兔后交叉韧带断裂后外侧胫骨平台退变的组织学研究

目的:探讨兔后交叉韧带(Posterior cruciate ligament,PCL)断裂对外侧胫骨平台组织学的影响。方法:48只家兔膝关节随机配对为实验侧和对照侧造模,造模后第4、8、16、24周各随机处死12只,行外侧胫骨平台大体观察、HE染色、免疫组化检测基质金属蛋白酶13(matrix metalloproteinase-13,MMP-13)、基质金属蛋白酶抑制剂1(Tisse inhibitor-1 of matrix metalloproteinase1,TIMP-1)表达。结果:①大体观察,随时间延长,实验组外侧胫骨平台软骨出现磨损,呈灰黄色,弹性差,骨赘形成。②组织学观察,随时间延长,胫骨平台软骨纤维化,细胞排列紊乱,簇聚细胞出现频率增加。③实验组MMP-13、TIMP-1表达均高于对照组,有显著性差异,P<0.05。④实验组MMP-13、TIMP-1表达阳性率第4、8、16周逐渐升高,24周下降,各组比较有显著性差异,P<0.05。结论:①兔膝关节PCL断裂会引起外侧胫骨平台软骨退行性变,且该退变随着时间的推移逐渐加重。②MMP-13与TIMP-1在PCL断裂膝关节外侧胫骨平台中的表达呈现先高后低的变化规律,造成MMP-13与TIMP-1的失衡,加速软骨退变。③MMP-13与TIMP-1表达增高提示MMP-13与TIMP-1可能参与了PCL断裂后外侧胫骨平台软骨的退变过程。     

羌活地黄汤对大鼠佐剂性关节炎软骨金属蛋白酶-1、13及基质金属蛋白酶抑制剂-1的影响

目的：观察羌活地黄汤对大鼠佐剂性关节炎软骨中基质金属蛋白酶-1（marxmetalloproteinase-1,MMP-1）、基质金属蛋白酶-13（matrixmetalloproteinase．13,MMP-13）及基质金属蛋白酶抑制剂-1（tissueinhibitorofmetalloprotease-1,TIMP-1）表达的影响。方法：Wistar大鼠32只,随机分为正常对照组、模型组、雷公藤对照组、羌活地黄汤组。制作大鼠佐剂性关节炎模型,造模第14天开始给药。羌活地黄汤组予混有羌活地黄汤的颗粒饲料,雷公藤组给予混有雷公藤多甙的饲料,正常组及模型组均给予普通饲料。第28天分别取各组胫骨平台关节软骨,采用免疫组织化学染色测定软骨中MMP-1、13及T1MP—1表达的阳性指数。结果：模型组MMP-1、MMP-13及TIMP—1表达的阳性指数水平明显高于正常组,差异有统计学意义（P〈0．01）,羌活地黄汤组MMP-1、13及TIMP-1表达阳性指数低于模型组,差异有统计学意义（P〈0．05）。结论：羌活地黄汤可能是通过调控软骨细胞外基质中MMP．1、MMP—13及TIMP-1表达变化而维持软骨的动态平衡,从而延缓RA骨骼破坏。     

关节腔注射强力霉素对兔膝骨关节炎模型的影响

目的:研究关节腔内注射强力霉素对兔制动性骨关节炎模型的影响.方法:30只新西兰大白兔随机分成正常组6只及实验组24只,试验组左膝关节伸直位石膏固定4周随机选取6只处死左膝关节取材证实造模成功后剩余18只为左膝骨关节炎模型,随机分为治疗组、阴性对照组和模型对照组,治疗组每日给予1.33%的强力霉素0.3毫升左膝关节腔内注射,阴性对照组每日给予生理盐水0.3毫升左膝关节腔注射,模型对照组不做处理,于8周处死取材.观察指标包括关节软骨大体形态,软骨Mankin's评分,软骨细胞基质金属蛋白酶-3(MMP-3)表达及滑膜细胞白介素-1(IL-1)表达.结果:强力霉素治疗组软骨面退变明显轻于模型组及生理盐水对照组,软骨大体评分,Mankin评分,MMP-3表达及滑膜IL-1表达亦显著降低.结论:强力霉素关节腔内注射对兔制动性骨关节炎模型软骨退变有明显的缓解作用.     

