兔髂动脉球囊损伤后血管狭窄模型的制作

目的探讨兔髂动脉球囊损伤后血管狭窄动物模型的制作。方法将36只新西兰大白兔随机分为球囊损伤组和空白对照组,每组18只,分剐于术后2．4、12周处死动物,取目标血管段行常规HE染色,采用病理图像分析系统H-100进行图像分析,计算血管管腔面积和外弹力膜包绕面积（平均动脉面积）进行形态学观察。结果球囊成形术后4和12周球囊损伤组兔髂动脉的管腔面积和外弹力膜包绕面积明显小于空白对照组（P〈0．01）．兔髂动脉球囊损伤后血管狭窄模型成功建立。结论此动物模型能较好地模拟经皮冠状动脉成形术（PTCA）后血管再狭窄的病理过程。     

曲匹地尔及阿斯匹林对球囊血管成形术后血管增生及重构的影响

目的从血管病理角度观察血小板源生长因子（ＰＤＧＦ）抑制剂曲匹地尔（ｔｒａｐｉｄｉｌ）及血小板抑制剂阿斯匹林（ａｓｐｉｒｉｎ）对血管球囊成形术后内膜增生及重构的影响，为临床用药提供实验依据。方法对实验兔行髂动脉球囊成形术，术前３ｄ分别用ｔｒａｐｉｄｉｌ（２５ｍｇ·ｄ－１）及ａｓｐｉｒｉｎ（２５ｍｇ·ｄ－１），至术后２８ｄ取病变血管段切片染色，用计算机图像分析血管内膜、中膜厚度和腔面积、平均动脉面积的变化。结果ｔｒａｐｉｄｉｌ使腔面积扩大，平均动脉面积（外弹力膜内横截面积ＥＥＬ）增加明显，而ａｓｐｉｒｉｎ腔面积较ｔｒａｐｉｄｉｌ减少但较对照扩大，ＥＥＬ较对照及ｔｒａｐｉｄｉｌ组比较均减少。结论ｔｒａ－ｐｉｄｉｌ和ａｓｐｉｒｉｎ均抑制血管增生反应（以中膜平滑肌细胞为主），对血管重构的影响ｔｒａｐｉｄｉｌ较ａｓｐｉｒｉｎ明显     

普罗布考抑制再狭窄与其调节功能性血管重构的关系

目的　研究普罗布考抗动脉成形术后再狭窄与其调节功能性血管重构的关系。方法　用 3 5F球囊导管构建兔动脉粥样硬化动脉成形术后再狭窄模型。动脉成形术 2wk后取其胸主动脉 ,固定染色并进行计算机图像分析 ;观察血管环对乙酰胆碱诱导的舒张百分率 ,然后再观察其对内源性收缩物质去甲肾上腺素 (NA)、KCl以及 5 羟色胺 (5 HT)的收缩反应性。同时 ,在动脉成形术 2wk后留其血清 ,观察普罗布考对动脉成形术后血清一氧化氮 (NO)含量的影响。结果　普罗布考明显增加血管管腔面积 ,减少新生内膜面积 ;可保护动脉成形术后血管的舒张功能 ,保护内皮细胞合成与释放内皮源性舒张因子NO ,降低血管对内源性收缩物质的收缩反应性。结论　普罗布考能提高扩张性血管重塑 ,抑制收缩性血管重塑 ,从而防止动脉成形术后管腔缩窄防止再狭窄的发生     

Irbesartanf对大鼠髂动脉球囊内皮剥脱后血管壁增殖的影响

目的 观察Ｉｒｂｅｓａｒｔａｎ对血管损伤后内膜增殖的作用。方法２４只髂总动脉球囊内膜剥脱的Ｗｉｓｔａｒ大鼠随机等分为三组，分别于本前１天至术后１４天食管内喂饲Ｉｒｂｅｓａｒｔａｎ ３０ｍｇ／ｋｇ·ｄ或蒸馏水。术后１４天对损伤血管进行形态学检查。结果 Ｉｒｂｅｓａｒｔａｎ显著抑制损伤血管壁中细胞计数增加和内膜增厚以及血管平滑肌细胞增殖，并且有量效关系。对新生内膜中细胞密度影响不大。结论 Ｉｒｂｅｓａｒｔａｎ能够抑制大鼠髂总动脉球囊损伤后内膜增殖，Ｉｒｂｅｓａｒｔａｎ可能是防治血管成形术后再狭窄的有效药物。     

