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論文摘要發炎反應(Inflammation)為組織受傷或受微生物侵入時，體內所產生的自然 ... 在機制的探討方面，LPS活化巨噬細胞後所產生的下游訊息傳遞鏈以MAPK路徑及NF-κB ... 資料載入處理中... 跳到主要內容 臺灣博碩士論文加值系統 ::: 網站導覽| 首頁| 關於本站| 聯絡我們| 國圖首頁| 常見問題| 操作說明 English |FB專頁 |Mobile 免費會員 登入| 註冊 功能切換導覽列 (167.99.71.17)您好！臺灣時間：2021/11/3002:53 字體大小：       ::: 詳目顯示 recordfocus 第1筆/ 共1筆  /1頁 論文基本資料 摘要 外文摘要 目次 參考文獻 紙本論文 QRCode 本論文永久網址: 複製永久網址Twitter研究生:張嘉文研究生(外文):Chia-WenChang論文名稱:化合物yuwen02f1之抗發炎作用及機轉之探討論文名稱(外文):Theanti-inflammatoryeffectsandmechanismsofcompoundyuwen02f1指導教授:黃德富學位類別:碩士校院名稱:國立臺灣大學系所名稱:藥理學研究所學門:醫藥衛生學門學類:藥學學類論文種類:學術論文論文出版年:2010畢業學年度:98語文別:英文論文頁數:90中文關鍵詞:發炎反應、巨噬細胞、敗血症、足腫現象、細菌內毒素外文關鍵詞:inflammation、macrophage、sepsis、pawedema、lipopolysaccaride、NF-kappaB相關次數: 被引用:0點閱:317評分:下載:0書目收藏:0 發炎反應(Inflammation)為組織受傷或受微生物侵入時，體內所產生的自然防禦機制，一般具有紅、腫、熱、痛之典型特徵，引起微血管擴張、血流加速、血管通透性增加及白血球移行(migrate)至發炎部位，進而吞噬或稀釋病原體及受傷組織。

在發炎反應的過程中，活化的免疫細胞還會分泌多種具有細胞毒殺作用(cytotoxic)或促發炎反應的細胞激素(proinflammatorycytokine)來促進並維持發炎反應的進行以助於個體清除外來的有害刺激，然而；在過度的發炎反應中，上述物質會大量產生而對個體產生傷害。

近來研究指出，發炎反應和多種疾病狀態有關，例如：關節炎、阿茲海默症、多發性硬化症、氣喘、動脈硬化、自體免疫疾病、癌症甚至是急性的敗血症。

因此；尋找具有抗發炎活性的藥物來抑制過度的發炎反應便成為藥物開發的重要方向。

在初步的藥物活性篩選過程中，我們發現化合物yuwen02f1具有抗發炎活性，並且在活性測試所使用的劑量下，不會影響細胞的存活率。

實驗指出化合物yuwen02f1在30μM時即可有效抑制受細菌內毒素(LPS)活化的鼠源巨噬細胞或人類的單核細胞所分泌的細胞激素，像是TNF-α及IL-6；也會抑制nitricoxide及自由基(ROS)的釋放，甚至抑制發炎反應過程中重要的移行現象。

在活體實驗中，我們使用了敗血症動物模式來模擬急性發炎也用關節炎動物模式來模擬慢性發炎，藉此研究化合物yuwen02f1在急性及慢性發炎中的抗發炎活性。

我們發現不論是在急、慢性發炎中，此化合物都具有抑制發炎的現象，例如：有效降低敗血症小鼠血清中的發炎細胞激素含量(TNF-α與IL-6)、降低LPS誘發敗血症小鼠之死亡率、改善敗血症小鼠所受到的器官損傷及血小板低下症，甚至是抑制關節炎小鼠的足腫現象。

在機制的探討方面，LPS活化巨噬細胞後所產生的下游訊息傳遞鏈以MAPK路徑及NF-κB路徑為主。

在MAPK路徑中，我們檢視了三種重要的激酶包括p-38、ERK1/2、JNK的磷酸化現象，發現化合物yuwen02f1對於這三種激酶的磷酸化都有抑制作用；另外也檢視了NF-κB活化路徑中重要的因子：IκB的降解(degradation)情形，發現化合物yuwen02f1也可將此降解現象反轉回來;此外，yuwen02f1也可從轉錄層級(transcriptionallevel)去抑制活化NF-κB路徑後所誘發的下游酵素，例如：iNOS及COX-2的表現。

