沙利度胺抑制兔实验性腹主动脉瘤生长的研究
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摘要
背景
腹主动脉瘤(abdominal aortic aneurysm, AAA)是腹主动脉的永久性、局限性扩张性疾病,多见于老年男性,男女发病率之比为3.5：1,据统计,在65～80岁的男性人群中,AAA的患病率达4-8%。AAA年新发病率为0.4-0.67%。在美国,每年有约150,000名患者因AAA住院,超过30,000人行AAA开腹手术治疗,有约15,000人最终死于AAA破裂。随着年龄增长,AAA发病率呈逐渐增高趋势,瘤体年扩张率亦加快,一旦发生破裂,死亡率可达90%。AAA俨然己成为具有高致死率、严重威胁人类健康的主要疾病之一。
AAA的高致死率主要缘于AAA的破裂。AAA直径是预测其破裂风险和决定治疗方式的主要指标。一般的,对于直径之5.5cm的AAA,其破裂的风险明显增加,动脉瘤切除人工血管置换和腔内支架隔绝术是防止AAA破裂的有效途径。然而,对于直径<5.5cm、瘤体扩张缓慢、近期破裂的风险很低的无症状小AAA,建议定期随访观察。相关的临床研究结果表明,对于小AAA,早期手术干预和定期随访观察两组患者的长期生存率并无明显差异,即早期手术并不能明显改善其长期生存率,这一结果也证实对于小AAA而言,定期随访观察是相对安全的,建议可在瘤体直径扩张率≥1cm/年或直径达到5.5cm时再行常规开腹或腔内修复术。但是,AAA的扩张是不可逆的,其一旦形成必然进行性增大,如果等到瘤体增大濒临破裂或出现症状再手术则随着患者年龄增大、全身状况进一步减退,手术治疗风险将数倍于早期治疗。显然,对于绝大多数小AAA患者,这种基于单纯“观察等待”基础上的策略是不够的,寻求一种更为积极的、无创的方法抑制甚或逆转动脉瘤扩张、防止其破裂或降低破裂风险或许更有意义。
AAA是遗传、环境、生物化学等多因素共同作用的结果,动脉粥样硬化、感染、炎症性疾病、胶原及弹性蛋白遗传缺陷、蛋白酶活性增强或抑制作用减弱以及机械性因素等,都有导致AAA的可能。各种因素导致血管壁受损,免疫反应被激活,引起局部炎症细胞浸润、炎症递质及各种蛋白水解酶异常表达与活化,进而导致动脉中膜弹力蛋白降解、胶原纤维代谢失衡、血管平滑肌细胞凋亡,最终动脉壁失去弹性,不能耐受血流冲击而进行性扩张形成动脉瘤。局部动脉瘤壁慢性炎症、细胞外基质(ECM)降解和重构、血管平滑肌细胞凋亡以及新生血管生成是腹主动脉瘤的主要病理学特征,尤其是以巨噬细胞、淋巴细胞为主的透壁性炎症细胞浸润与腹主动脉瘤的扩张成正相关。其一,浸润的炎性细胞可分泌大量的基质金属蛋白酶(MMPs)和其他蛋白水解酶,引起主动脉壁弹力蛋白和胶原纤维等结构性蛋白的降解,削弱动脉瘤壁、继发附壁血栓形成进而导致动脉瘤进展；其二,炎性细胞在瘤壁中分泌如肿瘤坏死因子-βα(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、干扰素-γ(IFN-γ)等多种炎性细胞因子,进一步促进炎症反应,加重动脉瘤的进展。动脉中层新生血管形成和血管平滑肌细胞减少也是腹主动脉瘤的重要特征。瘤腔内的附壁血栓可引起内膜组织细胞缺氧,进而诱发新生血管形成和炎症。血栓内的炎症细胞也可以释放诸如MMP-9、尿激酶型纤溶酶原激活剂等活性蛋白水解酶。
AAA形成及扩张机制的逐步阐明为应用药物来延缓、阻止甚至逆转动脉瘤的病理学进程提供了理论依据,即理论上通过药物抑制动脉壁炎症、新生血管生成以及调节免疫等方法可以抑制AAA的扩张。我们期待药物干预能为小AAA的稳定提供有效的治疗。而相对于开发新药,研究可能抑制AAA进程的现行一线临床药物的可行性可能更强。目前国外学者已经开展并证实对AAA形成有抑制作用的药物包括他汀类药物、四环素类、血管紧张素转化酶抑制剂、血管紧张素Ⅱ受体拮抗剂、免疫抑制剂、非甾体类抗炎药、核因子KB(NF-κB)抑制剂及c-jun氨基末端激酶(JNK)抑制剂等。
沙利度胺又名酞胺哌啶酮,最初作为镇静剂治疗妊娠呕吐,后因发现有明显的致畸作用(婴儿海豹肢)而被禁用。然而,各国学者对沙利度胺的研究从未因此停滞。近年来发现沙利度胺具有显著的抗炎、抗血管生成及免疫调节等作用而重新被应用于临床,用于麻风结节性红斑、系统性红斑狼疮、多发性骨髓瘤、类风湿性关节炎、白塞氏病等的治疗并显示出特有的疗效。最近研究表明,沙利度胺对大鼠颈动脉球囊损伤后新生内膜的增生及兔动脉粥样硬化形成有明显抑制,其机制可能主要与其下调TNF-α的表达有关。
基于炎症、免疫机制在AAA形成、扩张过程中的重要作用及沙利度胺的抗炎、抗血管生成、免疫调节等药理学作用,沙利度胺对AAA生长是否有抑制作用目前国内外均未见有关研究。推测沙利度胺可能通过其抗炎、免疫调节及抗血管生成作用在AAA的治疗中亦起重要作用。
目的
建立兔肾下AAA模型,就沙利度胺对AAA生长的影响从大体形态、影像学、组织病理学、分子生物学等方面进行全面、动态观察,研究沙利度胺对AAA的扩张是否有抑制作用,在此基础上进一步阐释AAA的发病机制,为AAA的临床药物治疗提供参考。
方法