机械性去负荷后心室明胶酶及其组织型抑制剂与细胞外基质变化

目的：探讨左心室在去除压力和容量负荷下心室组织基质金属蛋白酶-2和-9及金属蛋白酶组织型抑制剂-1和-2表达水平与细胞外基质沉积量的关系。方法：12周龄雄性Lewis大鼠建立Lewis-to-Lewis腹腔异位心脏移植模型,形成左心室去负荷状态,并以同龄雄性Lewis大鼠胸腔原位心脏作为对照。移植后14d采用天狼猩红-偏振光法对移植和对照组心脏的ECM沉积量进行分析。心室组织MMP-2和MMP-9活性检测采用明胶酶谱法。MMP-2、MMP-9、TIMP-1、TIMP-2的mRNA表达水平检测采用荧光定量PCR法;TIMP-1和TIMP-2蛋白含量采用Western blot测定。结果：手术后14d,与原位心脏比较,腹腔移植心脏心肌细胞横截面积减小,并伴有心肌ECM沉积量增多（胶原容积分数5．22％±1．6％VS2．21％±0．9％,P〈0．05）,并且MMP-2、MMP-9明胶酶活性明显增强,MMP-2、MMP-9及其组织型抑制剂T1MP-1、TIMP-2的mRNA表达均增加（P〈0．05）,但TIMP-1、TIMP-2增加幅度较MMP-2、MMP-9高,TIMP-1、TIMP-2的蛋白含量均增加（P〈0．05）,TIMP-1增加幅度更为明显。结论：左心室在去除压力和容量负荷状态下心脏心室组织胶原沉积量增加,伴有MMPs／TIMPs系统失衡,尤其是TIMPs系统的明显上调。     

T140阻断SDF-1/CXCR4信号通路并在骨关节炎疾病模型中防止软骨退化

为了探讨T140通过靶向阻断SDF-1/CXCR4信号通路调节体内关节软骨退变的作用,并为以后的临床研究提供一定的参考,将45只健康的Hartley豚鼠随机分成3组,分别为:T140处理组(n=15)、磷酸盐缓冲盐水对照组(n=15)和未处理对照组(n=15)。分别在处理的2周、6周、8周、10周和12周,通过酶联免疫吸附测定法定量血清中的SDF-1。在治疗12周时,收集膝关节胫骨的软骨用于HE和番红-O染色同时进行Mankin分级;使用RT-PCR测量基质金属蛋白酶(MMP-3, MMP-9和MMP-13),聚集蛋白聚糖(ACAN)和胶原蛋白Ⅱ(ColⅡ)的m RNA表达水平;通过蛋白质印迹测量ColⅡ蛋白的表达水平。T140组中的SDF-1含量升高。与对照相比,HE和番红-O染色显示T140处理的动物中的软骨损失较少。T140组软骨中MMP-3、MMP-9和MMP-13的mRNA表达水平明显低于其他组。而T140处理组软骨中ACAN和ColⅡ的mRNA表达水平明显升高,T140组和对照组中的ColⅡ蛋白水平各不相同。T140可以通过在体内阻断SDF-1/CRCR4信号传导途径来下调基质金属酶的表达水平并减轻软骨的变性,为治疗OA的药理学提供了靶标。     

丹参单体IH764-3通过下调H2O2刺激的肝星状细胞FAK水平影响MMP-13和TIMP-1的表达

目的：研究丹参单体IH764—3对H2O2刺激的肝星状细胞（HSC）基质金属蛋白酶-13（MMP-13）、基质金属蛋白酶组织抑制因子-1（TIMP-1）表达的影响以及此过程中粘着斑激酶（FAK）的变化。方法：应用RT-PCR方法检测MMP-13及FAKmRNA表达,原位杂交方法检测TIMP-1mRNA水平,Western blotting技术检测FAK及TIMP-1蛋白表达。结果：IH764—3干预组的MMP-13mRNA在2h的表达强度明显上调,而TIMP-1mRNA表达明显受抑,FAKmRNA表达强度明显下调;IH764—3干预24h组FAK及TIMP-1蛋白表达受抑制。结论：丹参单体IH764—3可以诱导MMP-13表达,抑制TIMP-1表达,下调FAK表达是其中的机制之一。     

