著床和機(jī)理第章

第章著床和著床機(jī)胞生長形成胎盤。胚胎著床的部位一般在體前、后壁。胚和內(nèi)膜必須同步發(fā)言并相互配合；④孕婦體內(nèi)必須有足夠數(shù)量的孕酮。首先后6～7天早期囊胚的透明帶，胚胎被引導(dǎo)到內(nèi)膜，附著于特定的部位，同時內(nèi)膜在孕激素的作用下分化到可接受胚胎種植的狀態(tài)。它包括內(nèi)膜形態(tài)上的一系列常復(fù)雜的過程，它涉及、內(nèi)膜以及胚胎。在周期中分泌激素的變化刺激內(nèi)膜的組織形態(tài)發(fā)生了相應(yīng)的變化首先在增生期，（一）胚胎的著從胚胎內(nèi)著床前的準(zhǔn)備始首先膜在孕直接或接作用部D3T細(xì)胞由4%10%56+K育至在著床期主要細(xì)胞分泌一些細(xì)因子和長因（G-β、LI，促進(jìn)了對胚胎的別。另外在內(nèi)的著床容受期形過程中，胎也起了要作用。發(fā)育良好的胚胎使內(nèi)膜進(jìn)一步做好接受胚泡植入的準(zhǔn)備，調(diào)節(jié)內(nèi)膜生物活性物質(zhì)的產(chǎn)生并控制著引導(dǎo)胚胎粘附于內(nèi)膜，完成著床的附著過程（appositionphase。該過程中的免疫變化主要包括，１．抗粘附分子降解抗粘附分子是內(nèi)膜上皮細(xì)胞頂端糖-蛋白結(jié)合物，是胚胎著床過程中的第一MUC-1的研究最深入。部。MUC1相關(guān)配基為選擇素。人的內(nèi)膜中的MUC1逐步增加，到分泌晚期合成下降。在雌激素替代治療中它缺乏周期性變化，MUC1的表達(dá)。細(xì)胞角蛋白染色進(jìn)一步證實(shí)，著床部位胚對內(nèi)膜上皮細(xì)胞分泌MUC1的能力進(jìn)行非常精細(xì)的調(diào)節(jié)。圖圖X-1.激素和囊胚 內(nèi)膜上皮細(xì)胞分泌MUC1的能力進(jìn)行的精細(xì)調(diào)2．趨化因子趨化因子是細(xì)胞因子超中的一員，多數(shù)為小分子多肽（70~80個氨基酸對定的白細(xì)胞有定向趨化作用它們參與分娩和胚胎著床以及一些病理狀態(tài)如早產(chǎn)、內(nèi)膜異位癥、OHSS和HIV。一般根據(jù)起始的2~4個連續(xù)絲氨酸殘基的位置將趨化因子分為兩類，αCXC趨化因子（IL-8）βCC趨化因子（MCP-1，RANTES對單核細(xì)胞、巨噬細(xì)胞、T細(xì)胞、嗜堿性粒細(xì)胞、肥大細(xì)胞和NK細(xì)胞有定向趨化和激活作用。RANTEST細(xì)胞的一種細(xì)胞趨化因子，主要由正常內(nèi)膜和異位種植的內(nèi)膜的實(shí)質(zhì)細(xì)胞產(chǎn)生。還能調(diào)節(jié)活化T細(xì)胞的合成和分泌功能。它不TT細(xì)胞的吸引，進(jìn)一步加速趨化作用。CarlosSimon等人就胚胎對趨化因子的調(diào)節(jié)進(jìn)行研究發(fā)現(xiàn)，IL-8、MCP-1及其相應(yīng)的受體表達(dá)于腺Blot方法進(jìn)行檢測時，在內(nèi)膜中僅檢測到RANTES-mRNA，而在體外與囊胚共培養(yǎng)的EECs中未RANTES-mRNAIL-8MCP-1mRNA，流式細(xì)胞檢測方法也證實(shí)了該中EECs合成IL-8和MCP-1。以上表明囊胚參與了囊胚附著期間內(nèi)膜趨化因子作用的調(diào)節(jié)和（二）phase，（pinopodes，降解，內(nèi)膜上皮粘附分子介導(dǎo)囊胚和內(nèi)膜的結(jié)合以及細(xì)胞因子、生長因子、leptin等生物活性物質(zhì)１．胞飲突（pinopodes）pinopode的形成通過掃描電鏡研究發(fā)現(xiàn)，著床期間內(nèi)膜上皮細(xì)胞表突僅在胚胎著床的粘附期出現(xiàn)，而且只表達(dá)在內(nèi)膜腔上皮頂端。