选取健康雄性新西兰白兔(体重2.5-3.0kg),采用猪胰Ⅰ型弹力蛋白酶灌注肾下腹主动脉建立兔AAA模型,术后1周对手术兔行腹主动脉超声检查,了解成瘤情况,测量灌注段最大内径,以灌注段腹主动脉扩张超过其近端正常腹主动脉直径的50%作为造模成功标准,计算扩张率及造模成功率。为研究沙利度胺对腹主动脉瘤生长的影响,术后1周时超声检查确认造模成功的兔15只,单盲、随机分为三组,即沙利度胺治疗组(AAA/Thd,n=5)和模型对照组(AAA/Con,n=5),于术后1周始,每天一次分别给予胃灌注沙利度胺生理盐水悬液(100mg/kg/day与5m1生理盐水混匀)和生理盐水(5ml/只/天),直至术后4周；其余5只术后1周时再次手术,以采集标本作为药物干预前的基础对照。另取未行手术造模的兔5只,于常规饲养1周后采集标本作为实验正常对照。各组兔于术前及术后1周、2周、4周先后行多普勒超声检查,评价比较腹主动脉术后扩张情况,于术后1周、4周时同时行腹主动脉造影,进一步评价AAA扩张情况。标本采集前于生理压力下测量、记录腹主动脉最大外径。采集的腹主动脉标本分成两份,一份分割后立即置于4%多聚甲醛溶液中固定,石蜡包埋用于组织病理学研究,另一份速冻于-80℃低温冰箱备用于Western Blot分析。术前及术后1周、4周时分组白兔耳缘静脉采集静脉血2ml,离心(3000转／分钟x5min,4℃)后取上清液置于-20℃冰箱保存备用。采用苏木素-伊红(HE)染色和弹力纤维EVG染色分别评价沙利度胺治疗前后动脉瘤壁炎性细胞浸润、管腔化微血管密度变化及弹力纤维降解情况。采用免疫组化、Western blot方法对组织标本中TNF-α、MMP-9、VEGF等炎性细胞因子的表达进行定性和定量研究,分析比较沙利度胺对其表达的影响。采用ELISA法研究沙利度胺对循环促炎细胞因子TNF-α、IL-1β的影响。所有计量数据以均数士标准差表示,应用SPSS13.0统计软件处理数据,采用单因素方差分析和t检验进行统计学分析,P<0.05判定差异的显著性。
结果
1.本课题应用肾下腹主动脉弹力蛋白酶加压灌注法成功建立兔AAA实验模型,18只兔分批建模,术后1周内死亡2只,1只截瘫,术后1周超声检查确认共有15只造模成功,成瘤率85%。15只成模兔术前、术后1周超声检测其腹主动脉最大内径分别为2.9±0.3mm和5.0+0.7mm,平均扩张率为71%。其中5只成模兔在术后1周时处死采集标本,剖视动脉瘤见其内膜失去正常光滑形态,壁增厚,有的腔内有附壁血栓形成。
2.为研究沙利度胺对AAA生长的影响,我们对兔AAA模型进行动态观察和评价。弹力蛋白酶灌注前及灌注后1周,沙利度胺治疗组和模型对照组腹主动脉最大外径、内径差异无统计学意义。弹力蛋白酶灌注后4周,模型对照组瘤体外径较1周时明显增大,而沙利度胺治疗组动脉瘤的生长被显著抑制,两组比较有统计学意义(P<0.001),治疗组瘤体扩张率平均降低46%(AAA/Tha:5.2±0.4mm vs. AAA/Con:7.6±0.9mm,P<0.001).该结果进一步被超声和血管造影检查结果所证实。血管超声检测结果显示,沙利度胺治疗1周后,与模型对照组相比较,AAA扩张明显减缓,治疗3周后动脉瘤最大内径明显低于模型对照组,扩张率平均降低49%。血管造影结果显示术后4周时沙利度胺治疗组AAA扩张程度明显低于模型对照组。
3.为了观察沙利度胺对兔AAA瘤壁炎症反应及血管生成的影响,对各组组织样本进行HE染色,显微镜下分别观察炎症细胞浸润及管腔化微血管形成情况。结果显示正常对照组腹主动脉壁无炎性细胞浸润,弹力蛋白酶灌注后1周动脉瘤壁可见大量炎症细胞浸润,浸润的炎症细胞主要位于中膜及外膜,以淋巴细胞和巨噬细胞为主；灌注后4周时模型对照组动脉瘤壁炎症细胞浸润进一步增多,与模型对照组相比,沙利度胺治疗3周后,瘤壁炎症显著减轻,组间比较有统计学意义(P<0.001)。弹力蛋白酶灌注后1周瘤壁管腔化微血管密度与正常腹主动脉相比未见明显变化,弹力蛋白酶灌注后4周时模型对照组见动脉瘤壁外膜管腔化微血管明显增加,沙利度胺治疗组管腔化微血管则明显低于模型对照组(P<0.001)。
4.免疫组化结果显示,正常腹主动脉TNF-α、MMP-9、VEGF均呈阴性表达,弹力蛋白酶灌注后1周表达均明显增强,阳性表达部位多以中膜和外膜为主；术后4周时模型对照组阳性表达的区域及强度进一步增加,动脉壁全层均可见大量棕黄色颗粒,与模型对照组比较,沙利度胺治疗组表达强度均明显减弱。
5. Western blot分析进一步显示,术后4周时沙利度胺治疗组TNF-α、MMP-9、VEGF表达水平与模型对照组相比分别平均降低47%、48%、75%。
6. ELISA法进一步检测各组兔血清中TNF-α和IL-1p水平。结果显示术后1周血清中TNF-α和IL-1p水平增高,术后4周时模型对照组TNF-α和IL-1β水平进一步明显增高,而沙利度胺组呈现下降或仅轻度升高趋势,与模型对照组相比有显著性差异(P<0.001)。
结论
本课题采用弹力蛋白酶灌注法成功建立了稳定的兔AAA实验模型,首次证实沙利度胺可通过其抗炎、免疫调节及抗血管生成等药理作用显著抑制兔实验性AAA的生长扩张,其具体机制是降低AAA进展过程中的重要蛋白酶及炎性细胞因子的水平,包括MMP-9、TNF-α、VEGF.IL-1p,进而抑制动脉瘤壁中炎症细胞浸润、血管新生及弹力蛋白降解等病理学进程。此外,通过本课题研究,进一步阐明了炎症免疫、新生血管生成、弹力蛋白降解在AAA进展过程中的作用。提示沙利度胺可作为治疗小AAA的潜在药物,对稳定、延缓小AAA的生长扩张具有重要的临床意义,亦为临床探索其他更为有效的治疗AAA的药物提供了参考。
Background