血管狭窄形成过程中血管塑形的作用

建立小型猪髂动脉内膜损伤后血管狭窄模型,结合计算机图像分析系统统计内膜及管腔变化过程。结果术后6天内,内弹力膜（IEL）下面积无明显变化,无血管狭窄形成;至第12天管腔狭窄形成,其中内膜增生占73．53％,IEL下面积减少占26．47％;至第30天,管腔狭窄加重,此时内膜增生占23.08％,IEL下面积减少占7692％。由此可见,血管狭窄的形成是由内膜增生和血管塑形共同作用的结果,在不同阶段二者的作用程度不同。     

重组人碱性成纤维细胞生长因子对大鼠动脉内皮损伤后再狭窄的影响

目的：探讨重组人碱性成纤维细胞生长因子（rh-bFGF)对经皮冠状动脉腔内成形术后再狭窄的预防效果。方法：用2F球囊导管造成大鼠左颈总动脉内皮损伤。治疗组每天im rh-bFGF 10kU/kg.分别于术后7天和14天,每组各处死大鼠10只,取左颈总动脉进行[^3H]胸腺嘧啶掺入测定和病理形态学检查。结果：在第7天和第14天时,与模型对照组相比,rh-bFGF治疗组颈总动脉平均新生内膜厚度明显变薄;平均中膜面积缩小;平滑肌细胞和弹力板层数减少;胶原含量及[^3H]胸腺嘧啶掺入量也比模型对照组明显降低。结论：适当应用rh-bFGF有抑制气囊损伤后动脉新生内膜增厚,降低再狭窄发生的作用。     

缬沙坦对球囊损伤后血管平滑肌细胞增生的影响

目的 探讨缬沙坦因子防治人类血管成形术后再狭窄的可行性方法观察新的非肽类血管紧张素Ⅱ的Ⅰ型(AT_1)受体拮抗剂,缬沙坦(Valsartan),对血管平滑肌细胞(VSMC)增生的影响。对大鼠髂动脉球囊内皮剥脱术后过度增生模型采用~3H-TdR和~3H-Leu掺入,免疫组化染色检测VSMC中增殖细胞核抗原(PCNA)的表达及图象分析血管壁形态学变化。结果 缬沙坦显著减少~3H-TdR和~3H-Leu的掺入量,减少新生内膜面积和PCNA阳性细胞数。结论 缬沙坦能抑制大鼠动脉的球褒内皮损伤后的VSMC增生,可能它是防治血管成形术再狭窄的有效药物。     

Irbesartanf对大鼠髂动脉球囊内皮剥脱后血管壁增殖的影响

目的 观察Irbesartan对血管损伤后内膜增殖的作用。方法 24只髂总动脉球囊内膜剥脱的Wistar大鼠随机等分为三组，分别于术前1天至术后14天食管内喂饲Irbesartan 30mg/kg·d或蒸馏水。术后14天对损伤血管进行形态学检查。结果 Irbesartan显抑制损伤血管壁中细胞计数增加和内膜增厚以及血管平滑肌细胞增殖，并且有量效关系。对新生内膜中细胞密度影响不大。结论 Irbesartan能够抑制大鼠髂总动脉球囊损伤后内膜增殖，Irbesartan可能是防治血管成形术后再狭窄的有效药物。     

