1。"
2.4 “血瘀”减轻铁超载以治疗膝骨关节炎的理论基础 2.4.1 膝骨关节炎与血瘀的辩证关系 “血瘀”而致人体骨骼关节处脉道不通,关节失于濡养是膝骨关节炎发生发展的一大因素[59]。历代医家对“骨痹”的临床治疗多为“实则泻之,虚则补之”,而“气为血帅,血为气母”“气行则血行,气虚则血虚”,血行不畅,久而成瘀[60],且《素问·举痛论》则曰:“不通则痛”“不荣则痛”“血瘀”也会加重膝骨关节炎的疼痛。除此之外,瘀血阻滞血络,妨碍新血的生成,也会进一步加重血瘀的程度,“旧瘀不去,新血不生”,新血不生则关节失养,导致膝骨关节炎的发生及进一步发展[61]。《景岳全书》曰:“盖痹者闭也,以血气为邪所闭,不得通行而病也。”国医大师周仲瑛极为重视血瘀在膝骨关节炎发病过程中的影响,强调使用鸡血藤、川芎等药充养血脉并活血祛瘀,使旧血去而新血生,营血调畅而“血行风自灭”[62]。黄磊等[63]用身痛逐瘀汤敷贴治疗气滞血瘀型膝骨关节炎,疗效显著;邱建清等[64]对气滞血瘀型膝骨关节炎患者的血海、足三里、阴陵泉及阳陵泉等穴位进行针刺配合拔罐治疗,也取得了良好的效果。在分子生物学方面,杨帆等[65]对兔进行膝骨关节炎造模,并用补肾活血方进行治疗,发现该方可通过调节转化生长因子β/骨形成蛋白通路,进而调节转化生长因子β1、骨形成蛋白4和骨形成蛋白7的分泌以保护受损软骨细胞,减缓膝骨关节炎的进展;也有研究表明,白细胞介素17能够分泌到胞外,激活核转录因子κB分子,诱导白细胞介素6分泌[66],进而激活血小板活化因子。白细胞介素6和血小板活化因子均为导致瘀血状态的重要因子[67-68],且对膝骨关节炎的发展也起重要作用[69]。 2.4.2 “血瘀”理论减轻铁超载进而治疗膝骨关节炎 在铁超载的治疗方面,现代铁螯合剂疗法种类少且费用高,不良反应也较大,这导致了患者的依从性较差,难以满足临床的需要。中医“血瘀”理论凭其先进的疾病理解以及治疗手段,在铁超载的治疗上有较大的优势,并在临床上取得较好的疗效。仇如意等[37]将中医补肾活血法与常规铁螯合剂疗法治疗慢性再生障碍性贫血合并输血相关铁超载的临床效果相比较,发现补肾活血法可能通过调节白细胞介素6、白细胞介素10对该类疾病起治疗作用,提示从“血瘀”论治铁超载具有一定的效果。THEPHINLAP等[70]将活血类中药提取物姜黄素与去铁胺联合用药,发现非转铁蛋白结合铁(non-transferrin-bound-iron,NTBI)清除率提高,并能够发挥铁螯合以及抗氧化作用。黄芪的主要活性成分黄芪甲苷则能够通过影响铁转运相关的蛋白质[二价金属转运蛋白1(divalentmetaltransporter 1,DMT1)和TFR1等],并抑制丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)以及核转录因子κB的激活进而减缓铁超载导致的细胞铁死亡[71]。而黄芪多糖处理骨髓间充质干细胞时,能够抑制线粒体活性氧积累,可显著抑制FAC诱导的铁超载引起的同源框蛋白(NANOG)、性别决定区Y框蛋白2(Sex Determining Region Y,Sox2)和八聚体结合转录因子(4 octamer-binding transcription factor 4,Oct4)下调以及骨髓间充质干细胞凋亡、衰老、增殖和多能性降低[72]。 在理论的应用方面,有研究者联想到黄芪在《日华子本草》的描述:“黄芪助气壮筋骨、长肉补血、破癖、治凛病、瘦赘、肠风、血崩、带下……产前后一切病,月候不匀,消渴,痰嗽” [73],并翻阅典籍发现黄芪补气通滞的特性,针对黄芪提取物鹰嘴豆素A进行了相关研究,研究显示铁超载时铁输入蛋白TFR1表达上升、铁外流蛋白膜铁转运蛋白(ferroportin,FPN)表达减少,表明铁稳态和铁转运蛋白参与了膝骨关节炎发病机制。而NRF2是挽救铁超载中软骨损伤的重要因子,其能够靶向增加血红素加氧酶 1[74],调控谷胱甘肽过氧化酶4(glutathione peroxidase 4,GPX4)[73]挽救软骨铁死亡。最终得出结论,鹰嘴豆素A可通过抑制 TFR1 和促进 FPN 直接降低细胞内铁浓度,但也靶向 NRF2/胱氨酸-谷氨酸反向转运蛋白 (System xc-)/GPX4 信号通路以清除活性氧,挽救线粒体膜电位的下降并防止脂质过氧化,表明了益气活血类药物可能在膝骨关节炎进展过程中调节铁稳态。而中药骨碎补补肾活血的特性,也推动了对其提取物柚皮素的相关研究,发现柚皮素减轻了FAC和白细胞介素1β 共培养引起的细胞活力、细胞凋亡和线粒体膜电位损伤,增加了丙二醛水平,降低了MMP3、MMP13 和Bax,并恢复了Ⅱ型胶原蛋白的表达,并且减轻了铁超载引起的软骨细胞中活性氧和脂肪活性氧 的积累,并上调了抗氧化基因NRF2和血红素加氧酶 1[75]。在动物实验中,柚皮素减少了膝骨关节炎小鼠的滑膜炎并减轻了软骨损伤和软骨下骨增殖,有效地验证了“血瘀”理论治疗铁超载的可行性。文章总结了活血药物缓解铁超载治疗膝骨关节炎机制,见图3。"
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