Abdominal aortic aneurysm (AAA) is a common degenerative condition that causes progressive aortic expansion and eventual rupture with high mortality. For large AAAs (≥5.5cm in diameter) with an increased risk of rupture,current treatments are preventive open or endovascular repair to prevent rupture. However, risk of rupture is negligible in small AAAs with a diameter<5.5cm, and early open or endovascular repair does not offer a survival advantage for them, the current management recommendations for these patients usually propose interval measurements of aneurysm size until elective repair is indicated based on rapid expansion (≥1cm/year) or size criteria (≥5.5cm). Obviously, the management based on such a "watchful-waiting" approach might not be sufficient for small AAAs.A more proactive and non-invasive measure is cried for to inhibit or slow down the expansion and risk of rupture, which might be a significant advance for a subset of patients with small AAAs.
The pathogenesis of AAAs represents a complex and multi-factorial process. Pathologically, AAAs are characterized by chronic aortic wall inflammation, destructive remodeling of the elastic media, neovascularization, and depletion of vascular smooth muscle cells (VSMC). Especially, AAA typically involves tissue inflammation as evidenced by the transmural infiltration of inflammatory cells mainly including macrophages and lymphocytes. On the one hand the infiltrating inflammatory cells secrete metalloproteinases (MMPs) and other proteases that degrade the aortic media and then weaken the aneurismal wall and subsequent thrombosis and AAA progression,on the other hand they release various inflammatory factors,such as tumor necrosis factor-a(TNF-a), interleukin-1β(IL-1β), interleukin-6(IL-6), interferon-y(IFN-y) and so on,that further promote the inflammation.Medial neovascularization and decreased vascular smooth muscle cells also characterize AAA lesions. The intraluminal thrombus may contribute to the process by causing a functional hypoxia at the luminal intima and inner media, thus inducing subsequent neovascularization and inflammation. Inflammatory cells in the thrombus also release active proteases such as matrix metalloproteinase (MMP)-9and urokinase-type plasminogen activator (u-PA).
In view of the improved understanding above, pharmacological strategies on modulating the pathological processes may represent a potential means for the stabilization of small AAAs. More recently, some of pharmacological agents have demonstrated an effective suppression of induced AAA formation or expansion in experimental models,such as statins,angiotensin-converting enzyme inhibitors, matrix metalloproteinase inhibitors,c-Jun N terminal kinase(JNK) inhibitor, and so on.