因此我們推測化合物yuwen02f1藉由抑制這兩條訊息傳遞路徑來抑制發炎反應。

Inflammation,usuallycharacterizedbyswelling,redness,pain,andheat,isacrucialfunctionoftheinnateimmunesystemanditisnecessarytoprotectthehostagainstpathogensandtoinitiatespecificimmunity.Uponbacterialinvasion,mammalianmonocytes/macrophagesreleaseavarietyofinflammatorymediatorssuchaspro-inflammatoryandcytotoxiccytokines,chemokinesandreactiveoxygen/nitrogenspeciestodefenseharmfulstimuli,butexcessiveinflammatoryreactionleadstoextensivetissuedamageandmanifestationofpathologicalstatessuchasmultiplesclerosis,asthma,arthritis,atherosclerosis,Alzheimer’sdiseaseandcancer.Therefore,targetingonuncontrolledinflammationseemsfeasibletocontrolnumerousinflammation-associateddiseases.Underthedrugscreeningprocessof5250derivatives,wediscoveredcompoundyuwen02f1,asyntheticphenylpyrazolecompound,possessesanti-inflammatoryeffectsindecreasingthereleaseofpro-inflammatorycytokinesincludingTNF-αandIL-6,nitricoxide,reactiveoxygenspecies(ROS)aswellasinhibitingmigrationofLPS-stimulatedphagocytes,andwealsoexcludeditscytotoxicitybycellviabilityandLDHreleaseassay.Furthermore,wefoundthatyuwen02f1attenuatessomepathologicalsyndromesofLPS-inducedsepsisandadjuvant-inducedarthritisinmice,suchasdecreasingthecytokineproduction,reversingthrombocytopenicsyndrome,protectingthemicefromtissueinjuryinsepticmiceandattenuatingpawedemainarthriticmiceaswell.Theseresultssuggestthebeneficialeffectsofyuwen02f1bothonacuteandchronicinflammation.InproteinexpressionofLPS-stimulatedmacrophages,weobservedthatthemolecularmechanismofyuwen02f1-mediatedanti-inflammationisassociatedwithdecreasingphosphorylationofMAPKmoleculessuchasERK1/2,JNKandp38.Yuwen02f1alsoreversesIκBdegradationandattenuatestheexpressionofNF-κB-relateddownstreaminducibleenzymeslikeiNOSandCOX-2.Theseresultsindicatethatyuwen02f1inhibitsLPS-stimulatedinflammationthroughtheblockadeofNF-κBandMAPKpathways. 中文摘要………………………………………………………………iAbstract……………………………………………………………iiiAbbreviationtable…………………………………………………vChapter1Introduction……………………………………………11.1Overviewofinflammation……………………………………11.2Roleofleukocytesininflammation………………………21.3Macrophage-derivedcytotoxicandproinflammatorymediators………………………………………………………………41.3.1Inflammatorycytokines………………………………………41.3.2Nitricoxide(NO)……………………………………………71.3.3Reactiveoxygenspecies……………………………………81.4Thesignalingpathwaysoflipopolysaccharide(LPS)…91.4.1TheMAPkinasepathway……………………………………101.4.2TheNF-κBpathway……………………………………………111.5Sepsis……………………………………………………………131.6Arthritis…………………………………………………………141.7Cancer……………………………………………………………161.8Yuwen02f1…………………………………………………………18Chapter2Materialsandmethods…………………………………282.1Materials…………………………………………………………282.2Cellcultures……………………………………………………282.2.1Cellculture–RAW264.7macrophagecell……………282.2.2Cellculture–Murineperitonealmacrophagecell…292.2.3Cellculture–HumanTHP-1monocyticleukemiacell……………………………………………………………………292.3Cytokineassays…………………………………………………302.4Nitricoxideassay……………………………………………312.5ROSmeasurement…………………………………………………312.6Cellviabilityassay…………………………………………322.7LDHreleaseassay………………………………………………332.8Migrationassay………………………………………………332.9Westernblotanalysis…………………………………………342.10Invivoassay…………………………………………………352.10.1Animals………………………………………………………352.10.2Acuteinflammationmodel:LPS-inducedsepsis……362.10.2.1LPSchallenge……………………………………………362.10.2.2Micewholebloodandplasmacollection……………362.10.2.3Measurementofcytokinelevels………………………362.10.2.4Histologicalexamination..……………………………372.10.3Chronicinflammationmodel:adjuvant-inducedarthritis………………………………………………………………372.10.3.1Inductionofarthritis…………………………………372.10.3.2Yuwen02f1treatmentandevaluationofarthritis………………………………………………………………372.10.3.3Histologicalexamination………………………………382.11Statisticalanalysis…………………………………………38Chapter3Results……………………………………………………393.1Theexplorationofanti-inflammatoryleadcompoundfrom5250-derivatives……………………………………………393.2Yuwen02f1inhibitspro-inflammatorycytokineslikeTNF-αandIL-6productioninLPS-stimulatedphagocytes………393.3Yuwen02f1inhibitsnitricoxideproductionandiNOSexpressioninLPS-stimulatedRAW264.7macrophages………403.4Yuwen02f1inhibitsCOX-2expressioninLPS-stimulatedRAW264.7cells………………………………………………………413.5Yuwen02f1inhibitsROSproductioninLPS-stimulatedRAW264.7macrophages……………………………………………………………413.6Cytotoxicityofyuwen02f1onmurinemacrophagesinvitroandexvivo……………………………………………………423.7Yuwen02f1inhibitsthemigrationofLPS-stimulatedmurinemacrophagesandhumanmonocytes………………………423.8Yuwen02f1inhibitsthephosphorylationofMAPKmoleculesinLPS-stimulatedRAW264.7cells………………433.9Yuwen02f1inhibitsIκBαdegradationinLPS-inducedRAW264.7macrophages………………………………………………433.10Theeffectsofyuwen02f1onacuteinflammationinvivo……………………………………………………………………443.10.1Yuwen02f1inhibitspro-inflammatorycytokinesincludingTNF-αandIL-6productioninvivo…………………453.10.2Yuwen02f1reversesLPS-inducedthrombocytopenia…453.10.3Effectsofyuwen02f1ontissueinjuryinendotoxemiaexaminedbyhistochemistry………………………463.11Theeffectsofyuwen02f1onchronicinflammationinvivo……………………………………………………………………463.11.1Yuwen02f1attenuatespawedemacausedbyadjuvant-inducedarthritis……………………………………………………473.11.2Theeffectsofyuwen02f1onhistopathologyofadjuvant-inducedarthritis………………………………………47Chapter4Discussion………………………………………………71Chapter5ConclusionandPerspectives…………………………76References……………………………………………………………78 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