药学学报  2022, Vol. 57 Issue (6): 1614-1620 DOI: 10.16438/j.0513-4870.2022-0079 |
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铁死亡是近年发现的一种新型细胞死亡方式, 其在形态学和生化方面具有独特的特征[1-6]。气道上皮细胞的损伤和死亡是哮喘发病的核心机制[7]。因此, 保护气道上皮细胞以维持气道上皮的完整性是哮喘治疗的有效策略。流行病学显示, 小儿哮喘的发病率正逐年上升[8]。目前, 哮喘治疗的策略以激素控制为主, 而激素对重症哮喘疗效不理想。越来越多的研究表明, 铁死亡在哮喘发生发展中发挥重要作用。本文聚焦了气道上皮细胞铁死亡在哮喘中的作用, 并综述了相关的分子机制, 有望为哮喘治疗寻求新的靶点和策略。
1 哮喘哮喘是一种复杂的慢性气道炎性疾病, 与气道上皮细胞损伤、多种炎症细胞浸润及细胞因子的分泌密切相关[9]。其主要病理特征包含: 肺组织内的炎症浸润和气道重塑[10]。研究表明, 气道上皮细胞的损伤和死亡导致气道上皮完整性被破坏, 是诱导哮喘相关病理特征出现的始动因素。气道上皮细胞间通过紧密连接互相结合形成呼吸道, 是机体抵御过敏原、细菌等外来损伤的第一道防线。气道上皮细胞受损后, 导致血小板源生长因子(platelet-derived growth factor, PDGF)、转化生长因子(transforming growth factor, TGF)、血清内皮素-1 (serum endothelin-1, ET-1) 等因子的释放, 促进炎症反应的发生。此外, 受损的气道上皮细胞还释放转化生长因子β (transforming growth factor beta, TGF-β)、血管内皮生长因子(vascular endothelial growth factor, VEGF)、白介素-1β (interleukin-1β, IL-1β) 等因子, 导致气道上皮基底膜增厚, 气道上皮下纤维化、新生血管生成和平滑肌细胞增生, 最后导致气道重塑的发生。因气道重塑和气道上皮细胞损伤导致的神经末梢的裸露, 诱导了气道高反应性(airway hyper reactivity, AHR) 的发生[7, 11-14]。现有基于气道上皮细胞损伤与哮喘发病的机制研究, 并不能完全解释哮喘复杂的病理机制。越来越多的研究表明, 气道上皮细胞的铁死亡在哮喘中发挥至关重要的作用[15]。
2 铁死亡铁死亡是一种以细胞内铁积累为起点, 脂质过氧化、脂质过氧化物在胞内积累为关键节点, 细胞死亡为终点的程序性死亡方式[1]。铁死亡在形态学上与至今发现的其他类型细胞程序性死亡不同, 其在形态学上的特征主要是: 线粒体膜皱缩、破裂、嵴消失, 细胞体积缩小, 胞膜破裂, 胞核不固缩, 染色质不凝集[1, 2]。目前, 铁死亡相关的分子机制主要包括脂质过氧化物、铁累积和抗氧化系统失衡[16]。
3 哮喘与铁死亡的联系铁死亡除了调控肿瘤[17-21]、缺血再灌注损伤[22, 23]、急性肾损伤[24, 25]等多种疾病, 在哮喘的发生发展过程中也起着重要的作用[26, 27]。哮喘小鼠肺组织的细胞病理学特点与铁死亡的细胞形态特征存在高度相似性: 线粒体嵴减少, 外膜破裂、皱缩, 这提示哮喘与铁死亡之间可能存在着紧密的联系[28]。目前, 铁死亡与哮喘互作的研究主要聚焦在气道上皮细胞的铁死亡方面, 因此, 本文主要从脂质过氧化、铁累积、抗氧化系统失衡这3个角度, 阐述气道上皮细胞铁死亡诱导哮喘发病的分子机制, 旨在为哮喘相关研究提供借鉴。
3.1 脂质过氧化诱导的铁死亡与哮喘的关系 3.1.1 脂氧合酶在哮喘炎症反应中发挥重要作用脂质代谢异常导致氧化磷脂形成, 氧自由基积累, 从而诱导细胞发生铁死亡。而带有不稳定碳碳双键的多不饱和脂肪酸(polyunsaturated fatty acid, PUFA) 则更容易被氧化。被氧化的PUFA主要包括花生四烯酸(arachidonic acid, AA)、亚油酸和二十二碳六烯酸。当胞内的PUFA和氧自由基(oxygen-derived free radicals, OFR) 结合在一起, 经过一系列复杂反应后生成了脂质过氧化物(liquid phase oxidation, LPO)。随着LPO水平的升高, 机体细胞及生物膜发生氧化反应, 致使机体细胞的正常生理结构向病理状态转变——细胞结构的不可逆性改变和生物膜的物理性质的改变。机体发生炎症反应时, 体内的PUFA过氧化反应随之增强, LPO水平升高, 导致铁死亡的发生。同时, LPO能促进炎症因子的释放, 引发新一轮的炎症风暴[29]。在这个过程中, 脂氧合酶(lipoxidase, ALOX) 起着关键作用, 不仅使PUFA与OFR结合生成LPO, 还参与机体的炎症反应, 使哮喘的炎症风暴提升了一个等级[30]。