Thalidomide was introduced in the late1950's for morning sickness in pregnancy, but was withdrawn from the market in1961after its association with teratogenesis was documented.However,it has more recently demonstrated anti-inflammatory, anti-angiogenesis, and immunomodulatory properties with new clinical applications in oncology and the treatment of inflammatory disease. Recent evidence has shown that thalidomide is capable of inhibiting atherogenesis in apoE-deficient mice and rabbits with high lipid diet, presumably by inhibition of TNF-alpha secretion.As the properties of thalidomide might be expected to inhibit the progression of small AAAs, this study was focused on thalidomide influencing aneurysm growth in a rabbit elastase-induced AAA model.
Objectives
Animal models are necessary to develop and test innovations in aneurysm therapy before clinical introduction.The establishment of animal model is the indispensable research approach to explore the pathogenesis and treatment of abdominal aortic aneurysm. To establish an elastase-induced rabbit abdominal aortic aneurysm model, we sought to examine the effect of thalidomide on the growth of AAA, and explain the mechanism.
Methods
Male New Zealand white rabbits (2.0-2.5kg) were used.An isolated segment of rabbit abdominal aorta was infused with type I pancreatic elastase. The diameter of the infused aortic segment was measured using a micrometer pre-infusion and while collecting aorta samples. One week after infusion with elastase, dilatation of the aorta was confirmed by ultrasonography, and only rabbits that developed AAA were used in the next regression study. Aneurysm formation was defined as a50%increase in aortic diameter compared to the uninfused aorta just proximal to the infused segment.The rabbits that developed AAA were randomly divided into thalidomide treatment group (AAA/Tha, n=5) and model control group (AAA/Con, n=5), which received daily intragastric administration of thalidomide suspension (100mg/kg/day in5ml of normal saline) and the same volume of normal saline alone respectively from1week until they were sacrificed at4weeks after operation. In addition, developed AAA rabbits (n=5) and normal rabbits(n=5) did not undergo aortic infusion with elastase and saline or thalidomide administration, which were sacrificed at1weeks after infusion and normally feeding. Ultrasonography was used to assess dilatation of the abdominal aorta before and1,2and4weeks after operation. Angiography was also performed to evaluate dilatation of the abdominal aorta before and1and4weeks after infusion with elastase. All aortas were harvested and cut into two equal segments,one was fixed in fresh cold4%polymerisatum for Hematoxylin-Eosin (HE) for inflamatory cell infiltration and neovascularization, for Elastic Van-Gieson(EVG) stain for elastin and for immunohistochemistry for qualitative study of TNF-a, MMP-9, VEGF. The second segment was immediately snap-frozen at-80℃for western blot analysis for quantitative analysis of TNF-α,MMP-9,VEGF. Blood samples were taken before and1weeks,4weeks after operation. Samples were centrifuged to separate the serum, and the levels of TNF-a and IL-1β were measured with ELISA.
Results
1.18rabbits received modeling operation in batches. Within1week,2died and1developed paraplegia.At1week post-operation,15developed AAA confirmed by ultrasonography, the model success rate was up to85%. Before operation, the mean aortic diameter was2.9mm,5.0mm afer1week, the average aortic dilation rate were71%. Morphologically, the segments of infused aorta exhibited wall thickening, thrombosis could be seen in some samples.
2.Four weeks later the infusion with pancreatic elastase, aortic diameter was enlarged furtherly in AAA/CON by gross morphology, ultrasonography and arteriography, but in AAA/Tha the expansion was inhibited markedly, the expansion rate of aorta in AAA/Tha group was decreased by an average of46%compared to the rate in AAA/Con group(AAA/Tha,5.2±0.4mm vs. AAA/Con,7.6±0.9mm,P<0.001).
3. At4weeks post-operation, HE staining showed that infiltration of inflamatory cells and neovascularization in aneurismal wall was prominent in AAA/Con,however,it was attenuated in AAA/Tha.EVG stain exibited progressive destruction of the elastic lamellar wavy stucture with flattening, fragmentation and even disappearance of elastin fibers accompanies aortic expansion in AAA/Con, whereas the wavy structure of the elastic lamellar is largely preserved in AAA/Tha.
4. Immunohistochemical staining for TNF-α, MMP-9, and VEGF in the rabbit aortic wall is shown. Protein expression of TNF-α, MMP-9, and VEGF was negative in normal aortic wall, and1week post-operation, the expression became positive, and the positive position was mainly observed in media and adventitia of the aneurismal wall.At4weeks post-operation, whereas their further expression evaluated was extensive and transmural in AAA/Con, the levels were detected slightly in AAA/Tha. Furtherly, western blot analysis indicated that thalidomide treatment attenuated markedly TNF-α,MMP-9,VEGF by an average of47%,48%,75%respectively. The increased serum IL-1β and TNF-a expression was reduced by thalidomide treatment compared to AAA/CON (P<0.001).
Conclusions
Infusion of an isolated segment of rabbit aorta with elastase provide a reproducible animal model of AAA.Treatment with thalidomide in rabbit prevented the development of elastase-induced AAA, in association with reduced inflammation, neoangiogenesis, and extracellular matrix disruption.These findings suggest therapeutic potential of thalidomide for AAA.