如，在后D6（接受性）婦女B受體表達(dá)下調(diào)有關(guān)。目前MUC-1在著床期間的變化已在附著期詳細(xì)介紹。３．粘附分子介導(dǎo)囊胚與內(nèi)膜的粘附孵化胚胎對內(nèi)膜上皮的粘附依賴與粘附分子的表達(dá)。這些分子包括免疫球蛋白超和選擇素有人認(rèn)為Trophin、Bystin和Tastin形成的細(xì)胞粘附分子復(fù)合物可能介導(dǎo)了粘囊胚和內(nèi)膜的初被整合素等其他粘附分子取代，使囊胚與內(nèi)膜形成更牢固的粘附關(guān)系。期（相當(dāng)于著床窗時期）僅表達(dá)于內(nèi)膜的腺上皮。αvβ3整合素的出現(xiàn)于著床窗時期，它在著如合并和內(nèi)異癥時，過多的表達(dá)補(bǔ)體可能導(dǎo)致粘附失敗。（三）侵入期（invasion，在侵入期內(nèi)膜基質(zhì)蛋白酶的變化，導(dǎo)致細(xì)胞外間質(zhì)降解，并保持局部的止血和蛻膜中新生血管的形成而內(nèi)膜上皮細(xì)胞的凋亡使胚泡能內(nèi)膜上皮屏障植入內(nèi)膜著床后蛻膜胎盤形成，，LIFEGFMMP-9２．EECs凋亡的調(diào)節(jié)細(xì)胞凋亡參與了多種的生殖過程，如的功能、內(nèi)膜生理變化、著細(xì)胞，內(nèi)膜基質(zhì)細(xì)胞很少波及。Fas(CD95)和Fas-L(CD95L)在整個周期共表達(dá)于人內(nèi)膜腺體的內(nèi)膜上皮細(xì)胞凋亡是侵蝕上皮細(xì)胞關(guān)鍵步驟。Galan等人研究了附著期和粘附期單個囊胚對培養(yǎng)的人內(nèi)EEC凋亡數(shù)（35.2%）EEC（48.8%，P<0.05（39.2%EEC中出現(xiàn)了大量的凋亡產(chǎn)生。這種胚胎的誘導(dǎo)作用可能是囊胚外胚層和EECs的直接作用。Fas/Fas-L系統(tǒng)是囊胚穿過上皮細(xì)胞屏障的重要機(jī)制，后的生長明顯下降(40%versus82.8%)。（四）后第7天,滋養(yǎng)細(xì)胞分泌蛋白酶類物質(zhì),內(nèi)膜上皮局部溶解破壞，滋養(yǎng)細(xì)胞上皮，第8～9天，合體滋養(yǎng)層深人內(nèi)膜中，繼續(xù)侵蝕。消化和破壞基質(zhì)，形成眾多滋養(yǎng)腔隙，其間充滿母血第11～12天整個囊腔埋植于基質(zhì)中植迅速被內(nèi)膜上皮包蓋著床過程完成。VEGFPLGFPAFHGF以及上皮細(xì)胞上表達(dá)的c-mettyrosinekinase受體，參與細(xì)胞滋養(yǎng)細(xì)胞的分化、生長，可能還參與對侵蝕深度其他參與調(diào)節(jié)滋養(yǎng)細(xì)胞生長的還有，IL-1、干細(xì)胞因子、CSF-1、IGF、Th細(xì)胞因子。IL-1CSF-1IGFBP-1Th-1IFN-γTNF限制滋養(yǎng)細(xì)胞的生長。hCG和孕酮的合成。素作用下，內(nèi)膜HOXA-9，HOXA-10和HOXA-11調(diào)節(jié)內(nèi)膜實(shí)質(zhì)細(xì)胞的生長。HOXA-11還能促進(jìn)LIF表達(dá)。HOXA-10和LIF影響內(nèi)孕酮受體的表達(dá)，促進(jìn)蛻膜化。IL-11也可能參與了蛻膜化，經(jīng)IL-11受體的小鼠存在蛻膜化不完全的表現(xiàn)。泡的一段短暫時期，即所謂的“著床窗”或“種植窗。內(nèi)膜的著床窗是短暫，同時在各個周期出現(xiàn)時是有空間性的。它代表了內(nèi)膜上皮細(xì)胞的接受性。此時內(nèi)膜的上皮細(xì)胞（EE）和滋養(yǎng)外胚，（TE）進(jìn)行了直接的接觸內(nèi)膜出現(xiàn)許多的細(xì)胞和生物化學(xué)的改變作為標(biāo)記。