ALOX在脂质过氧化过程中扮演着最重要的角色。人类ALOX家族具有6个功能亚型(ALOX5、ALOX12、ALOX12B、ALOX15、ALOX15B和ALOXE3), 其中, 15-脂氧合酶1 (15-lipoxygenase-1, 15LO1) 是脂质过氧化过程中的关键酶之一, 在代谢花生四烯酸时, 将氧分子插入到多不饱和脂肪酸中形成氢过氧化二十碳四烯酸, 该产物继续被还原成15-羟基二十碳四烯酸(15-hydroxyeicosatetraenoic acid, 15-HETE)。白介素-13 (interleukin-13, IL-13) 是哮喘发生时由活化的Th2淋巴细胞大量产生的多效性细胞因子。研究表明, IL-13能促进人哮喘气道上皮细胞中15LO1的表达; 上调的15LO1导致15-HETE的合成水平升高, 并且15LO1和15-HETE的含量与哮喘严重程度呈正相关[26, 31]。黏糖蛋白5AC (mucin 5 subtype AC, MUC5AC) 是气道上皮细胞分泌黏液的主要成分, 15LO1及其主要代谢产物15-HETE-PE增强了IL-13诱导的MUC5AC的表达; 而抑制15LO1的表达, MUC5AC的分泌显著降低[32]。
在IL-13的刺激下, 气道上皮细胞中高表达的15LO1与磷脂酰乙醇胺结合蛋白1 (phosphatidylethanolamine binding protein-1, PEBP1) 结合后, 激活脂质过氧化, 生成能够同时激活铁死亡与自噬的15-羟基过氧二十烷四氢酸[15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine, 15-HpETE-PE][15, 33]。15LO1-PEBP1和自噬蛋白微管相关轻链3 (microtubule-associate protein 1 light chain 3, LC3) 发生相互作用: 15LO1与PEBP1结合后, 生成的15-HpETE-PE促进LC3的脂化, 且15LO1与PEBP1的竞争性结合解除了PEBP1对LC3脂化的抑制作用, 激活铁死亡与自噬[26]。另有研究表明, 自噬可以抑制铁死亡的发生[26, 34, 35]。通过调控气道上皮细胞中15LO1与PEBP1的作用, 可以调节铁死亡与自噬之间的平衡, 从而抑制线粒体损伤导致的线粒体DNA (mitochondrial DNA, mtDNA) 释放, 最终抑制炎症反应缓解哮喘[26]。此外, NO可通过抑制气道上皮细胞内15LOA与PEBP1的结合来抵御细胞发生脂质过氧化, 抑制气道上皮细胞发生铁死亡[34]。由此可见, 15LO1的特异性抑制剂可能是潜在的哮喘治疗药物。
3.1.2 ACSL4和LPCAT3在哮喘中的作用酰基辅酶A合成酶长链家族成员4 (acyl-CoA synthetase long-chain family member 4, ACSL4) 和溶血卵磷脂转酰酶3 (lysophosphatidyltransferase 3, LPCAT3) 分别在脂质合成和修饰中发挥作用。AA和辅酶A (coenzyme A, CoA) 在ACSL4作用下合成乙酰乙酰辅酶A (acetoacetyl coenzyme A, AA-CoA), 随后在LPCAT3的诱导下AA-CoA被修饰为花生四烯酸磷脂酰乙醇胺(arachidonic acid-phosphatidylethanolamines, AA-PE)。AA-PE可作为底物, 在15LOX的作用下发生脂质过氧化, 生成脂质过氧化物。脂质过氧化物的大量累积能够诱导铁死亡的发生[36-39]。相反, 敲除ACSL4和LPCAT3基因, 会降低脂质过氧化物相关底物的生成。因底物不足导致生成的脂质过氧化物的量大打折扣, 从而增强了细胞对铁死亡的抵抗力。在ACSL4和LPCAT3基因敲除的细胞中, 加入AA等脂质过氧化物生成所必需的底物, 能提高细胞对铁死亡的敏感性, 促进铁死亡的发生[40, 41]。ACSL4和LPCAT3在哮喘肺组织中高表达, 从而增加了脂质过氧化底物——脂肪酸的合成, 这些增加的底物在15LO1的作用下生成大量的LPO, 最终导致肺组织对铁死亡的敏感性增加, 促进了肺组织中炎症反应的发生, 加重了哮喘的症状, 提高了重症哮喘的发生风险(图 1)。