腹主动脉瘤(abdominal aortic aneurysm, AAA)是腹主动脉的永久性、局限性扩张性疾病,多见于老年男性,男女发病率之比为3.5：1,据统计,在65～80岁的男性人群中,AAA的患病率达4-8%。AAA年新发病率为0.4-0.67%。在美国,每年有约150,000名患者因AAA住院,超过30,000人行AAA开腹手术治疗,有约15,000人最终死于AAA破裂。随着年龄增长,AAA发病率呈逐渐增高趋势,瘤体年扩张率亦加快,一旦发生破裂,死亡率可达90%。AAA俨然己成为具有高致死率、严重威胁人类健康的主要疾病之一。
AAA的高致死率主要缘于AAA的破裂。AAA直径是预测其破裂风险和决定治疗方式的主要指标。一般的,对于直径之5.5cm的AAA,其破裂的风险明显增加,动脉瘤切除人工血管置换和腔内支架隔绝术是防止AAA破裂的有效途径。然而,对于直径<5.5cm、瘤体扩张缓慢、近期破裂的风险很低的无症状小AAA,建议定期随访观察。相关的临床研究结果表明,对于小AAA,早期手术干预和定期随访观察两组患者的长期生存率并无明显差异,即早期手术并不能明显改善其长期生存率,这一结果也证实对于小AAA而言,定期随访观察是相对安全的,建议可在瘤体直径扩张率≥1cm/年或直径达到5.5cm时再行常规开腹或腔内修复术。但是,AAA的扩张是不可逆的,其一旦形成必然进行性增大,如果等到瘤体增大濒临破裂或出现症状再手术则随着患者年龄增大、全身状况进一步减退,手术治疗风险将数倍于早期治疗。显然,对于绝大多数小AAA患者,这种基于单纯“观察等待”基础上的策略是不够的,寻求一种更为积极的、无创的方法抑制甚或逆转动脉瘤扩张、防止其破裂或降低破裂风险或许更有意义。
AAA是遗传、环境、生物化学等多因素共同作用的结果,动脉粥样硬化、感染、炎症性疾病、胶原及弹性蛋白遗传缺陷、蛋白酶活性增强或抑制作用减弱以及机械性因素等,都有导致AAA的可能。各种因素导致血管壁受损,免疫反应被激活,引起局部炎症细胞浸润、炎症递质及各种蛋白水解酶异常表达与活化,进而导致动脉中膜弹力蛋白降解、胶原纤维代谢失衡、血管平滑肌细胞凋亡,最终动脉壁失去弹性,不能耐受血流冲击而进行性扩张形成动脉瘤。局部动脉瘤壁慢性炎症、细胞外基质(ECM)降解和重构、血管平滑肌细胞凋亡以及新生血管生成是腹主动脉瘤的主要病理学特征,尤其是以巨噬细胞、淋巴细胞为主的透壁性炎症细胞浸润与腹主动脉瘤的扩张成正相关。其一,浸润的炎性细胞可分泌大量的基质金属蛋白酶(MMPs)和其他蛋白水解酶,引起主动脉壁弹力蛋白和胶原纤维等结构性蛋白的降解,削弱动脉瘤壁、继发附壁血栓形成进而导致动脉瘤进展；其二,炎性细胞在瘤壁中分泌如肿瘤坏死因子-βα(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、干扰素-γ(IFN-γ)等多种炎性细胞因子,进一步促进炎症反应,加重动脉瘤的进展。动脉中层新生血管形成和血管平滑肌细胞减少也是腹主动脉瘤的重要特征。瘤腔内的附壁血栓可引起内膜组织细胞缺氧,进而诱发新生血管形成和炎症。血栓内的炎症细胞也可以释放诸如MMP-9、尿激酶型纤溶酶原激活剂等活性蛋白水解酶。
AAA形成及扩张机制的逐步阐明为应用药物来延缓、阻止甚至逆转动脉瘤的病理学进程提供了理论依据,即理论上通过药物抑制动脉壁炎症、新生血管生成以及调节免疫等方法可以抑制AAA的扩张。我们期待药物干预能为小AAA的稳定提供有效的治疗。而相对于开发新药,研究可能抑制AAA进程的现行一线临床药物的可行性可能更强。目前国外学者已经开展并证实对AAA形成有抑制作用的药物包括他汀类药物、四环素类、血管紧张素转化酶抑制剂、血管紧张素Ⅱ受体拮抗剂、免疫抑制剂、非甾体类抗炎药、核因子KB(NF-κB)抑制剂及c-jun氨基末端激酶(JNK)抑制剂等。
沙利度胺又名酞胺哌啶酮,最初作为镇静剂治疗妊娠呕吐,后因发现有明显的致畸作用(婴儿海豹肢)而被禁用。然而,各国学者对沙利度胺的研究从未因此停滞。近年来发现沙利度胺具有显著的抗炎、抗血管生成及免疫调节等作用而重新被应用于临床,用于麻风结节性红斑、系统性红斑狼疮、多发性骨髓瘤、类风湿性关节炎、白塞氏病等的治疗并显示出特有的疗效。最近研究表明,沙利度胺对大鼠颈动脉球囊损伤后新生内膜的增生及兔动脉粥样硬化形成有明显抑制,其机制可能主要与其下调TNF-α的表达有关。
基于炎症、免疫机制在AAA形成、扩张过程中的重要作用及沙利度胺的抗炎、抗血管生成、免疫调节等药理学作用,沙利度胺对AAA生长是否有抑制作用目前国内外均未见有关研究。推测沙利度胺可能通过其抗炎、免疫调节及抗血管生成作用在AAA的治疗中亦起重要作用。
目的
建立兔肾下AAA模型,就沙利度胺对AAA生长的影响从大体形态、影像学、组织病理学、分子生物学等方面进行全面、动态观察,研究沙利度胺对AAA的扩张是否有抑制作用,在此基础上进一步阐释AAA的发病机制,为AAA的临床药物治疗提供参考。
方法
