Chinese Journal of Tissue Engineering Research ›› 2013, Vol. 17 ›› Issue (5): 945-950.doi: 10.3969/j.issn.2095-4344.2013.05.027
Xu Jian-ji1, Zeng Zhong2, Chen Xi-hua1
Received:
2012-04-01
Revised:
2012-04-13
Online:
2013-01-29
Published:
2013-01-29
Contact:
Chen Xi-hua, Doctor, Department of Geneal Surgery, Cixi People’s Hospital, Cixi 315300, Zhejiang Province, China
zzong@medmail.com.cn
About author:
Xu Jian-ji★, Master, Department of General Surgery, Cixi People’s Hospital, Cixi 315300, Zhejiang Province, China
x1417@sina.com
CLC Number:
Xu Jian-ji, Zeng Zhong, Chen Xi-hua. Heme oxygenase-1 protects against ischemia-reperfusion injury following liver transplantation[J]. Chinese Journal of Tissue Engineering Research, 2013, 17(5): 945-950.
2.1 HO-1介绍 HO系统是生物体内催化血红素分解为胆绿素、一氧化碳和铁离子的关键限速酶[1],由Tenhunen等[2]于1986年首次发现存在于组织细胞微粒体中。迄今为止已经发现3种哺乳动物源的HO:在代谢降解含血红素蛋白的器官组织中的可诱导型 HO-1;脑、睾丸表达很高的非诱导型HO-2[3-4];类似HO-2却只有极低催化活性的HO-3[5]。HO-1和HO-2、HO-3有40%相似的氨基酸序列,而HO-2和HO-3有90%同源序列。HO-1是Wise等[6]最先在体外实验中发现的一种降解血红素的酶,命名为HO-1。Llesuy等[7]研究报道,HO-1可能具有细胞保护作用。近年的一些研究也显示,HO-1与其反应产物一样,具有抗氧化、抗炎症和抗凋亡等方面的作用,是一种潜在的具有保护细胞功能的酶[8]。尤其在器官移植中所起的保护作用更是受到国内外移植专家学者的重视。 HO-1为诱导型,其相对分子质量为32 000,又被称为热休克蛋白32(heat shock protein 32)[9]。人HO-1大约有233个氨基酸。许多因素可引起其活性及蛋白含量增加。包括金属离子、谷胱甘肽耗竭、细菌的脂多糖、低氧血症、溶血与缺血、炎症因子、放射和热应激、缺血再灌注损伤等,这些刺激的共同特点是能造成氧化应激。HO-1广泛存在于人体和动物体内,但在生理状态下,许多细胞低表达或测不出,仅在脾脏、肝脏中浓度较高,特别是在脾脏中浓度最高,约为肝脏的10倍[5]。HO-1基因位于人染色体22q12,具有4个内含子和5个外显子,目前的研究表明,HO-1基因表达的调控主要发生在转录水平,转录因子如氧化应激转录因子核因子κB和AP-1等调控HO-1基因激活。丝裂原蛋白激酶途径、蛋白激酶C途径、蛋白激酶A途径、蛋白激酶G途径、及蛋白磷酸化等信号途径参与HO-1的基因调节[10-12]。 2.2 HO-1及其产物的功能 HO-1催化血红素在体内降解为胆绿素、一氧化碳以及游离铁。胆绿素还能在哺乳动物体内被胆绿素还原酶还原成胆红素。一度认为,血红素的降解产物是有毒的废物[13],近来研究证明,HO-1及其降解产物在缺血再灌注损伤中具有细胞保护作用[14]。 胆绿素及其转化产物胆红素,一直被认为是有毒的代谢产物,如可引起新生儿黄疸。近年研究表明,它是体内一种具有细胞保护作用的抗氧化剂[15]。正常生理水平胆红素即可有效保护细胞膜被脂质过氧化,清除氧自由基对血管内皮细胞和平滑肌细胞的损害,其抗氧化能力优于维生素C和维生素E[16-18]。胆红素分子上的白蛋白的不对称性促使胆红素C10上的氢转化为活性氢离子,可与氧自由基结合形成加合物,直接清除氧自由基。