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Figure 1 The crosstalk between lipid peroxidation-induced ferroptosis and asthma. ① ACSL4 and LPCAT3 mediate lipid synthesis and remodeling. AA and CoA act as substrates to form AA-CoA in the presence of ACSL4. AA-CoA is subsequently modified to AA-PE in response to LPCAT3. ② Lipoxygenase plays an important role in the inflammatory response of asthma: under the induction of IL-13, lipoxygenase 15LO1 oxidizes AA-PE to 15-HETE. ③ 15-HETE binds to PEBP1 and generates LPO, which mediates lipid peroxidation of membrane phospholipids. The binding of PEBP1 to 15-HETE can be inhibited by NO.. When asthma occurs, the structure of airway epithelial cells is damaged, leading to the differentiation of airway epithelial cells to goblet cells and increased secretion of MUC5AC. In brief, lipid peroxidation induced by these pathways promotes the ferroptosis of airway epithelial cells, thereby aggravating the incidence of asthma. 15-HETE: 15-Hydroxyeicosatetraenoic acid; 15LO1: 15-Lipoxygenase-1; AA: Arachidonic acid; AA-CoA: Acetoacetyl coenzyme A; AA-PE: Arachidonic acid-phosphatidylethanolamines; ACSL4: Acyl-CoA synthetase long-chain family member 4; CoA: Coenzyme A; IL-13: Interleukin-13; LPCAT3: Lysophosphatidyltransferase 3; LPO: Liquid phase oxidation; NO.: Nitric oxide; MUC5AC: Mucin 5 subtype AC; PEBP1: Phosphatidylethanolamine binding protein-1 |
铁在线粒体呼吸、中间代谢、宿主防御和细胞信号传导等多种生理功能中发挥重要作用。生物体内的铁主要有Fe2+和Fe3+两种形态。细胞外Fe3+与转铁蛋白(transferrin, Tf) 结合, 通过细胞膜上的转铁蛋白受体(transferrin receptor, TFR) 转运进入细胞。Fe3+经过一系列作用被还原为机体可利用的Fe2+, 最后被传递至不稳定铁池内[42]。不稳定铁池内的Fe2+去向有: ①在胞质内直接被利用; ②转运进入铁代谢的主要枢纽——线粒体被利用; ③储存于胞质的铁蛋白(ferritin, Fn) 内; ④经铁转运蛋白1 (ferroportin-1, FPN-1) 运送出细胞。上述任何一个环节受到影响, 都会影响胞内的铁的载量。当胞内铁过载时, 过载的Fe2+就会在芬顿反应下催化脂质过氧化物及羟自由基的生成。生成的脂质过氧化物在胞内积累, 最终导致细胞发生铁死亡。同时, 在此过程中生成的自由基也会破坏胞内的蛋白质、核酸和脂质, 进一步促进铁死亡的发生[4]。
哮喘患者的气道上皮细胞中, 转铁蛋白受体1 (transferrin receptor 1, TFR1) 和转铁蛋白受体2 (transferrin receptor 2, TFR2) 的表达水平升高, 铁离子被TFR1和TFR2由气道微环境转运进气道上皮细胞, 导致铁离子在气道上皮细胞中的积累, 气道上皮细胞对铁死亡敏感性增加, 哮喘症状加重[43]。此外, 铁含量的增加会使细胞内发生芬顿反应并诱导铁死亡的发生。气道上皮细胞发生铁死亡后, 其细胞结构受损, 导致气道屏障被破坏, 从而诱发了气道重塑和气道高反应性, 并激发气道上皮细胞向杯状细胞分化, 促进黏液的分泌。另一方面, 气道上皮细胞胞内铁含量的增加, 促进IL-13的分泌, 从而诱导气道高反应性和气道重塑的发生。由此引发的气道重塑使得哮喘患者在哮喘发作期间发生气道感染的风险增加[44]。可见, 因铁离子累积诱导的气道上皮细胞铁死亡, 加重了哮喘相关症状, 诱发了轻中度哮喘向重度哮喘的转变。