选取健康雄性新西兰白兔(体重2.5-3.0kg),采用猪胰Ⅰ型弹力蛋白酶灌注肾下腹主动脉建立兔AAA模型,术后1周对手术兔行腹主动脉超声检查,了解成瘤情况,测量灌注段最大内径,以灌注段腹主动脉扩张超过其近端正常腹主动脉直径的50%作为造模成功标准,计算扩张率及造模成功率。为研究沙利度胺对腹主动脉瘤生长的影响,术后1周时超声检查确认造模成功的兔15只,单盲、随机分为三组,即沙利度胺治疗组(AAA/Thd,n=5)和模型对照组(AAA/Con,n=5),于术后1周始,每天一次分别给予胃灌注沙利度胺生理盐水悬液(100mg/kg/day与5m1生理盐水混匀)和生理盐水(5ml/只/天),直至术后4周；其余5只术后1周时再次手术,以采集标本作为药物干预前的基础对照。另取未行手术造模的兔5只,于常规饲养1周后采集标本作为实验正常对照。各组兔于术前及术后1周、2周、4周先后行多普勒超声检查,评价比较腹主动脉术后扩张情况,于术后1周、4周时同时行腹主动脉造影,进一步评价AAA扩张情况。标本采集前于生理压力下测量、记录腹主动脉最大外径。采集的腹主动脉标本分成两份,一份分割后立即置于4%多聚甲醛溶液中固定,石蜡包埋用于组织病理学研究,另一份速冻于-80℃低温冰箱备用于Western Blot分析。术前及术后1周、4周时分组白兔耳缘静脉采集静脉血2ml,离心(3000转／分钟x5min,4℃)后取上清液置于-20℃冰箱保存备用。采用苏木素-伊红(HE)染色和弹力纤维EVG染色分别评价沙利度胺治疗前后动脉瘤壁炎性细胞浸润、管腔化微血管密度变化及弹力纤维降解情况。采用免疫组化、Western blot方法对组织标本中TNF-α、MMP-9、VEGF等炎性细胞因子的表达进行定性和定量研究,分析比较沙利度胺对其表达的影响。采用ELISA法研究沙利度胺对循环促炎细胞因子TNF-α、IL-1β的影响。所有计量数据以均数士标准差表示,应用SPSS13.0统计软件处理数据,采用单因素方差分析和t检验进行统计学分析,P<0.05判定差异的显著性。
结果
1.本课题应用肾下腹主动脉弹力蛋白酶加压灌注法成功建立兔AAA实验模型,18只兔分批建模,术后1周内死亡2只,1只截瘫,术后1周超声检查确认共有15只造模成功,成瘤率85%。15只成模兔术前、术后1周超声检测其腹主动脉最大内径分别为2.9±0.3mm和5.0+0.7mm,平均扩张率为71%。其中5只成模兔在术后1周时处死采集标本,剖视动脉瘤见其内膜失去正常光滑形态,壁增厚,有的腔内有附壁血栓形成。
2.为研究沙利度胺对AAA生长的影响,我们对兔AAA模型进行动态观察和评价。弹力蛋白酶灌注前及灌注后1周,沙利度胺治疗组和模型对照组腹主动脉最大外径、内径差异无统计学意义。弹力蛋白酶灌注后4周,模型对照组瘤体外径较1周时明显增大,而沙利度胺治疗组动脉瘤的生长被显著抑制,两组比较有统计学意义(P<0.001),治疗组瘤体扩张率平均降低46%(AAA/Tha:5.2±0.4mm vs. AAA/Con:7.6±0.9mm,P<0.001).该结果进一步被超声和血管造影检查结果所证实。血管超声检测结果显示,沙利度胺治疗1周后,与模型对照组相比较,AAA扩张明显减缓,治疗3周后动脉瘤最大内径明显低于模型对照组,扩张率平均降低49%。血管造影结果显示术后4周时沙利度胺治疗组AAA扩张程度明显低于模型对照组。
3.为了观察沙利度胺对兔AAA瘤壁炎症反应及血管生成的影响,对各组组织样本进行HE染色,显微镜下分别观察炎症细胞浸润及管腔化微血管形成情况。结果显示正常对照组腹主动脉壁无炎性细胞浸润,弹力蛋白酶灌注后1周动脉瘤壁可见大量炎症细胞浸润,浸润的炎症细胞主要位于中膜及外膜,以淋巴细胞和巨噬细胞为主；灌注后4周时模型对照组动脉瘤壁炎症细胞浸润进一步增多,与模型对照组相比,沙利度胺治疗3周后,瘤壁炎症显著减轻,组间比较有统计学意义(P<0.001)。弹力蛋白酶灌注后1周瘤壁管腔化微血管密度与正常腹主动脉相比未见明显变化,弹力蛋白酶灌注后4周时模型对照组见动脉瘤壁外膜管腔化微血管明显增加,沙利度胺治疗组管腔化微血管则明显低于模型对照组(P<0.001)。
4.免疫组化结果显示,正常腹主动脉TNF-α、MMP-9、VEGF均呈阴性表达,弹力蛋白酶灌注后1周表达均明显增强,阳性表达部位多以中膜和外膜为主；术后4周时模型对照组阳性表达的区域及强度进一步增加,动脉壁全层均可见大量棕黄色颗粒,与模型对照组比较,沙利度胺治疗组表达强度均明显减弱。
5. Western blot分析进一步显示,术后4周时沙利度胺治疗组TNF-α、MMP-9、VEGF表达水平与模型对照组相比分别平均降低47%、48%、75%。
6. ELISA法进一步检测各组兔血清中TNF-α和IL-1p水平。结果显示术后1周血清中TNF-α和IL-1p水平增高,术后4周时模型对照组TNF-α和IL-1β水平进一步明显增高,而沙利度胺组呈现下降或仅轻度升高趋势,与模型对照组相比有显著性差异(P<0.001)。
结论
本课题采用弹力蛋白酶灌注法成功建立了稳定的兔AAA实验模型,首次证实沙利度胺可通过其抗炎、免疫调节及抗血管生成等药理作用显著抑制兔实验性AAA的生长扩张,其具体机制是降低AAA进展过程中的重要蛋白酶及炎性细胞因子的水平,包括MMP-9、TNF-α、VEGF.IL-1p,进而抑制动脉瘤壁中炎症细胞浸润、血管新生及弹力蛋白降解等病理学进程。此外,通过本课题研究,进一步阐明了炎症免疫、新生血管生成、弹力蛋白降解在AAA进展过程中的作用。提示沙利度胺可作为治疗小AAA的潜在药物,对稳定、延缓小AAA的生长扩张具有重要的临床意义,亦为临床探索其他更为有效的治疗AAA的药物提供了参考。
Background
