【摘要】：研究背景隨著社會(huì)老齡化的到來和人民生活水平的提高,血管系統(tǒng)疾病的發(fā)病率逐年上升,而以主動(dòng)脈夾層(aortic dissection,AD)為代表的主動(dòng)脈擴(kuò)張病是其中最兇險(xiǎn)的一類。盡管AD的治療方式從巨創(chuàng)向微創(chuàng)發(fā)生了革命性變化,夾層的并發(fā)癥率和死亡率有了明顯降低,但仍有很多患者在明確診斷前或開始救治前即因夾層破裂而死亡。因此,闡明AD發(fā)病和轉(zhuǎn)歸的機(jī)制,對(duì)改善夾層預(yù)后至關(guān)重要。有證據(jù)表明血管炎癥反應(yīng)在主動(dòng)脈血管重構(gòu)過程中起著重要作用,而糖皮質(zhì)激素因其強(qiáng)大的抗炎作用被廣泛用于臨床。最新的隨機(jī)對(duì)照臨床研究表明術(shù)前單次應(yīng)用大劑量的糖皮質(zhì)激素,在沒有增加不良事件發(fā)生率的基礎(chǔ)上能明顯降低腹主動(dòng)脈瘤患者腔內(nèi)隔絕術(shù)后全身炎癥反應(yīng)綜合征的發(fā)生率,但糖皮質(zhì)激素與AD的關(guān)系仍模糊不清。研究目的探討糖皮質(zhì)激素在AD的發(fā)生、發(fā)展和轉(zhuǎn)歸中的作用,并進(jìn)一步闡明糖皮質(zhì)激素參與主動(dòng)脈血管重構(gòu)的細(xì)胞分子機(jī)制。研究方法1臨床樣本研究:在符合倫理審查和患者知情同意情況下,收集AD、非破裂主動(dòng)脈瘤(non-ruptured aortic aneurysm,n AA)和健康對(duì)照者的血液標(biāo)本,放射免疫法檢測(cè)血清皮質(zhì)醇、血漿促腎上腺皮質(zhì)激素(adrenocorticotropic hormone,ACTH)的含量;同時(shí)收集行開放手術(shù)的AD、n AA患者和遺體捐獻(xiàn)者的主動(dòng)脈,免疫組化法檢測(cè)主動(dòng)脈中糖皮質(zhì)激素受體(glucocorticoid receptor,GCR)表達(dá)水平;收集夾層患者的臨床信息進(jìn)行多元線性回歸分析,探討血清皮質(zhì)醇含量的影響因素。2動(dòng)物實(shí)驗(yàn)研究:在獲得第二軍醫(yī)大學(xué)動(dòng)物保護(hù)和使用協(xié)會(huì)的批準(zhǔn)后,切除80只C57BL/6小鼠的雙側(cè)腎上腺,按2:2:1完全隨機(jī)分成三組,用血管緊張素II建立AD模型,外加糖皮質(zhì)激素或溶劑對(duì)照干預(yù),三組分別為糖皮質(zhì)激素干預(yù)組、模型組、溶劑對(duì)照組:記錄小鼠的死亡時(shí)間,Kaplan-Meier曲線計(jì)算小鼠累積生存率;血管緊張素II干預(yù)前后每周尾動(dòng)脈測(cè)壓,驗(yàn)證血管緊張素II是否起效;解剖獲取小鼠主動(dòng)脈,借助Image-Pro Plus軟件測(cè)量小鼠主動(dòng)脈外徑;蘇木素-伊紅染色,測(cè)量主動(dòng)脈中膜厚度及觀察夾層發(fā)生率;Masson染色,檢測(cè)主動(dòng)脈膠原容積分?jǐn)?shù);免疫組化法檢測(cè)小鼠主動(dòng)脈GCR表達(dá)及巨噬細(xì)胞的含量。3細(xì)胞分子研究:體外培養(yǎng)人主動(dòng)脈平滑肌細(xì)胞(human aortic smooth muscle cell,HA-SMC)和巨噬細(xì)胞,酶聯(lián)免疫吸附實(shí)驗(yàn)檢測(cè)糖皮質(zhì)激素對(duì)巨噬細(xì)胞分泌基質(zhì)金屬蛋白酶-2(matrix metalloproteinase-2,MMP-2)、基質(zhì)金屬蛋白酶-2抑制劑(tissue inhibitor of metalloproteinase-2,TIMP-2)、腫瘤壞死因子-α(tumor necrosis factor-α,TNF-α)的影響;劃痕實(shí)驗(yàn)檢測(cè)糖皮質(zhì)激素對(duì)HA-SMC遷移的影響,細(xì)胞免疫熒光檢測(cè)糖皮質(zhì)激素對(duì)HA-SMC表型轉(zhuǎn)換的影響;建立HA-SMC和巨噬細(xì)胞間接共培養(yǎng)體系,細(xì)胞流式實(shí)驗(yàn)檢測(cè)細(xì)胞共培養(yǎng)及糖皮質(zhì)激素對(duì)HA-SMC凋亡的影響,細(xì)胞免疫熒光檢測(cè)細(xì)胞共培養(yǎng)及糖皮質(zhì)激素對(duì)HA-SMC遷移的影響;高通量蛋白微陣列芯片檢測(cè)細(xì)胞間相互作用的關(guān)鍵因子,并用相應(yīng)因子的中和抗體驗(yàn)證其作用;應(yīng)激和凋亡通路試劑盒檢測(cè)關(guān)鍵因子參與血管重構(gòu)的信號(hào)分子通路,western blot驗(yàn)證該信號(hào)分子的變化。結(jié)果1臨床樣本研究:2012年10月至2013年12月,共收集在我血管外科中心治療經(jīng)可靠影像學(xué)方法診斷的82例AD,68例n AA及在我院體檢中心體檢的76例健康者的血液樣本,三組人群血清皮質(zhì)醇含量分別為173.98±23.44 ng/m L,136.60±21.83 ng/m L和129.00±27.56 ng/m L,AD組明顯高于n AA組(P0.001)和健康體檢組(P0.001);三組人群血漿ACTH含量分別為26.76±7.41 pg/m L,24.75±8.21pg/m L和25.64±7.38 pg/m L,三組間未見統(tǒng)計(jì)學(xué)差異;同期收集行開放手術(shù)的8例AD,8例n AA和8例遺體捐獻(xiàn)者的主動(dòng)脈,三組GCR含量分別為14.25±1.31%,13.39±1.42%和12.55±2.12%,未見明顯統(tǒng)計(jì)學(xué)差異;收集夾層患者的臨床信息行多元回歸分析發(fā)現(xiàn)夾層裂口數(shù)目是血清皮質(zhì)醇含量的影響因素(偏回歸系數(shù)0.920,P=0.029)。