血管内膜增生模型的建立:颈总动脉挤压法

目的　挤压大鼠颈总动脉 ,造成类似血管成形术后再狭窄的血管内膜增生病理模型。方法　暴露大鼠颈总动脉 ,在其上下各置一块 13mm× 5mm× 1mm钢片 ,以止血钳钳夹钢片 2 5min ,术后 2h、14d进行形态学观察。结果　术后2h ,扫描电镜可见血管内皮细胞变形、脱落 ,附有大量血小板。光镜可见血管壁有炎症细胞浸润 ,管腔内有血栓形成。术后 14d ,免疫组化血管壁PCNA表达强阳性 ,内膜面积占有率、中膜 +内膜面积占有率明显增加 ,管腔面积占有率明显缩小。类肝素、阿司匹林药物对PCNA表达及内膜增生有明显抑制作用。结论　挤压大鼠颈总动脉 ,可引起类似血管成形术后再狭窄的内膜增生病变     

动脉粥样硬化狭窄和再狭窄动物模型的实验研究

目的 :为经皮冠状动脉介入治疗(PCI)术后再狭窄研究提供理想动物模型。方法 :采用颈动脉逆行入径 ,用球囊导管对中国白兔双侧髂动脉行内膜损伤术 ,后给予高脂饮食建立双侧髂动脉粥样硬化狭窄模型 ,在此基础上行血管成形术建立再狭窄模型。结果 :(1)饲养后1 ,3,6周的血清胆固醇和甘油三酯水平显著高于饲养前 (P<0.01)。(2)血管成形术前髂动脉平均狭窄度左侧为 (50.80±14.12) %,右侧为 (51.20±13.94) % ,两者差别无统计学意义 (P>0.05),血管成形术后5周再狭窄程度模型组为 (55.20±14.47) %。 (3)病理HE染色及Masson染色示内膜显著增厚 ,主要由泡沫细胞、平滑肌细胞构成 ,内弹力膜分离断裂 ,中膜平滑肌细胞迁移入内膜层。 (4)透射电镜示膜结构破坏 ,胞浆内可见大小不等的脂质空泡沉积融合 ,多量胶原纤维束状增生。结论 :本方法成功建立了动脉粥样硬化狭窄和再狭窄动物实验模型 ,且简单、易行 ,模型稳定 ,重复性好     

通心络对兔外周血管球囊损伤后血栓形成及内膜增生的影响

目的观察中成药通心络对兔腹主动脉及骼动脉球囊损伤后血栓形成及内膜增生的影响。方法新西兰兔36只,随机分为3组通心络组16只,阿司匹林组11只,安慰剂组9只。各组服药剂量通心络0.38g     

Evidence supporting changes in Nogo-B levels as a marker of neointimal expansion but not adaptive arterial remodeling

Both neointimal hyperplasia and inward remodeling contribute to restenosis and lumen loss. Nogo-B has been recently described as an inhibitor of vascular injury and neointimal hyperplasia. To determine whether Nogo-B expression may be a mediator of inward remodeling, we examine the localization of expression of Nogo-B in an in vivo model that examines both neointimal hyperplasia and inward remodeling. The rabbit carotid artery was subjected to balloon injury, outflow branch ligation to reduce flow, or both balloon injury and reduction in flow. In balloon injury-induced neointimal hyperplasia Nogo-B expression was reduced in the intima and media but stimulated in the adventitia. In low flow-induced inward remodeling medial Nogo-B expression was not reduced and adventitial Nogo-B expression was not stimulated. Low flow significantly augmented balloon injury-induced neointimal hyperplasia and was accompanied by reduced intimal and medial Nogo-B expression, and increased adventitial Nogo-B expression in both smooth muscle cells and macrophages. Low flow-induced inward remodeling is not associated with changes in medial Nogo-B expression and is distinct from injury-induced neointimal hyperplasia. Pharmacological strategies to inhibit neointimal hyperplasia and restenosis using normal flow models may only partially account for lumen loss and therefore may not accurately predict responses in patients with extensive outflow disease.     