MMP-2, -9, -14及其抑制剂TIMP-1, -2, -3在恒河猴周期黄体中的时空表达

用原位杂交和免疫组织化学方法研究了基质金属蛋白酶MMP-2, -9, -14及其组织抑制因子TIMP-1, -2, -3在恒河猴周期黄体发育不同阶段的协同表达. 结果显示: MMP-2 mRNA及其蛋白主要表达在早中期发育黄体的内皮细胞上, 在晚期黄体发生萎缩时则大量表达于黄体细胞; MMP-9, -14及其TIMP-1, -2, -3主要表达于黄体细胞; MMP-14 mRNA在早期和晚期黄体中高表达, MMP-9蛋白只在晚期黄体中高表达; TIMP-3蛋白在早、中、晚三期黄体中表达均较高, 但很明显晚期表达降低. 结果提示: MMP/TIMP系统参与灵长类黄体发育的调控, MMP-2, -14及其TIMP-1, -3可能参与黄体的形成和功能维持, 同时MMP-2, -9, -14及其TIMP-1, -2, -3在黄体萎缩期的协同表达, 提示它们可能在黄体发生萎缩时发挥作用.     

己酮可可碱对肺纤维化大鼠MMP-2和TIMP-1表达的影响

目的观察己酮可可碱(pentoxifylline, PTX)对博来霉素致肺纤维化大鼠肺组织基质金属蛋白酶2(matrix metalloproteinase-2)和基质金属蛋白酶组织抑制剂1(tissue inhibitor of matrix metalloproteinase-1)表达的影响,初步探讨其抗肺纤维化的作用机制.方法 SD大鼠36只,随机分为模型组、治疗组和对照组.模型组和治疗组气管内注射博来霉素诱导肺纤维化,对照组在相同条件下给予生理盐水.第二天起治疗组大鼠腹腔给予己酮可可碱6mg/kg.d,其余两组相同条件下给予生理盐水.治疗的第7d和28d,处死动物取出肺组织,用RT-PCR和免疫组化ABC法观察各组鼠肺组织MMP-2和TIMP-1表达的变化. 结果与模型组比较,治疗组经PTX作用的第7d和28d肺组织中MMP-2和TIMP-1 mRNA的基因转录均有减少,MMP-2 mRNA表达分别降低33.4%和35.5%(P＜0.001),TIMP-1 mRNA表达分别降低25.3%和33.0%(P＜0.05).免疫组化结果则显示,PTX作用的第7d和28dMMP-2分别较模型组降低30.7%和41.7%(P＜0.05),TIMP-1分别降低13.1%和19.8%(P＜0.05).结论 PTX对肺纤维化不同时期肺组织中MMP-2和TIMP-1的表达均有一定程度的降低作用,其可能通过调整MMP-2和TIMP-1比值使其趋于平衡,从而延缓甚至抑制纤维化的进程.     

慢性肾小球肾炎患者血清MMP-9和TIMP-1的浓度及意义

目的:观察慢性肾小球肾炎血清基质金属蛋白酶9(matrix metalo protein-ase-9,MMP-9)、金属蛋白酶组织抑制剂1(tissue inhibitors of metalloproteinases,TIMP-1)的浓度与肾组织中MMP-9、TIMP-1表达的相关性,探讨慢性肾小球肾炎血清MMP-9、TIMP-1对肾脏纤维化的判断价值。方法:通过肾组织活检病理检查,将入选慢性肾炎的病例分增生组(A组)15例,纤维化组(B组)15例,另选10例志愿者作为健康对照组C组。应用免疫组化法观察A、B两组MMP-9、TIMP-1在肾组织中的表达情况,并且进行半定量分析,比较它们之间有无差别。应用ELISA双抗体夹心法检测A、B、C三组MMP-9、TIMP-1在血清中的浓度,比较它们之间有无差别。观察A、B两组MMP-9、TIMP-1在肾组织中的表达水平与在血清的浓度有无相关性。结果:A、B两组MMP-9在肾小球和肾间质少见表达,主要在肾小管上皮细胞浆中表达增高,两组之间表达的强度有显著差异性;A组TIMP-1在肾小球中少见表达,在肾小管上皮细胞增强。B组TIMP-1在肾小球中有少量表达,在肾小管上皮细胞较A组进一步增强,两组之间表达的强度有显著差异性(P0.05)。血清中MMP-9、TIMP-1浓度在A、B组显著高于C组,血清中MMP-9在A、B两组之间无显著差异性,血清中TIMP-1在A、B、C三组间两两比较有显著差别(P0.05)。结论:慢性肾炎患者血清中MMP-9、TIMP-1浓度与肾脏组织中MMP-9、TIMP-1的表达呈正相关。MMP-9、TIMP-1的相关性分析P值小于0.01。血清MMP-9、TIMP-1参与了肾脏纤维化的进展,慢性肾小球肾炎血清中MMP-9、TIMP-1的浓度可在一定程度上反映肾脏纤维化程度。     