铁蛋白重链1 (ferritin heavy polypeptide 1, FTH1) 是铁蛋白的组成成分之一, 具有氧化酶活性, 可将细胞内的Fe2+氧化为Fe3+。被氧化的Fe2+以Fe3+状态与铁蛋白结合并储存于铁蛋白中[45]。细胞内的FTH1表达水平下降, 导致储存于铁蛋白中的Fe3+含量下降, 胞内游离Fe2+含量增加, 最终促进了芬顿反应的发生[46]。白介素-6 (interleukin-6, IL-6) 已被证实在哮喘患者中高表达, 在BEAS-2B细胞中加入梯度浓度的IL-6, 细胞的活力会随IL-6浓度的升高而下降; 经IL-6处理的细胞中FTH1表达下降, 导致铁蛋白储存Fe3+的能力下降, 细胞内游离Fe2+累积, 最终促进芬顿反应的发生。向BEAS-2B细胞添加铁补充剂后, 细胞的活力下降。而给予铁死亡抑制剂ferrostatin-1 (Fer-1), 则使FTH1的表达水平升高, 细胞内铁蛋白储存Fe3+能力增强, 游离Fe2+水平下降, 细胞内脂质过氧化水平降低, 导致细胞对铁死亡的敏感性降低[47, 48]。可见, 炎症因子IL-6通过破坏气道上皮细胞的铁稳态来诱导气道上皮细胞发生铁死亡(图 2)。
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Figure 2 Accumulation of irons in airway epithelial cells aggravates the symptoms of asthma. ① Inflammatory factor IL-6 can destroy the iron homeostasis of airway epithelial cells, induce Fenton reaction, lead to lipid peroxidation of membrane phospholipids, and finally trigger ferroptosis of airway epithelial cells. Fe2+ accumulation-induced ferroptosis triggers airway remodeling and promotes the pathophysiological process of asthma. ② Ferroptosis inhibitor ferrostatin-1 (Fer-1) inhibits Fenton reaction and lipid peroxidation of membrane phospholipids by up-regulating the expression levels of FTH1. IL-6: Interleukin-6; FTH1: Ferritin heavy polypeptide 1 |
谷氨酸/胱氨酸转运体(glutamate/cystine transpoter, Xc-) 和谷胱甘肽过氧化物酶4 (glutathione peroxidase 4, GPX4) 抗氧化系统在铁死亡中发挥作用[16]。Xc-锚定在细胞膜上, 由溶质载体家族7成员11 (solute carrier family 7 member 11, SLC7A11) 和溶质载体家族3成员2 (solute carrier family 3 member 2, SLC3A2) 组成, 可将半胱氨酸转运进入细胞。被Xc-转运进入细胞的半胱氨酸再经过一系列的转化最终形成谷胱甘肽(glutathione, GSH)。GSH和GPX4是抗氧化系统的重要成员, 可将LPO还原为脂质醇, 从而抑制膜磷脂发生脂质过氧化[49]。