2動(dòng)物實(shí)驗(yàn)研究:最終納入糖皮質(zhì)激素干預(yù)組、模型組和溶劑對(duì)照組分析的小鼠數(shù)量分別是31、27和13;模型組與糖皮質(zhì)激素干預(yù)組(P=0.139)或溶劑對(duì)照組(P=0.107)的累積生存率無(wú)統(tǒng)計(jì)學(xué)差異(Log-rank檢驗(yàn));模型組的小鼠收縮壓在血管緊張素II干預(yù)后明顯高于溶劑對(duì)照組,在血管緊張素II干預(yù)后7天、14天、21天明顯低于糖皮質(zhì)激素干預(yù)組;模型組的小鼠主動(dòng)脈外徑明顯大于溶劑對(duì)照組(升主動(dòng)脈:1458.49±257.96μm vs.1094.61±154.57μm,P0.001;主動(dòng)脈弓:1449.48±290.34μm vs.986.38±151.16μm,P0.001;降主動(dòng)脈:1343.47±238.48μm vs.980.36±98.48μm,P0.001),模型組小鼠的升主動(dòng)脈外徑明顯大于糖皮質(zhì)激素干預(yù)組(1458.49±257.96μm vs.1279.17±204.24μm,P=0.005),主動(dòng)脈弓和降主動(dòng)脈外徑無(wú)明顯差異;模型組(29.6%)的小鼠AD發(fā)生率明顯高于糖皮質(zhì)激素干預(yù)組(6.5%,P=0.034)和溶劑對(duì)照組(0%,P=0.037);模型組小鼠的主動(dòng)脈中膜厚度明顯高于溶劑對(duì)照組(89.6±14.7μm vs.68.4±11.6μm,P0.001),但糖皮質(zhì)激素干預(yù)組與模型組之間無(wú)統(tǒng)計(jì)學(xué)差異(89.8±13.5μm vs.89.6±14.7μm,P=0.937);模型組(24.2±6.0%)小鼠的主動(dòng)脈膠原容積分?jǐn)?shù)明顯低于溶劑對(duì)照組(31.7±6.3%,P=0.001)和糖皮質(zhì)激素干預(yù)組(30.1±8.2%,P=0.003);模型組(9.3±3.0%)小鼠的主動(dòng)脈GCR水平與糖皮質(zhì)激素干預(yù)組(8.5±2.1%,P=0.235)或溶劑對(duì)照組(7.6±1.1%,P=0.115)無(wú)明顯不同;但模型組(9.3±3.5%)小鼠的主動(dòng)脈巨噬細(xì)胞含量明顯高于溶劑對(duì)照組(2.2±1.0%,P0.001)或糖皮質(zhì)激素干預(yù)組(7.4±3.2%,P=0.041)。3細(xì)胞分子研究:結(jié)果表明糖皮質(zhì)激素能明顯抑制巨噬細(xì)胞分泌MMP-2,對(duì)TIMP-2的分泌無(wú)明顯影響;另外,高濃度糖皮質(zhì)激素抑制巨噬細(xì)胞分泌TNF-α,低濃度糖皮質(zhì)激素促進(jìn)TNF-α的分泌;糖皮質(zhì)激素減少HA-SMC的遷移,抑制HA-SMC向分泌型表型轉(zhuǎn)換;HA-SMC與巨噬細(xì)胞共培養(yǎng)抑制了HA-SMC的凋亡,糖皮質(zhì)激素加強(qiáng)這一效應(yīng),但對(duì)細(xì)胞遷移無(wú)影響;高通量蛋白微陣列鑒定出白介素-6(interleuin-6,IL-6)和可溶性腫瘤壞死因子II型受體(soluble tumor necrosis factor receptor II,TNF-s RII)可能是細(xì)胞間相互作用的關(guān)鍵因子,但抗體中和實(shí)驗(yàn)證實(shí)了TNF-s RII是關(guān)鍵因子,IL-6的作用未得到驗(yàn)證。細(xì)胞共培養(yǎng)或糖皮質(zhì)激素干預(yù)時(shí),應(yīng)激和凋亡通路試劑盒檢測(cè)到bad、HSP27、p38MAPK和Ik Ba信號(hào)分子磷酸化水平的變化,western blot結(jié)果表明細(xì)胞共培養(yǎng)和糖皮質(zhì)激素干預(yù)影響了p38MAPK和HSP27的磷酸化通路,參與血管重構(gòu)。結(jié)論糖皮質(zhì)激素正性調(diào)控主動(dòng)脈血管重構(gòu),對(duì)AD的發(fā)生起著保護(hù)性作用。AD患者的血清皮質(zhì)醇含量升高是機(jī)體為應(yīng)對(duì)病理性血管重構(gòu)作出的積極反應(yīng)。糖皮質(zhì)激素降低巨噬細(xì)胞分泌MMP-2減少主動(dòng)脈膠原的降解,抑制巨噬細(xì)胞分泌TNF-α減輕管壁炎癥反應(yīng),抑制HA-SMC遷移維持管壁SMC數(shù)量穩(wěn)定,抑制HA-SMC向分泌型轉(zhuǎn)變維持管壁功能穩(wěn)態(tài);HA-SMC與巨噬細(xì)胞共培養(yǎng)增加了游離TNF-s RII的含量,抑制p38MAPK-HSP27信號(hào)分子磷酸化,糖皮質(zhì)激素干預(yù)進(jìn)一步降低了TNF-α/TNF-s RII的比值,積極參與主動(dòng)脈血管重構(gòu)。也許在將來,糖皮質(zhì)激素或TNF-s RII能成為主動(dòng)脈血管重構(gòu)的可干預(yù)靶標(biāo)。
[Abstract]:Background With the advent of social aging and the improvement of people's living standards, the incidence of vascular diseases is increasing year by year, and aortic dissection (AD) represented by aortic dissection is one of the most dangerous. The morbidity and mortality have been significantly reduced, but many patients die of dissection rupture before diagnosis or treatment. Therefore, it is important to clarify the pathogenesis and prognosis of AD to improve the prognosis of dissection. Latest randomized controlled clinical studies have shown that a single dose of glucocorticoids before surgery can significantly reduce the incidence of systemic inflammatory response syndrome in patients with abdominal aortic aneurysms after endovascular exclusion without increasing the incidence of adverse events, but glucocorticoids and AD Objective To investigate the role of glucocorticoids in the occurrence, development and prognosis of AD, and further elucidate the cellular and molecular mechanisms of glucocorticoids involved in aortic remodeling. Methods 1 Clinical sample study: AD, non-ruptured aortic aneurysm (n) was collected with ethical review and informed consent of patients. Blood