基质金属蛋白酶及其抑制剂在乳腺癌中的表达

目的:研究基质金属蛋白酶2(Matrix Metalloproteinase-2,MMP-2),基质金属蛋白酶7(MMP-7),基质金属蛋白酶9(MMP-9),膜型基质金属蛋白酶(Membrane Type-1 Matrix Metalloproteinase,MT1-MMP),金属蛋白酶组织抑制剂1(Tissue Inhibitor of Metalloproteinase,TIMP-1),金属蛋白酶组织抑制剂2(TIMP-2)在乳腺癌组织中mRNA的表达,及与临床病理变量之间的关联。方法:采用150例乳腺癌患者的组织样本。使用半定量逆转录-聚合酶链反应(RT-PCR)法来测定肿瘤组织和正常乳腺组织中MMP-2,MMP-7,MMP-9,MT1-MMP,TIMP-1和TIMP-2的mRNA表达。结果:MMP-2,MMP-7,MMP-9,MT1-MMP,TIMP-1和TIMP-2在乳腺癌中的mRNA表达显著高于正常组织。结论:MMP-2,MMP-7,MMP-9,和MTI-MMP的表达增加和临床病理参数之间的关联,可以用来预测乳腺癌的侵害行为。     

基质金属蛋白酶及其抑制因子与扩张型心肌病的关系

目的研究基质金属蛋白酶-2(MMP-2)及金属蛋白酶组织抑制因子(TIMP-1)在扩张型心肌病(DCM)中的变化,探讨血管紧张素转换酶抑制剂(ACEI)对心肌纤维化的影响及其调控机制。方法雄性SD大鼠腹腔注射阿霉素(2 mg/kg,每周1次,连续8周)建立扩张型心肌病模型。将达到DCM诊断标准的大鼠分3组:①H组(卡托普利高剂量干预组,50mg/Kg.d);②L组(卡托普利低剂量干预组,25mg/Kg.d);③C组(DCM对照组)。HE染色和苦味酸天狼星红染色观察各组大鼠心肌细胞和间质胶原变化,RT-PCR法检测心肌MMP-2及TIMP-1的表达。结果与正常对照组比较,DCM组心肌细胞坏死明显、胶原纤维和胶原容积分数增加(P<0.05);而H组和L组的胶原纤维较C组减少(P<0.05)。DCM组心肌MMP-2 mRNA表达较正常对照组显著增加(P<0.01),H组和L组较C组降低(P<0.05)。DCM组TIMP-1mRNA的表达较正常对照组降低(P<0.05),H组较C组有所增加(P<0.05)。结论 MMP-2及TIMP-1与心肌细胞外基质的重塑密切相关,ACEI有降解MMP-2的作用,可以减轻心肌间质的...     

Age-related changes in the expression of gelatinase and tissue inhibitor of metalloproteinase genes in mandibular condylar,growth plate,and articular cartilage in rats

Summary Mandibular condylar cartilage acts as both articular and growth plate cartilage during growth, and then becomes articular cartilage after growth is complete. Cartilaginous extracellular matrix is remodeled continuously via a combination of production, degradation by matrix metalloproteinases (MMPs), and inhibition of MMP activity by tissue inhibitors of metalloproteinases (TIMPs). This study attempted to clarify the age-related changes in the mRNA expression patterns of MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-3 in mandibular condylar cartilage in comparison to tibial growth plate and articular cartilage using an in situ hybridization method in growing and adult rats. MMP-2 and MMP-9 were expressed in a wide range of condylar cartilage cells during growth, and their expression domains became limited to mature chondrocytes in adults. The patterns of TIMP-1 and TIMP-2 expression were similar to those of MMP-2 and MMP-9 during growth, and were maintained until adulthood. TIMP-3 was localized to hypertrophic chondrocytes throughout the growth stage. Therefore, we concluded that TIMP-1 and TIMP-2 were general inhibitors of MMP-2 and MMP-9 in condylar cartilage, while TIMP-3 regulates the collagenolytic degradation of the hypertrophic cartilage matrix.     