Abdominal aortic aneurysm (AAA) is a common degenerative condition that causes progressive aortic expansion and eventual rupture with high mortality. For large AAAs (≥5.5cm in diameter) with an increased risk of rupture,current treatments are preventive open or endovascular repair to prevent rupture. However, risk of rupture is negligible in small AAAs with a diameter<5.5cm, and early open or endovascular repair does not offer a survival advantage for them, the current management recommendations for these patients usually propose interval measurements of aneurysm size until elective repair is indicated based on rapid expansion (≥1cm/year) or size criteria (≥5.5cm). Obviously, the management based on such a "watchful-waiting" approach might not be sufficient for small AAAs.A more proactive and non-invasive measure is cried for to inhibit or slow down the expansion and risk of rupture, which might be a significant advance for a subset of patients with small AAAs.
The pathogenesis of AAAs represents a complex and multi-factorial process. Pathologically, AAAs are characterized by chronic aortic wall inflammation, destructive remodeling of the elastic media, neovascularization, and depletion of vascular smooth muscle cells (VSMC). Especially, AAA typically involves tissue inflammation as evidenced by the transmural infiltration of inflammatory cells mainly including macrophages and lymphocytes. On the one hand the infiltrating inflammatory cells secrete metalloproteinases (MMPs) and other proteases that degrade the aortic media and then weaken the aneurismal wall and subsequent thrombosis and AAA progression,on the other hand they release various inflammatory factors,such as tumor necrosis factor-a(TNF-a), interleukin-1β(IL-1β), interleukin-6(IL-6), interferon-y(IFN-y) and so on,that further promote the inflammation.Medial neovascularization and decreased vascular smooth muscle cells also characterize AAA lesions. The intraluminal thrombus may contribute to the process by causing a functional hypoxia at the luminal intima and inner media, thus inducing subsequent neovascularization and inflammation. Inflammatory cells in the thrombus also release active proteases such as matrix metalloproteinase (MMP)-9and urokinase-type plasminogen activator (u-PA).
In view of the improved understanding above, pharmacological strategies on modulating the pathological processes may represent a potential means for the stabilization of small AAAs. More recently, some of pharmacological agents have demonstrated an effective suppression of induced AAA formation or expansion in experimental models,such as statins,angiotensin-converting enzyme inhibitors, matrix metalloproteinase inhibitors,c-Jun N terminal kinase(JNK) inhibitor, and so on.