這些改變是受到，①表達(dá)于內(nèi)膜上皮細(xì)胞②它應(yīng)該是甾體激素依賴性的，尤其是孕激素依賴性的，具有周期性變化④knock-out動物模型表現(xiàn)為著床人們對胚胎著床的認(rèn)識是隨著科學(xué)研究的不斷發(fā)展而不斷深入的。knock-out小鼠模型建立技術(shù)，發(fā)現(xiàn)了許多在著床中起重要作用的生物活性物質(zhì)。體外囊胚-單層內(nèi)膜上皮細(xì)胞培養(yǎng)體系目前已知的著床窗標(biāo)記物包括如下分子：①細(xì)胞因子：包括IL-1-18，CSF，IFN，TNF，和趨化因1．胞飲突（pinopodes）胞飲突是著床窗在細(xì)胞水平上的標(biāo)志。胞飲突是孕激素依賴的，僅出現(xiàn)于囊胚粘附期，也見于分泌中期的內(nèi)膜。大劑量的雌激素抑制胞飲突的形成，同時也抑制了著床過程。它的形成維持不到48小時，出現(xiàn)的鼎盛時期是第19~21天（以28天周期為例，多在20天。正常周期：D19~21，多在D20（D13為LH峰時間D18~8（D4：D20~22，（ECM合素受甾體激素調(diào)節(jié)，如α1和α4是孕酮驅(qū)動的，在孕酮開始產(chǎn)生，孕酮受體達(dá)到最大峰值時出現(xiàn)，β1在孕酮達(dá)到峰值，孕酮受體最少時產(chǎn)生。對不同整合素敲除的小鼠進(jìn)行研究發(fā)現(xiàn)，β1敲除小鼠的胚胎能夠發(fā)育到囊胚，但不能著床，α4、α5、α6、αv、β3敲除的小鼠沒有著床相關(guān)現(xiàn)象。類除了注意組織學(xué)表現(xiàn)的變化外，還兼顧了整合素αvβ3的表達(dá)情況。新的內(nèi)膜缺陷分類如下：型組織學(xué)表現(xiàn)為內(nèi)膜分泌變化延遲，同時缺乏αvβ3型無組織學(xué)表現(xiàn)，但接受性標(biāo)記αvβ3缺乏，多見于輕微內(nèi)異癥患者、積水、不明原因不孕、PCOS患者。３．Trophin、Bystin、Tastin復(fù)合體Trophinin是一種型的細(xì)胞膜內(nèi)在蛋白，屬于細(xì)胞膜粘trophinin、bystin、tastinEECs的粘附。而小鼠實(shí)驗(yàn)中，trophinin蛋白在其內(nèi)膜的表達(dá)僅限于胚胎著床窗時期，trophinin位點(diǎn)突變的胚胎大多于假想的著床窗時期。成人正常組織細(xì)胞中trophinin、bystin、tastin僅表達(dá)于單核巨噬細(xì)胞、參與著床的分泌期內(nèi)6~8周的胎盤絨毛細(xì)胞４．L-選擇素（L-selectin）L-選擇素是一種糖基結(jié)合蛋白，它通過特殊的寡糖結(jié)構(gòu)，作用于白細(xì)的連接，從而移行到局部組織。D.OlgaL-選擇素是胚胎著床的初始步驟。法在分泌期的內(nèi)膜和內(nèi)膜上皮細(xì)胞中也檢測到瘦素及其受體的表達(dá)。ob/ob突變的小鼠分泌缺乏活性的瘦素蛋白片段，表現(xiàn)為肥胖和不孕，這些小鼠的生殖功能能６．白血病抑制因子（LeukemiaInhibitoryFactor，LIF）白血病抑制因子是一種由180個氨基酸組成的糖蛋白，單拷貝，高度保守，通過LIF-R和gp130（glycoprotein130）作用于靶細(xì)胞，參與LIF敲除小鼠囊胚不著床但其囊胚移植到正常小鼠后種植成功在其腹腔內(nèi)注射LIF也R，LIF能促進(jìn)胚胎發(fā)育和囊胚孵化。原因不明不孕婦女通過檢測發(fā)現(xiàn)沖洗液中LIF表達(dá)下降，部７．同源框（homeobox，Hox）Hox是一類控制胚胎發(fā)育和細(xì)胞分化的調(diào)節(jié)，其同或種植不久被吸收——內(nèi)膜血管通透性和蛻膜化嚴(yán)重?fù)p傷。Hoxa11缺陷小鼠存在生殖功能缺陷，Hoxa10突變小鼠LIF及其受體表達(dá)正常，而LIF是Hoxa10的上游調(diào)節(jié)Hoxa10突變小鼠COX-2表達(dá)顯著下降，提示Hoxa10是其上游調(diào)節(jié)，而Hoxa11突變小鼠以上說明LIF–HOX-COX-2之間存在相控８．