脈絡(luò)膜新生血管階段一課件目前一頁\總數(shù)十九頁\編于二十一點(diǎn)CNV的發(fā)生機(jī)制RPE-Bruch膜-脈絡(luò)膜毛細(xì)血管復(fù)合體改變對(duì)CNV的影響目前二頁\總數(shù)十九頁\編于二十一點(diǎn)目前三頁\總數(shù)十九頁\編于二十一點(diǎn)C57BL/6J（B6）Laser-inducedCNV腹腔麻醉：0.5%戊巴比妥鈉散瞳：托品酰胺苯腎上腺素激光：647.1nm;50mmspotsize;0.05sduration;360mW.1PD；3,6,9,12o’clockpositions目前四頁\總數(shù)十九頁\編于二十一點(diǎn)Fundusfluoresceinangiography3minafterintraperitonealinjectionof0.3mLof2%fluoresceinsodiumwasinjectedintotheintraperitonealcavityofthemice.目前五頁\總數(shù)十九頁\編于二十一點(diǎn)細(xì)胞名稱細(xì)胞株內(nèi)皮細(xì)胞themurinecelllineb-End3;humanumbilicalveinendothelialcells;Choroid-retinal

endothelialcellline

RPEhumancelllineARPE-19; 巨噬細(xì)胞themurinecelllineRAW264.7目前六頁\總數(shù)十九頁\編于二十一點(diǎn)新生血管形成過程內(nèi)皮細(xì)胞的活化（缺氧）(HIF-1)VEGFNO(血管舒張);

內(nèi)皮細(xì)胞通透性增加，有利于血漿向組織擴(kuò)散血管外基質(zhì)的降解內(nèi)皮細(xì)胞的增生、移行

新生血管的成熟VEGF,bFGFT-PA,u-PATNF-a,IL-1MMP-1,MMP-3上調(diào)VEGFNOcGMPMAPKbFGF,整合素avB3等PDGF,aFGF,Ang及受體Tie-1,Tie-2目前七頁\總數(shù)十九頁\編于二十一點(diǎn)RPE對(duì)CNV的雙重調(diào)節(jié)功能1.促進(jìn)作用生成促進(jìn)血管內(nèi)皮細(xì)胞增生和移行的VEGF,FGF,TGF-a,TNF-a等等誘導(dǎo)體內(nèi)血管內(nèi)皮細(xì)胞形成窗孔結(jié)構(gòu)，影響新生血管的成熟2.抑制作用直接接觸抑制血管內(nèi)皮細(xì)胞的移行分泌抑制血管內(nèi)皮細(xì)胞生長的物質(zhì)：TGF-b,PEDF

釋放凝血酶原激活物抑制因子，使纖維酶原向纖溶酶的轉(zhuǎn)化受阻，細(xì)胞外基質(zhì)不能降解目前八頁\總數(shù)十九頁\編于二十一點(diǎn)巨噬細(xì)胞

激光誘導(dǎo)CNV，第一天巨噬細(xì)胞出現(xiàn)，第三天達(dá)到高峰，5-7天后開始減少。VEGF，MMP-9蛋白水解酶（玻璃膜）IL-1a,IL-1b,TNF-aIL-8,MCP-1生成血管活性因子巨噬細(xì)胞+RPE目前九頁\總數(shù)十九頁\編于二十一點(diǎn)參與血管內(nèi)皮生長因子誘發(fā)脈絡(luò)膜新生血管的信號(hào)通路MAPK途徑PI-3K-AKt/PKB途徑鈣離子依賴性激酶途徑NO途徑目前十頁\總數(shù)十九頁\編于二十一點(diǎn)P38內(nèi)皮細(xì)胞移行VEGF誘導(dǎo)活化:ERK,JNK目前十一頁\總數(shù)十九頁\編于二十一點(diǎn)PI-3K:CEC增生ILK：內(nèi)皮細(xì)胞增生和移行目前十二頁\總數(shù)十九頁\編于二十一點(diǎn)目前十三頁\總數(shù)十九頁\編于二十一點(diǎn)目前十四頁\總數(shù)十九頁\編于二十一點(diǎn)轉(zhuǎn)錄因子STAT3NF-kappa-BHIF-1目前十五頁\總數(shù)十九頁\編于二十一點(diǎn)STAT3Signaltransducerandtranscriptionactivator