samples from on-ruptured aortic aneurysm (n AA) and healthy controls were examined for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels by radioimmunoassay, and aortas from patients with AD, n AA and cadaver donors undergoing open surgery were collected and glucocorticoid stimulation was detected by immunohistochemistry. Glucocorticoid receptor (GCR) expression level; clinical information of dissection patients was collected for multiple linear regression analysis to explore the influencing factors of serum cortisol content. 2 Animal experimental study: 80 C57BL/6 mice were excised bilateral adrenal glands after obtaining the approval of the Animal Protection and Use Association of the Second Military Medical University, and completed by 2:2:1. All the mice were randomly divided into three groups: the AD model was established with angiotensin II, and the AD model was treated with glucocorticoid or solvent. The three groups were divided into glucocorticoid intervention group, model group and solvent control group. The time of death was recorded, and the cumulative survival rate was calculated by Kaplan-Meier curve. Angiotensin II was effective; aorta of mice was dissected and the diameter of aorta was measured by image-Pro Plus software; aortic media thickness and dissection rate were measured by hematoxylin-eosin staining; aortic collagen volume fraction was detected by Masson staining; GCR expression and macrophages were detected by immunohistochemistry method. Content. 3 Cell Molecular Study: Human aortic smooth muscle cell (HA-SMC) and macrophages were cultured in vitro. Enzyme-linked immunosorbent assay was used to detect the secretion of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-2 inhibitor of macrophages by glucocorticoids. Metaloproteinase-2, TIMP-2, tumor necrosis factor-alpha (TNF-alpha) effect; scratch test to detect the effect of glucocorticoids on the migration of HA-SMC, cell immunofluorescence to detect the effect of glucocorticoids on the phenotype conversion of HA-SMC; establish HA-SMC and macrophage indirect co-culture system, cell flow cytometry to detect the cell. The effects of co-culture and glucocorticoids on apoptosis of HA-SMC, the effects of co-culture and glucocorticoids on migration of HA-SMC, the key factors of cell-to-cell interaction were detected by high-throughput protein microarray chip, and the neutralizing experience of the corresponding factors was used to verify the role of co-culture and glucocorticoids on apoptosis of HA-SMC. Results 1 Clinical sample study: From October 2012 to December 2013, blood samples from 82 AD patients, 68 n AA patients and 76 healthy volunteers who underwent physical examination in our vascular surgery center were collected. The levels of serum cortisol in AD group were significantly higher than those in n AA group (P The GCR levels of 8 AD patients, 8 NAA patients and 8 cadaver donors were 14.25 (+ 1.31%), 13.39 (+ 1.42%) and 12.55 (+ 2.12%) respectively, and there was no significant difference among the three groups. 