抑制多不饱和脂肪酸在多室脂质体中的氧化作用来保护细胞免受氧化应激损伤。有学者观察到胆红素和胆绿素均可抑制感染过程中的补体反应,表明胆红素在一定程度上可抑制炎症反应。胆红素还能抑制具有免疫原性的氧化低密度脂蛋白产生,从而使细胞避免氧化低密度脂蛋白引起的补体活化和炎症反应带来的损伤。胆红素还可以抑制人蛋白激酶C活性,而蛋白激酶C介导氧化应激对血管细胞的作用,因此,胆红素可发挥非抗氧化特性的细胞保护作用。 一氧化碳可与机体内血红蛋白结合生成碳氧血红蛋白,使血液运输氧的能力发生障碍,一直被认为是对人体有毒的气体。直到20世纪90年代初,随着内源性一氧化氮生物学功能的进一步揭示,与一氧化氮功能类似,一氧化碳作为体内重要的信息分子才被人们所关注。哺乳动物体内一氧化碳绝大部分来源于血红素分解产生,小部分由氧化耦联的化学机制,即依赖NADPH的微粒体脂质过氧化产生。一氧化碳通过活化P38MAPK途径下调巨噬细胞源性促炎分子,使炎性分子白细胞介素10发挥抗炎作用,同时,活化P38MAPK途径来抑制CD95/FasL介导的肝细胞的凋亡和抑制血小板活化,并通过cGMP途径和P38MAPK途径舒张血管平滑肌,增加血流量而改善微循环[19]。一氧化碳还能抑制Ca离子进入细胞内,促进K离子向细胞内流动,抑制内皮素1、二十烷酸等血管活性物质的产生,从而发挥扩血管的作用。此外,一氧化碳尚可通过激活前列腺素环化酶和抑制单胺氧化酶的活性而发挥舒张血管效应[20]。 游离铁曾被认为是潜在的氧化分子,它可以与过氧化氢反应生成羟自由基,后者与膜磷脂中的非饱和脂肪酸反应生成脂质过氧化物,并进一步分解为多种自由基,引起组织损伤。现在研究证明,HO-1降解血红素产生的游离铁能上调铁蛋白的合成,限制游离铁参与Fenton反应,防止活性氧的产生[21]。铁蛋白发挥着清除氧自由基,减少活性氧的产生而具有抗氧化作用,并且作为游离铁的储存库,限制铁与过氧化氢反应,减少氧自由基的毒性作用。研究发现,游离铁对移植肝的内皮细胞和肝细胞均有抗凋亡作用。其机制可能是由HO-1介导调节的。当细胞过度表达HO-1时,血红素释放游离铁,铁蛋白水平随之升高,铁泵被激活,将大量铁离子泵出细胞外,保护细胞免于凋亡[22]。 游离血红素具有强大的催化氧化能力,使机体产生大量的氧自由基,造成细胞损害,同时又具有高度的亲脂性,能直接攻击细胞膜的脂质双层结构和细胞骨架等直接对细胞产生细胞毒作用。位于血管内皮细胞的细胞毒作用可以激活补体级联反应,促进血小板聚集,暴露内皮细胞下层基质。加之红细胞凝集,血管内微血栓的形成,造成组织的缺血再灌注损伤。HO能将体内的血红素降解为有益于拮抗损伤的胆绿素、一氧化碳、游离铁,对组织起到保护作用[23]。 2.3 移植肝缺血再灌注损伤的机制 缺血再灌注损伤是指组织器官由于缺血缺氧,与后期出现组织损伤,而液体复苏或侧支循环的建立等可使循环得以改善,但血供恢复后,使原有损伤加重。移植肝缺血再灌注损伤的发生机制尚未完全清楚,可能与以下因素有关: Kupffer细胞是肝窦周围间隙的长驻足巨噬细胞。移植肝经过较长时间保存后,肝窦内皮细胞失活,而肝内Kupffer细胞激活。激活后的kupffer细胞具有较强的吞噬能力,并能释放水溶性酶和多种炎症递质和细胞因子,如肿瘤坏死因子a、氧自由基、二十烷类、白细胞介素1和白细胞介素6等直接对内皮细胞和肝细胞产生损伤。当清除大鼠肝脏内的Kuppffer细胞后,在肝脏缺血再灌注后,关注也中的炎症因子如白细胞介素1被完全抑制[24]。也有研究认为Kupffer细胞在肝脏缺血再灌注损伤中具有保护作用。Kupffer细胞是肝脏中HO的主要来源,当清除Kupffer细胞后,大鼠肝脏再灌注初期胆红素分泌量明显下降,而转录酶却明显升高[25]。当然,Kupffer细胞在肝脏缺血再灌注损伤中的作用有待进一步研究明确。 移植肝再灌注后,由Kupffer细胞介导产生大量活性氧,血小板激活因子和许多细胞炎症因子。诱导肝内皮细胞、肝细胞和白细胞表达淋巴细胞功能相关抗原1,2,3,巨噬细胞抗原复合体1、细胞间黏附分子、内皮-白细胞黏附分子1和血管细胞黏附分子1,淋巴细胞功能相关抗原1、巨噬细胞抗原复合体1与配体细胞间黏附分子1结合,参与白细胞和肝窦内皮细胞的黏附,形成跨膜迁移黏附损伤肝细胞[26]。同样,内皮-白细胞黏附分子1使白细胞黏附于内皮细胞,VLA-4与VLAM-1结合,介导T淋巴细胞和自然杀伤细胞黏附于内皮细胞,对肝细胞产生毒性作用,发生跨膜迁移损害肝细胞。 