Thalidomide was introduced in the late1950's for morning sickness in pregnancy, but was withdrawn from the market in1961after its association with teratogenesis was documented.However,it has more recently demonstrated anti-inflammatory, anti-angiogenesis, and immunomodulatory properties with new clinical applications in oncology and the treatment of inflammatory disease. Recent evidence has shown that thalidomide is capable of inhibiting atherogenesis in apoE-deficient mice and rabbits with high lipid diet, presumably by inhibition of TNF-alpha secretion.As the properties of thalidomide might be expected to inhibit the progression of small AAAs, this study was focused on thalidomide influencing aneurysm growth in a rabbit elastase-induced AAA model.
Objectives
Animal models are necessary to develop and test innovations in aneurysm therapy before clinical introduction.The establishment of animal model is the indispensable research approach to explore the pathogenesis and treatment of abdominal aortic aneurysm. To establish an elastase-induced rabbit abdominal aortic aneurysm model, we sought to examine the effect of thalidomide on the growth of AAA, and explain the mechanism.
Methods
Male New Zealand white rabbits (2.0-2.5kg) were used.An isolated segment of rabbit abdominal aorta was infused with type I pancreatic elastase. The diameter of the infused aortic segment was measured using a micrometer pre-infusion and while collecting aorta samples. One week after infusion with elastase, dilatation of the aorta was confirmed by ultrasonography, and only rabbits that developed AAA were used in the next regression study. Aneurysm formation was defined as a50%increase in aortic diameter compared to the uninfused aorta just proximal to the infused segment.The rabbits that developed AAA were randomly divided into thalidomide treatment group (AAA/Tha, n=5) and model control group (AAA/Con, n=5), which received daily intragastric administration of thalidomide suspension (100mg/kg/day in5ml of normal saline) and the same volume of normal saline alone respectively from1week until they were sacrificed at4weeks after operation. In addition, developed AAA rabbits (n=5) and normal rabbits(n=5) did not undergo aortic infusion with elastase and saline or thalidomide administration, which were sacrificed at1weeks after infusion and normally feeding. Ultrasonography was used to assess dilatation of the abdominal aorta before and1,2and4weeks after operation. Angiography was also performed to evaluate dilatation of the abdominal aorta before and1and4weeks after infusion with elastase. All aortas were harvested and cut into two equal segments,one was fixed in fresh cold4%polymerisatum for Hematoxylin-Eosin (HE) for inflamatory cell infiltration and neovascularization, for Elastic Van-Gieson(EVG) stain for elastin and for immunohistochemistry for qualitative study of TNF-a, MMP-9, VEGF. The second segment was immediately snap-frozen at-80℃for western blot analysis for quantitative analysis of TNF-α,MMP-9,VEGF. Blood samples were taken before and1weeks,4weeks after operation. Samples were centrifuged to separate the serum, and the levels of TNF-a and IL-1β were measured with ELISA.
Results
1.18rabbits received modeling operation in batches. Within1week,2died and1developed paraplegia.At1week post-operation,15developed AAA confirmed by ultrasonography, the model success rate was up to85%. Before operation, the mean aortic diameter was2.9mm,5.0mm afer1week, the average aortic dilation rate were71%. Morphologically, the segments of infused aorta exhibited wall thickening, thrombosis could be seen in some samples.
2.Four weeks later the infusion with pancreatic elastase, aortic diameter was enlarged furtherly in AAA/CON by gross morphology, ultrasonography and arteriography, but in AAA/Tha the expansion was inhibited markedly, the expansion rate of aorta in AAA/Tha group was decreased by an average of46%compared to the rate in AAA/Con group(AAA/Tha,5.2±0.4mm vs. AAA/Con,7.6±0.9mm,P<0.001).
3. At4weeks post-operation, HE staining showed that infiltration of inflamatory cells and neovascularization in aneurismal wall was prominent in AAA/Con,however,it was attenuated in AAA/Tha.EVG stain exibited progressive destruction of the elastic lamellar wavy stucture with flattening, fragmentation and even disappearance of elastin fibers accompanies aortic expansion in AAA/Con, whereas the wavy structure of the elastic lamellar is largely preserved in AAA/Tha.
4. Immunohistochemical staining for TNF-α, MMP-9, and VEGF in the rabbit aortic wall is shown. Protein expression of TNF-α, MMP-9, and VEGF was negative in normal aortic wall, and1week post-operation, the expression became positive, and the positive position was mainly observed in media and adventitia of the aneurismal wall.At4weeks post-operation, whereas their further expression evaluated was extensive and transmural in AAA/Con, the levels were detected slightly in AAA/Tha. Furtherly, western blot analysis indicated that thalidomide treatment attenuated markedly TNF-α,MMP-9,VEGF by an average of47%,48%,75%respectively. The increased serum IL-1β and TNF-a expression was reduced by thalidomide treatment compared to AAA/CON (P<0.001).
Conclusions
Infusion of an isolated segment of rabbit aorta with elastase provide a reproducible animal model of AAA.Treatment with thalidomide in rabbit prevented the development of elastase-induced AAA, in association with reduced inflammation, neoangiogenesis, and extracellular matrix disruption.These findings suggest therapeutic potential of thalidomide for AAA.
引文
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