An in situ hybridization study of MMP-2, -9, -13, -14, TIMP-1, and -2 mRNA in fetal mouse mandibular condylar cartilage as compared with limb bud cartilage

The main purpose of this in situ hybridization study was to investigate MMPs and TIMPs mRNA expression in developing mandibular condylar cartilage and limb bud cartilage. At E14.0, MMP-2, -14, TIMP-1 and -2 mRNAs were expressed in the periosteum of mandibular bone, and in the condylar anlage. At E15.0 MMP-2, -14, TIMP-1 and -2 mRNAs were expressed in the perichondrium of newly formed condylar cartilage and the periosteum of developing bone collar, whereas, expression of MMP-14 and TIMP-1 mRNAs were restricted to the inner layer of the periosteum/perichondrium. This expression patterns continued until E18.0. Further, from E13.0 to 14.0, in the developing tibial cartilage, MMP-2, -14, and TIMP-2 mRNAs were expressed in the periosteum/perichondrium, but weak MMP-14 and no TIMP-1 mRNA expression was recognized in the perichondrium. These results confirmed that the perichondrium of condylar cartilage has characteristics of periosteum, and suggested that MMPs and/or TIMPs are more actively involved in the development of condylar (secondary) cartilage than tibial (primary) cartilage. MMP-9-positive cells were observed in the bone collar of both types of cartilage, and they were consistent with osteoclasts/chondroclasts. MMP-13 mRNA expression was restricted to the chondrocytes of the lower hypertrophic cell zone in tibial cartilage at E14.0, indicating MMP-13 can be used as a marker for lower hypertrophic cell zone. It was also expressed in chondrocytes of newly formed condylar cartilage at E15.0, and continuously expressed in the lower hypertrophic cell zone until E18.0. These results confirmed that progenitor cells of condylar cartilage are rapidly differentiated into hypertrophic chondrocytes, which is a unique structural feature of secondary cartilage different from that of primary cartilage.     

外源性uPA对兔椎间盘作用的初步研究

目的：通过不同浓度外源性尿激酶型纤溶酶原激活剂（uPA）兔椎间盘内注射,探讨uPA对椎间盘作用。方法：健康大白兔72只,随机分为实验组48只,阴性对照组16只,空白对照组8只。实验组：分为三个亚组,L4／5椎间盘内分别注射浓度为10、20、40ng／μl的uPA各1μl。阴性对照组：椎间盘内注射1μl的生理盐水。空白对照组：不作任何处理。分别于第3、6周取相应椎间盘,大体观察、HE染色、SABC法测基质金属蛋白酶-3（MMP-3）的表达及蛋白多糖含量测定。结果：实验组MMP．3表达显著增强,蛋白多糖含量明显降低,与同期对照组比较（P〈0．05）,有显著统计学意义。实验组在不同时间及不同浓度比较也有统计学意义。结论：外源性uPA能够导致兔椎间盘内蛋白多糖含量降低,MMP-3表达显著增强,可能在椎间盘退变过程中其重要作用。     

Chronic changes in the rabbit tibial plateau following blunt trauma to the tibiofemoral joint

The knee is often a site of injury that can often lead to a chronic disease known as osteoarthritis (OA). The disease may be initiated, in part, by acute injuries to joint cartilage and its cells. In a recent study by this laboratory, using Flemish Giant rabbits, an impact compressive load on the tibial femoral joint was shown to cause significant levels of acute damage to chondrocytes in cartilage of the medial and lateral tibial plateaus. In the current study, using the same model, histological and mechanical data from the plateaus were documented at 6 and 12 months post impact, and compared to the unimpacted control limbs and a limb from unimpacted, control animals. The mechanical properties of cartilage were measured with indentation relaxation tests on the medial and lateral plateaus in regions covered and uncovered by the meniscus. The histological studies on impacted limbs showed surface lesions on both plateaus, thickening of the underlying subchondral bone at 12 months and numerous occult microcracks at the calcified cartilage–subchondral bone interface at 6 and 12 months, without significant changes in cartilage thickness or its mechanical properties versus controls. Yet, there was an increase in both the matrix and fiber moduli and a decrease in the permeability of uncovered, medial plateau cartilage in both limbs of impacted animals between 6 and 12 months post impact that was not documented in control animals.     