退化期CNV的RPE細(xì)胞中，有STAT3的高表達(dá)，而在已纖維化的盤狀瘢痕中，STAT3的表達(dá)呈陰性，提示STAT3的活化與CNV的纖維化有關(guān)。目前十六頁\總數(shù)十九頁\編于二十一點(diǎn)STAT3+CNV1.AnovelprotectiverolefortheinnateimmunityToll-LikeReceptor3(TLR3)intheretinaviaStat3.MolCellNeurosci.2014Sep28;63C:38-48IF:3.732.CNTF-mediatedprotectionofphotoreceptorsrequiresinitialactivationofthecytokinereceptorgp130inMüllerglialcells.ProcNatlAcadSciUSA.2013Nov19;110(47):E4520-9IF:9.813.Toll-likereceptor3(TLR3)protectsretinalpigmentedepithelium(RPE)cellsfromoxidativestressthroughaSTAT3-dependentmechanism.MolImmunol.2013Jun;54(2):122-31IF:3.04.SuppressionofchoroidalneovascularizationthroughinhibitionofAPE1/Ref-1redoxactivity.

5.IL-27inhibitspathophysiologicalintraocularneovascularizationduetolaserburn.JLeukocBiol.2012Feb;91(2):267-73IF:4.36.Interleukin-6receptor-mediatedactivationofsignaltransducerandactivatoroftranscription-3(STAT3)promoteschoroidalneovascularization.AmJPathol.2007Jun;170(6):2149-58IF:4.67.Hyperglycaemiaexacerbateschoroidalneovascularisationinmiceviatheoxidativestress-inducedactivationofSTAT3

signallingin

RPE

cells.PLoSOne.2012;7(10):e47600.doi:10.1371/journal.pone.0047600.Epub2012Oct19目前十七頁\總數(shù)十九頁\編于二十一點(diǎn)NF-kappa-BNFKBisatranscriptionregulatorthatisactivatedbyvariousintra-andextra-cellularstimulisuchascytokines,oxidant-freeradicals,ultravioletirradiation,andbacterialorviralproducts.ActivatedNFKBtranslocatesintothenucleusandstimulatestheexpressionofgenesinvolvedinawidevarietyofbiologicalfunctions.InappropriateactivationofNFKBhasbeenassociatedwithanumberofinflammatorydiseaseswhilepersistentinhibitionofNFKBleadstoinappropriateimmunecelldevelopmentordelayedcellgrowth.

NFκB受多種細(xì)胞內(nèi)和細(xì)胞外的刺激如細(xì)胞因子，氧化劑自由基，紫外線照射，細(xì)菌性或病毒性產(chǎn)物激活的轉(zhuǎn)錄調(diào)節(jié)子。激活的NFκB易位到細(xì)胞核中，并刺激參與多種生物功能的基因的表達(dá)。NFκB的不適當(dāng)活化已經(jīng)與許多炎癥性疾病相關(guān)，而NFKB的持久性抑制導(dǎo)致不適當(dāng)?shù)拿庖呒?xì)胞的發(fā)育或延緩細(xì)胞生長。

目前十八頁\總數(shù)十九頁\編于二十一點(diǎn)NF-kappa-B1.Rolesfortheubiquitin-proteasomepathwayinproteinqualitycontrolandsignalingintheretina:implicationsinthepathogenesisofage-relatedmaculardegeneration.MolAspectsMed.2012Aug;33(4):446-66IF:10.32.Macularpigmentluteinisantiinflammatoryinpreventingchoroidalneovascularization.ArteriosclerThrombVascBiol.2007Dec;27(12):2555-62IF:5.533.IKK2inhibitionattenuateslaser-inducedchoroidalneovascularization.PLoSOne.2014;9(1):e87530IF:3.534.TNF-αdecreasesVEGFsecretioninhighlypolarizedRPEcellsbutincreasesitinnon-polarizedRPEcellsrelatedtocrosstalkbetweenJNKandNF-κBpathways.PLoSOne.2013;8(7):e69994IF:3.535.NLRP3inflammasomeactivationinretinalpigmentepithelialcellsbylysosomaldestabilization:implicationsforage-relatedmaculardegeneration.InvestOphthalmolVisSci.2013Jan7;54(1):110-20IF:3.666.RegulatoryroleofHIF-1alphainthepathogene