集落刺激因子-1（ColonyStimulatingFactor-1，CSF-1）CSF-1由巨噬細(xì)胞分泌，調(diào)節(jié)巨噬細(xì)胞增殖分化，受雌孕激素調(diào)節(jié)，由內(nèi)膜上皮細(xì)胞、成纖維細(xì)胞以及上皮細(xì)胞分泌。CSF－l存在兩種形式，可溶性的CSF-1和內(nèi)膜上皮細(xì)胞成膜結(jié)合形式。可溶性的CSF-1在兩力低下，子代偏小，有研究表明可能與其周期延長有關(guān)。患者中CSF-1水平低于正常婦女。甚至有作者認(rèn)為外周血低CSF-1可能與復(fù)發(fā)性有關(guān)。９．白細(xì)胞介素-1（Interleukin-1，IL-1）IL-1是由多種細(xì)胞產(chǎn)生的一種多肽，有兩種亞型：IL-1α和IL-1?。其受體屬于免疫球蛋白超，可能是胎母交流中第一個被活化的因子，并引起一系列的IL-1是胚胎著床過程的主要影響因素。IL-1knock-out小鼠模型不孕，可能直接影響了內(nèi)膜，給予IL-1ra能囊胚粘附——正常內(nèi)膜形態(tài)的轉(zhuǎn)化，還能下調(diào)內(nèi)膜整合素α4，αv、?3的表達(dá)。受IL-1ra處理的小鼠胚胎在正常中發(fā)育正常，但不能著床。，內(nèi)膜中發(fā)揮功能中期明顯升高。IL-1R主要表達(dá)于蛻膜和胎盤。種植前胚胎表達(dá)IL-1?、IL-1ra、IL-1RtImRNA。，IL-1PGE2?3和LIF表達(dá)增IL-1?。肝素結(jié)合性表皮生長因子（heparin-bindingepidermalgrowthfactor，HB-EGF）HB-EGF是表皮生長因子（EGF）超成員之一，為分子量約22kD的單鏈蛋白質(zhì)，通過細(xì)胞表面的EGF受體較強(qiáng)的親和性而得名。HB-EGFproHB-EGF）為其前體的形式存在于細(xì)胞HB-EGF在小鼠胚泡著床前和著床部位的內(nèi)膜，以及豬胚泡種植前的內(nèi)膜腺上皮細(xì)胞均有高表達(dá)。HB-EGF在人內(nèi)膜周期中各期均有表達(dá)，受體內(nèi)雌、孕激素的調(diào)節(jié)，呈明顯的周期性變化。人內(nèi)膜腔上皮和腺上皮細(xì)胞HB-EGF蛋白表達(dá)在植入期出現(xiàn)峰值表達(dá)，在來潮前顯高，然后在分泌早期下降;還是在分泌中期升高未有定論。育。HB-EGF在體內(nèi)、體外直接引起小鼠基質(zhì)細(xì)胞多倍性和蛻膜化，與早期胎盤的形成有關(guān)。（LIF整合素β-3表達(dá)調(diào)控的容受性。環(huán)氧化酶(cyclooxygenase,COX)環(huán)氧化酶又稱素合成酶，是素COX-1COX-2有COX-2在內(nèi)質(zhì)網(wǎng)（endosmireticular,ER）和核膜均有表達(dá)，說明PGｓ通過兩種不同的受體系統(tǒng)EP1~4PGs的受體；另外一種是核受體途徑，主要通過核醛X受體（retinoidXreceptor,RXR）中的一員形成二聚體來發(fā)揮作用。2-細(xì)胞期、4~8細(xì)胞期、桑椹胚等不同發(fā)COX2-COX-2mRNA和蛋白主要在滋養(yǎng)外胚層表達(dá)，提示COX-2可能促進(jìn)胚泡的分化和著床，達(dá)到母胎之間同步發(fā)育的目的，COX-2PGI2PPAR的活化發(fā)在野生型小鼠懷孕d5時，檢測著床點(diǎn)和著床點(diǎn)間的PGs水平，發(fā)現(xiàn)PGI2最高，PGE2其次，并且PGI2在著床點(diǎn)的水平明顯高于著床點(diǎn)旁。小鼠在妊娠d1~4上午中PPAR表達(dá)很低，但d4晚上（22:00～23:00）PPARd5表達(dá)于胚胎周圍，d6~8COX-2PGI2的表達(dá)具有與著床一致的時空性。