嗜酸性粒细胞和中性粒细胞在过敏原的刺激下分泌过氧化物酶和髓过氧化物酶, 在活性氧的作用下激活了氧化应激, 而抗氧化系统能抑制脂质过氧化物生成, 把脂质过氧化物还原为无毒的脂质醇[50-52]。抗氧化系统通过抑制脂质过氧化的发生, 对受到氧化应激损伤的气道上皮细胞起到保护。哮喘肺组织中GSH、GPX4的水平和SLC7A11的活性显著降低, 细胞内氧化与抗氧化体系失衡, 导致质膜多不饱和脂肪酸大量过氧化, 最终诱导了铁死亡的发生[28, 53-55]。在气道上皮细胞中, 15LO1与PEBP1结合后生成的产物15-羟基二十二碳四烯酸磷脂酰乙醇胺(15-HETE-phosphatidylethanolamine, 15-HETE-PE) 可通过消耗GSH和GPX4, 抑制SLC7A11的表达, 破坏气道上皮细胞中的GSH-GPX4抗氧化系统的平衡, 促进气道上皮细胞发生铁死亡。此外, 将LPO添加到GPX4失活的细胞中也会导致铁死亡[27] (图 3)。因此, 在哮喘的治疗过程中可以试图通过增加GSH和GPX4的水平, 达到降低哮喘患者靶器官和靶细胞对铁死亡的敏感性。
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Figure 3 Effects of antioxidant system imbalance on asthma. ① SLC7A11 and SLC3A2 comprise the Xc- system, which is responsible for transporting cysteine into cells. Cysteine goes through a series of reactions to form GSH, which together with GPX4 inhibit lipid peroxidation. ② LPO synthesized by 15LO1 and AA-PE leads to the inactivation of GPX4. Inactivating GPX4 leads to the weakening of its inhibition of lipid peroxidation, thus promoting lipid peroxidation of membrane phospholipids. GPX4: Glutathione peroxidase 4; SLC3A2: Solute carrier family 3 member 2; SLC7A11: Solute carrier family 7 member 11; Xc-: Glutamate/cystine transporter |
铁死亡自2012年首次被报道后就受到了极大的关注, 其分子机制的研究也愈发深入。气道上皮构成气道黏膜表面的保护屏障。气道上皮细胞的损伤和脱落是哮喘的重要病理学特征, 气道上皮损伤与AHR、气道慢性炎症和哮喘的反复发作有关。一方面, 哮喘的发生诱发了气道上皮细胞的铁死亡; 另一方面, 上皮细胞中脂质过氧化物累积、铁累积和抗氧化系统失衡也将促使其发生铁死亡, 由此引发的气道上皮细胞的损伤和功能失调是哮喘发病的始动因素。气道上皮细胞的死亡导致气道中神经末梢裸露, 气道对过敏原的敏感性升高, 气道发生重塑, 促使气道上皮细胞向杯状细胞分化, 黏液分泌增加, 哮喘原有的症状加重。本文以铁死亡与气道上皮细胞损伤之间的联系为切入点, 寻找缓解哮喘症状, 提高哮喘患者生活质量的新思路。铁死亡抑制剂中不少是中药, 如黄芩素[56]、天麻素[57]等, 利用好中药活性成分对铁死亡的抑制作用, 以及它们本身所特有的缓解哮喘的特点, 或许能让哮喘患者的生活质量得到大幅度的提高。已有研究证实, 针灸通过下调哮喘小鼠肺组织SLC3A2和ATP1A3的蛋白表达抑制铁死亡, 缓解哮喘症状[55]。基于铁死亡的分子机制寻求中药制剂及天然产物缓解哮喘症状、提高哮喘患者生存质量的治疗靶点, 可为寻求有效缓解哮喘症状的药物提供新的思路。目前, 有关气道上皮细胞铁死亡与哮喘的研究主要关注了脂氧合酶和炎症因子的互作, 而铁积累和抗氧化系统失衡与哮喘发病的机制探索还需更深入的研究。鉴于此, 除了15LO1之外, 探索以铁积累及抗氧化系统失衡为靶点的新型治疗药物, 有望为治疗激素耐药性哮喘提供新的策略。此外, 气道上皮细胞铁死亡与哮喘现有的研究大多集中在小鼠和细胞模型中, 相关临床研究还未兴起, 气道上皮细胞铁死亡在哮喘发病中的临床价值还未被挖掘。未来, 研究者可以从临床哮喘患者入手, 探寻气道上皮细胞铁死亡与哮喘发病及预后的关系; 阐明其具体的分子调控机制; 检验具有铁死亡抑制活性的中药制剂及天然产物在临床治疗中的有效性; 为哮喘相关病理机制的认识和临床诊治提供有价值的科学依据。
作者贡献: 陈雪梅是综述的主要撰写人, 完成相关文献资料的收集和分析及论文初稿的写作; 梁娟、宋秀玲、刘小花、薛楚鹏参与文献资料的分析、整理; 黄宇戈参与论文的修订; 李文是项目的构思者及负责人, 指导论文写作和修改。全体作者都阅读并同意最终的文本。
利益冲突: 无利益冲突。
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