Adrenomedullin alleviates not only neointimal formation but also perivascular hyperplasia following arterial injury in rats

Producing components of the extracellular matrix, the vascular adventitia has been recognized as an important modulator of the vascular remodeling process, which determines the vessel architecture. In this study, we examined the effect of the vasodilator peptide adrenomedullin on vascular remodeling induced by balloon injury of rat carotid arteries. Endothelial denudation with wall stretch by ballooning not only induced neointimal formation accompanied with a reduced ratio of the lumen to vessel area, but also increased the fibroblast number and collagen deposition in the adventitial layer. When compared with the saline infusion, intravenous adrenomedullin infusion at 200 ng/h for 14 days suppressed the neointimal formation (-33%, P=0.033), reversing the ratio of lumen to vessel ratio (P=0.030), without affecting systolic blood pressure. Moreover, the adrenomedullin infusion decreased the number of adventitial fibroblasts (-41%, P<0.001) and the collagen deposition (-36%, P=0.006) in the adventitial layer of the injured artery. In conclusion, the intravenous adrenomedullin infusion effectively attenuates vascular remodeling following the arterial injury via suppression of hyperplasia in the intima and adventitia, suggesting a potential of adrenomedullin as a therapeutic tool against vascular remodeling.     

Novel approaches for the prevention of restenosis

Restenosis, the re-narrowing of the lumen of the coronary artery, in the months following a successful percutaneous balloon angioplasty or stenting, remains the main limitation to percutaneous coronary revascularisation. Serial intravascular ultrasound studies have shown that restenosis after conventional balloon angioplasty represents a complex interplay between elastic recoil, smooth muscle proliferation and vascular remodelling, while restenosis after stent deployment is due almost entirely to smooth muscle hyperplasia and matrix proliferation. Despite intensive investigation in animal models and in clinical trials, most pharmacological agents have been found to be ineffective in preventing restenosis after percutaneous balloon angioplasty or stenting. Although studies frequently report success in the suppression of neointimal proliferation in animal models of balloon vascular injury, few of them have been successful in clinical trials. Lately, the advent of endovascular radiation, new antiproliferative agents, recombinant DNA, growth factor regulators and novel local drug delivery systems have shown promising results. In the past five years, intracoronary radiation with gamma- and beta-emitting sources has been evaluated intensively with very encouraging results. This is the first potent non-pharmacological approach that has been successful in a large number of patients in controlling excessive tissue proliferation. It is very likely that a combination of stents and pharmacological and/or non-pharmacological inhibition of neointimal hyperplasia will likely result in further reductions in the incidence if restenosis. The continued attractiveness of percutaneous coronary revascularisation, as an alternative to medical treatment or bypass surgery for patients with coronary artery disease, will depend upon our ability to control the restenotic process. Due to the vast literature on the subject, this review will focus mainly on clinical trials that show the most promise and will highlight those that warrant further investigation.     

雌二醇抑制动脉球囊损伤后平滑肌细胞增殖

探讨雌二醇对去势大鼠颈总动脉球囊损伤后内膜增殖的影响。方法8～10wkSD大鼠雌性 (n=21)、雄性 (n=21) ,各分3个组 :非去势对照组 (n=7) ,去势对照组 (n=7) ,实验组 (n=7 ,去势 雌二醇 )。腹腔注射雌二醇3d后 ,2.0FPTCA球囊损伤左颈总动脉。损伤2wk后处死大鼠 ,测量内膜面积和中膜面积、内膜面积与中膜面积的比值。结果雄性实验组内膜面积 (0.072±0.020)mm2、内膜面积与中膜面积的比值0.533±0.037均显著小于非去势对照组 (0.110±0.018)mm2,0.740±0.051,P均<0.01 ,也均小于去势对照组 (0.098±0.014)mm2,0.701±0.040,P均<0.05。雌性实验组内膜面积 (0.061±0.015)mm2、内膜面积与中膜面积比值0.525±0.030均显著小于去势对照组 (0.101±0.018)mm2,0.710±0.031,P均<0.01,但与非去势对照组 (0.078±0.012)mm2、0.619±0.041差异不显著 ,P均>0.05。结论雌二醇能够抑制去势大鼠动脉损伤后内膜增殖。     

Neointimal formation after balloon-induced vascular injury in Yucatan minipigs is reduced by oral rapamycin.