，在敲除的動物模型中，COX-1缺陷小鼠表現(xiàn)為分娩延遲，但是有能力；而COX-2基因缺陷小鼠卻有諸如率降低，著床、蛻膜化等生殖缺陷。并且該缺陷引起的生殖并非垂體促激素、激素或靶對激素的反應(yīng)性降低，而是由于靶COX-2的缺陷直接導(dǎo)致的。這些證實(shí)，COX-2是著床過程中重要的參加者。，對著床失敗的COX-2剔除小鼠將少量胚泡移植到P4方法誘導(dǎo)的COX-2剔除假孕小鼠，COX-2基COX-2增加著床點(diǎn)血管通透性，促進(jìn)血管生成，是它在此外，COX-2還能促進(jìn)著床過程中內(nèi)膜細(xì)胞的蛻膜化。對假孕野生型小鼠角注射或不注射油有表達(dá)；同時PGI2激動劑cPGI（carbaprostacyclin）能恢復(fù)COX-2剔除小鼠內(nèi)注射油劑引起COX-1COX-2mRNA和蛋白的表達(dá)。生物過程，另一方面對不孕癥、習(xí)慣性、妊高征的發(fā)病機(jī)理研究、診斷和治療將提供重要的線索。隨著技術(shù)的飛速發(fā)展可以采用先進(jìn)的技術(shù)大規(guī)模的篩查著床相關(guān)并進(jìn)行功能的研究，（主編．現(xiàn)代輔助技術(shù)．：人民軍醫(yī)姜群英，，．雌、孕激素調(diào)控人內(nèi)膜間質(zhì)細(xì)胞HB-EGF的表達(dá)．中華，，姜群英．類肝素結(jié)合性表皮生長因子在人內(nèi)膜植入窗期的表達(dá)和意義．生殖，，9：334-Alexander,J.P.,J.R.Samples&T.S.Acott.GrowthfactorandcytokinemodulationoftrabecularmeshworkmatrixmetalloproteinaseandTIMPexpression.Curr.EyeRes.1998;17:276-285AnetteLindahard,UrsulaBentin-Ley,VibekeRavn,etal.Biochemicalevaluationofendometrialfunctionatthetimeofimntation.Fertil.Steril.2002;78:221-233AokiR,FukudaMN.Recentmolecularapproachestoelucidatethemechanismofembryoimntation:trophinin,bystin,andtastinasmoleculesinvolvedintheinitialattaentofblastocyststotheuterusinhumans.Semin.Reprod.Med.AranchaGalan,RaquelHerrer,JoseRemohi,etal.Embryonicregulationofendometrialepithelialapoptosisduringhumanimntation.Hum.Reprod.2000;15(suppl):74-80Arici,A.,J.R.Head,P.C.MacDonald&M.L.Casey.Regulationofinterleukin-8geneexpressioninhumanendometrialcellsinculture.Mol.Cell.Endocrinol.1993;94:195-204Arici,A.,P.C.McDonald&M.L.Casey.Regulationofmonocytechemotacticprotein-1geneexpressioninhumanendometrialcellsincultures.Mol.Cell.Endocrinol.1995;107:189-197.Baggiolini,M.&A.Dahinden.CCChemokinesinallergic 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