曲美他嗪对肺动脉栓塞所致右心衰竭的保护作用

目的：评价曲美他嗪（TrimetazidineTMZ）对肺动脉栓塞所致右心衰竭的保护作用,及其对MMP-2,MMP-9和TIMP-1mRNA在右心室中表达的影响。方法：雄性wistar大鼠随机分为三组：右心衰竭组（RHF）左侧股静脉注射1％玻球微粒3mV100g;等量生理盐水注射为对照组（CON）;曲美他嗪治疗组（TMZ）为肺动脉栓塞后给TMZl0mg／kg／天。6周后各组大鼠首先进行经胸超声评价右心功能后取材进行病理学检测,以及RT—PCR检测右心室MMP-2,MMP-9,TIMP-1mRNA表达水平。结果：RHF组大鼠超声检测发现右心室内径扩大并伴有三尖瓣反流,三尖瓣环收缩期峰值位移下降（TAPSE）;Masson染色显示右心室纤维化增加;RTPCR结果显示MMP-2,MMP-9和TIMP-1mRNA表达水平明显升高;经TMZ治疗组大鼠右心室内径减小,TAPSE增加,而MMP-2,MMP-9和TIMP-1mRNA表达水平下降。结论：曲美他嗪能够抑制右心室纤维化,改善右心功能,可能与调节MMP-2,MMP-9和TIMP-1表达水平有关。     

Alleviation of osteoarthritis by Trichostatin A, a histone deacetylase inhibitor, in experimental osteoarthritis

This study investigated the effects of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on cartilage degradation in an experimental model of osteoarthritis (OA). Thirty-two male New Zealand rabbits underwent unilateral anterior cruciate ligament transection (ACLT) on left knee joints to induce OA and were randomly divided into two groups (n = 16), the TSA group was injected intra-articularly with 0.3 ml TSA [250 ng/ml in the dimethylsulphoxide (DMSO)], the OA group received DSMO since 4 weeks after operation once a week for 5 weeks. Rabbits were killed seven days after the last injection. Left knee cartilage was harvested for morphological, histological and genetic analysis. Another ten rabbits were used for normal control and received no injection. The TSA group showed less cartilage degradation as compared to the OA group assessed by morphological and histological evaluation. Gene expression of matrix metalloproteinase-1 (MMP-1), MMP-3, MMP-13, and interleukin-1 (IL-1) was increased significantly in the OA group compared to the normal group. The elevated expression was reduced by TSA. Our results suggest that TSA could be considered as a potential agent for treatment for OA.     

非小细胞肺癌中基质金属蛋白酶13和其抑制剂1表达及与预后的关系研究

目的研究非小细胞肺癌MMP-13、TIMP-1蛋白表达,探讨其与淋巴结转移及预后的关系。方法应用免疫组织化学检测99例非小细胞肺癌组织以及32例正常肺组织中MMP-13、TIMP-1蛋白的表达。结果①MMP-13、TIMP-1蛋白在非小细胞肺癌组织的阳性率分别为51．5％（51／99）和59．6％（59／99）,较正常肺组织中阳性率0%（0／32）和15．6％（5／32）显著增高（P〈0．05）。MMP-13、TIMP-1蛋白表达在不同性别、年龄、组织学类型之间无显著性差异,而与淋巴结转移以及临床分期显著相关（P〈0．01）。MMP-13蛋白表达与临床分期以及淋巴结转移呈正相关（P〈0．01）;TIMP-1蛋白表达与临床分期以及淋巴结转移呈负相关（P〈0．01）。②Kaplan-Meier法显示MMP-13、TIMP-1蛋白与非小细胞肺癌预后相关,Cox多因素模型分析显示MMP-13蛋白表达可以作为非小细胞肺癌独立的预后因子,其过表达提示预后不良;而TIMP-1不能作为独立的预后因子。结论MMP-13是影响预后的独立指标;TIMP-1是影响预后有意义的指标。