920, P = 0.029).2 Animal experiment: The number of mice in the model group and the solvent control group were 31, 27 and 13, respectively. The cumulative survival rates of the model group and the glucocorticoid intervention group (P = 0.139) or the solvent control group (P = 0.107) were not significantly different (Log-rank test). The diameter of aorta in the model group was significantly larger than that in the solvent group (ascending aorta: 1458.49 + 257.96 microns vs. 1094.61 + 154.57 microns, P 0.001; aortic arch: 1449.48 + 290.34 microns vs. 986.38 + 151.38 microns). The diameter of ascending aorta in the model group was significantly larger than that in the glucocorticoid intervention group (1458.49 257.966550 The thickness of aortic media in the model group was significantly higher than that in the solvent group (89.6 65507 The volume fraction of collagen in aorta of rats was significantly lower than that of solvent control group (31.7 65507 The content of macrophages in the aorta of mice was significantly higher than that of the solvent control group (2.2+1.0%, P 0.001) or the glucocorticoid intervention group (7.4+3.2%, P=0.041). The results showed that glucocorticoid could significantly inhibit the secretion of MMP-2 by macrophages, but had no significant effect on the secretion of TIMP-2. TNF-a secretion was promoted by low concentration of glucocorticoids; glucocorticoids reduced the migration of HA-SMC and inhibited the transformation of HA-SMC to secretory phenotype; HA-SMC co-cultured with macrophages inhibited the apoptosis of HA-SMC, glucocorticoids enhanced the effect, but had no effect on cell migration; high-throughput protein microarray identified interleukin-6 (inte-6). Rleuin-6, IL-6 and soluble tumor necrosis factor receptor II (TNF-s RII) may be the key factor s in cell-cell interaction, but antibody neutralization confirmed that TNF-s RII is the key factor, and the role of IL-6 has not been verified. Stress and apoptosis are mediated by cell co-culture or glucocorticoid intervention. The phosphorylation levels of bad, HSP27, p38 MAPK and Ik Ba signaling molecules were detected by the kit. Western blot analysis showed that co-culture and glucocorticoid intervention affected the phosphorylation pathway of p38 MAPK and HSP27 and involved in vascular remodeling. Glucocorticoid reduces the secretion of MMP-2 by macrophages, decreases the degradation of collagen in aorta, inhibits the secretion of TNF-alpha by macrophages, reduces inflammation in vascular wall, inhibits the migration of HA-SMC and maintains the stability of SMC in vascular wall, and inhibits the secretion of HA-SMC. HA-SMC co-cultured with macrophages increased the content of free TNF-s RII, inhibited the phosphorylation of p38MAPK-HSP27 signal molecule, and glucocorticoid intervention further reduced the ratio of TNF-a to TNF-s RII and actively participated in aortic vascular remodeling. Perhaps in the future, glucocorticoid or TNF-s RII could become aortic blood. The reconfigurable target of tube reconstruction.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R543.1

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