Rapamycin, a macrolide antibiotic known to prevent allograft rejection, is a potent inhibitor of cell proliferation. Therefore we studied the effects of orally administered rapamycin in a pig model of balloon injury in an attempt to reduce the cellular proliferation and neointimal formation thought to play a role in restenosis. Twenty Yucatan minipigs, divided into groups of 10 animals each, were subjected to balloon inflation of the carotid arteries. One group received the methylcellulose vehicle for rapamycin, whereas the second group was treated for a total of 31 days with 2.0 mg/kg of rapamycin administered daily by oral gavage. This dose and treatment regimen produced significant (p < 0.05) reductions in neointimal area (59%) and in the maximal thickness of the neointima (59%) when comparisons were made with vehicle-treated animals. These effects were accompanied by a significant increase in the lumen area in animals that received rapamycin (33%). Medial area was decreased by 18% in these animals. Blood samples from rapamycin-treated pigs indicated peak concentrations of 1.87 +/- 0.45 and 1.70 +/- 0.24 ng/ml at 2 and 4 weeks after balloon angioplasty, respectively. Significant increases in blood pressure of 21 mm Hg and decreases in heart rate of 25 beats/min also were observed in rapamycin-treated animals relative to those that received vehicle. These results indicate that the antiproliferative effect of rapamycin can be demonstrated after oral dosing in a pig vascular injury model, suggesting a possible therapeutic utility for rapamycin or its analogs in patients undergoing balloon angioplasty.     

A critical role of COX-2 in the progression of neointimal formation after wire injury in mice

Background: Inflammation plays an important role in neointimal hyperplasia after vascular injury. COX-2 is a key mediator of inflammation and contributes to several inflammatory diseases. Although selective COX-2 inhibitors affect pathological conditions in inflammatory diseases, little is known about the effects on vascular remodeling after mechanical injury. Methods: To clarify the role of COX-2 in vascular remodeling after arterial injury, we made a wire-injury model using C57BL/6J mice. These mice were orally administrated a selective COX-2 inhibitor twice a day. COX-2 mRNA expression was analyzed in injured femoral arteries. Results: COX-2 expression was markedly enhanced in the arterial wall on day 7; the expression was gradually decreased from day 14. In histopathological analyses, the COX-2 inhibitor significantly suppressed the progression of neointimal formation in comparison with non-treated mice. In an in vitro study, RNA was collected from macrophages after stimulation. The stimulation resulted in enhanced expression of IL-6 compared with the control, and the COX-2 inhibitor decreased this expression. Conclusion: COX-2 is enhanced in the neointima after mechanical injury, and inhibition attenuated this. Therefore, regulation of COX-2 may be useful for preventing neointimal formation after coronary intervention.     

外照射结合~(192)Ir近距离组织间插植治疗外阴癌

目的探讨192Ir近距离组织间插植结合外照射治疗外阴癌的方法和预后。方法1995-03～1998-04治疗24例外阴癌(T2N0M08例,T3N1M012例,T2N2M04例),其中11例单纯外照射放疗,肿瘤剂量为40～50Gy。13例192Ir近距离组织间插植结合外照射,外照射肿瘤剂量为40～50Gy;192Ir近距离组织间插植术,插植钢针3～6枚。治疗剂量6～8Gy/次,每周1次,共4～6次,总剂量30～32Gy。结果单纯外照射组11例,1年肿瘤复发率46.0%,3年肿瘤复发率64.0%,5年肿瘤复发率90.0%。192Ir近距离组织间插植结合外照射组13例,1年肿瘤复发率15.0%,3年肿瘤复发率31.0%,5年肿瘤复发率38.5%。结论192Ir近距离组织间插植结合外照射治疗外阴癌优于单纯外照射,可明显降低外阴癌的肿瘤复发率。