由于肝脏微循环的紊乱和肝窦壁黏附的白细胞阻塞肝窦,移植肝出现“无复流”现象,是移植肝缺血再灌注损伤的重要原因。当肝脏发生缺血再灌注损伤时,首先受损的是内皮细胞,然后进一步损伤肝细胞。内皮细胞在肝脏缺血再灌注损伤时,表面的黏附分子表达明显增高,使中性粒细胞的聚集增强,缩血管因子的增强进一步影响血供,从而导致肝脏局部的继续坏死。 活性氧自由基在缺血再灌注损伤进程中起到重要作用。包括超氧化物自由基、过氧化氢氢氧根等,与再灌注后的复氧损伤有关,主要损伤肝脏的内皮细胞。损伤作用包括:引起细胞脂质过氧化和蛋白质的氧化修饰及蛋白质解体和DNA损伤[27];激活细胞膜表面磷脂酶A2,催化脂质分子产生血小板激活因子和白三烯,诱导白细胞和内皮细胞之间的黏附,导致微循环障碍;氧自由基还可使细胞内的线粒体大量损伤。因此,通过清除氧自由基可以减少缺血再灌注损伤,有效保护移植肝。 内皮素是血管内皮细胞分泌的肽类物质,具有较强的缩血管作用,缺血缺氧、氧自由基、肿瘤坏死因子a及内毒素都能诱导它的释放。一氧化氮是由血管内皮细胞、巨噬细胞、中性粒细胞等多种细胞分泌的介质,能舒张血管、抑制血小板聚集、抑制白细胞和内皮细胞黏附。研究证实,缺血再灌注期间,血浆一氧化氮水平明显下降,而内皮素水平逐渐增高两者呈负相关,且随着时间延长,两者相关性增强[28]。 2.4 HO-1对移植肝缺血再灌注损伤的保护作用 2.4.1 抗氧化作用 HO-1及其催化血红素分解的产物在缺血再灌注损伤中具有抗氧化作用。缺血时,线粒体受损,氧化磷酸化停止,ATP含量下降,肝组织以无氧酵解为主。在再灌注早期,肝脏对氧的要求远远超过实际需要。过多的氧被黄嘌呤氧化酶、细胞色素P450转化为具有损伤性的氧自由基。HO-1的氧化需要消耗3分子O2,因此,HO-1消耗氧分子在缺血再灌注损伤中通过减少氧自由基的产生间接地起到细胞保护作用。Zeng等[29]通过实验证明,HO-1过表达提高了肝组织抗氧化活性,明显减轻肝脏缺血再灌注损伤。 2.4.2 维持微循环 肝脏缺血及再灌注过程中,氧自由基和血小板激活因子等诱导白细胞和肝脏微血管内皮细胞中的黏附分子的表达,导致微血管内白细胞聚集、黏附,堵塞微循环,造成组织损伤。Amersi等[30]利用特制的体外灌流装置,分别在灌流液中补充一氧化碳平衡的空气和单纯补充空气(含体积分数为21%的O2)来观察一氧化碳对肝脏的保护作用。结果发现,一氧化碳组谷草转氨酶水平明显低于对照组。对照组灌流1 h出现肝窦和中央静脉充血合并广泛的小叶中心肿胀和坏死,而一氧化碳组肝脏结构正常,无肝窦和中央静脉充血和小叶中心肿胀、坏死。证实一氧化碳在应激下可以保护肝脏微循环。其原因可能为,一氧化碳活化P38MAPK途径来抑制CD95/FasL介导的肝细胞的凋亡和抑制血小板活化,并通过cGMP途径和P38MAPK途径舒张血管平滑肌,增加血流量而改善微循环。 2.4.3 调节细胞周期 缺血及再灌注都可引起细胞凋亡。研究证实,HO-1过表达可明显抑制肝脏缺血再灌注损伤中的细胞凋亡。Wolin等[31]报道了在内皮细胞培养中,HO-1通过一氧化碳介导P38有丝分裂原激活蛋白激酶途径来抑制细胞凋亡。长时间缺氧可引起血管重塑,大量血管平滑肌细胞增殖,大量细胞外基质在血管壁沉积。Duckers等[32]证实在体内和体外,HO-1表达都能明显抑制血管平滑肌细胞的增殖。在血管平滑肌细胞系中,一氧化碳尚可明显抑制其生长,在缺血再灌注损伤中起到保护作用[33]。 2.4.4 抗炎症作用 血红素降解和HO-1过表达可直接或间接的抑制炎症连锁反应。在激活的单核/巨噬细胞中产生的一氧化碳能够抑制致炎细胞因子肿瘤坏死因子a的分泌,并促进抗炎细胞因子白细胞介素10的分泌,起到防止缺血再灌注损伤的毒性作用[34]。一氧化碳和白细胞介素10都可以抑制致炎因子基因的表达,如肿瘤坏死因子a、粒-巨噬细胞集落刺激因子等。一氧化碳可单独发挥作用,而白细胞介素10发挥作用必须有HO-1的表达和一氧化碳的产生。白细胞介素10和HO-1形成一个正反馈循环,在这个循环中白细胞介素10诱导HO-1表达,反过来HO-1又诱导白细胞介素10表达。这一结果证明了HO-1和白细胞介素10在缺血再灌注损伤中具有抗炎保护作用。"
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