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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 余佳慧(Linda Chia-Hui Yu) | |
dc.contributor.author | Yi-Chen Huang | en |
dc.contributor.author | 黃怡禎 | zh_TW |
dc.date.accessioned | 2021-06-13T17:24:34Z | - |
dc.date.available | 2016-10-05 | |
dc.date.copyright | 2011-10-05 | |
dc.date.issued | 2011 | |
dc.date.submitted | 2011-07-13 | |
dc.identifier.citation | 1. Suckow MA, Weisbroth SH, Franklin CL. The laboratory rat. (2nd ed). Elsevier: Amsterdam ; Boston, 2006.
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Quercetin enhances intestinal barrier function through the assembly of zonula [corrected] occludens-2, occludin, and claudin-1 and the expression of claudin-4 in Caco-2 cells. J Nutr 2009; 139: 965-974. 184. Suzuki T, Yoshida S, Hara H. Physiological concentrations of short-chain fatty acids immediately suppress colonic epithelial permeability. Br J Nutr 2008; 100: 297-305. 185. Boivin MA, Ye D, Kennedy JC, et al. Mechanism of glucocorticoid regulation of the intestinal tight junction barrier. Am J Physiol Gastrointest Liver Physiol 2007; 292: G590- | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/39229 | - |
dc.description.abstract | 腸道缺血再灌流 (ischemia/reperfusion,I/R) 會導致黏膜層受損、上皮細胞間緊密連接構造破壞及屏障功能失調等。過去許多研究指出,低氧預處理可減低腦、心臟、肺及腎臟等器官受缺血刺激造成的傷害。本實驗室過去研究結果顯示,低氧預處理 (hypoxic preconditioning,HPC) 會啟動嗜中性白血球之預活化(neutrophil priming),達到抑制腸道I/R誘發細菌轉移之功效; 然而目前低氧對腸道上皮細胞的保護機制尚未釐清。因此本研究目的為探討低氧對腸道上皮細胞屏障功能的直接影響及其中所牽涉的訊息傳遞路徑。實驗方式為給予Wistar 大鼠常氧 (normoxia) 或低氧預處理 (HPC) 3天、7天或21天後,再進行腸繫膜動脈缺血再灌流的手術處理。結果顯示,大鼠在HPC處理7天及21天的血容比和嗜中性白血球活性相較於常氧組有顯著性的上升,此結果可確認大鼠於生理上有感受到低氧環境。低氧預處理7天和21天可減緩I/R引發的腸道絨毛構造變形、腺窩部位增生量降低及腸道組織通透性上升的現象。為了進一步探討低氧直接對腸道上皮細胞的影響,實驗中將人類腸道上皮Caco-2細胞培養至過滿並確立緊密連接(tight junction)已形成狀態,給予常氧(5% CO2 和95 % 空氣)及低氧(5% CO2 和95 % N2)多重時間點的處理。當給予Caco-2細胞1、2及4小時的低氧處理會使跨上皮細胞電阻(transepithelial electrical resistance,TER)上升,但在48小時低氧處理則會使TER顯著性下降。相似的結果也發現在以模擬低氧藥物(例如oligomycin A,OA和Rotenone)處理的Caco-2細胞中,2至18小時的OA和rotenone處理皆會促使Caco-2細胞TER升高,而OA和rotenone作用48小時則使TER大幅下降。此外,低氧1小時會使NP-40不可溶蛋白部分的occludin、ZO-1、claudin-1及JAM1蛋白表現量上升,顯示緊密連接蛋白由細胞質部分轉移至細胞骨架鄰近細胞膜部位。PI3K抑制劑 (如Wortmannin及LY-294002)和PKC抑制劑(如PKCζ pseudosubstrate)會減緩低氧1小時所造成的TER升高,其他抑制劑如Akt和p38 MAPK抑制劑則不影響低氧造成的上皮電阻改變。實驗亦觀察到低氧1小時會引起細胞質之PI3K和PKCζ蛋白轉移到細胞膜的情形。此外, Akt及其下游訊息傳遞分子的磷酸化如mTOR、FoxO1/O3a或GSK3蛋白在低氧1小時後則是顯著降低。綜論之,低氧可透過PI3K和PKCζ依賴性的訊息傳遞路徑,促進腸道上皮細胞緊密連接蛋白的組合及跨上皮細胞電阻值的提升,此保護機制或許有參與避免腸道缺血再灌流引發之屏障失常。 | zh_TW |
dc.description.abstract | Intestinal ischemia/reperfusion (I/R) causes mucosal histopathology, epithelial tight junctional disruption and barrier damage. Hypoxic preconditioning (HPC) was shown to attenuate ischemic injury in brain, heart, lung and kidney. Our previous study demonstrated that HPC induced neutrophil priming and prevented intestinal I/R-induced bacterial translocation. Nevertheless, the protective mechanism of HPC on intestinal epithelial cells remains unknown. Our aim is to characterize the effect of hypoxia on enterocytes and the underlying signaling pathways for tight junctional assembly and barrier enhancement. Rats were raised in normoxia or kept in a hypoxic hypobaric chamber (380 mmHg) 17 hrs/day for 3, 7 or 21 days, and then subjected to mesenteric I/R. Higher levels of hematocrit and neutrophil respiratory burst activity were seen in HPC rats after 7 or 21 days, confirming the preconditioning status. I/R-induced villous deformation, loss of proliferating cell nuclear antigen staining in crypts, and increase of transmural macromolecular flux in intestinal tissues were partly attenuated by HPC-21d and HPC-7d. To examine whether hypoxia modify epithelial barrier function, post-confluent human intestinal epithelial Caco-2 cells that established tight junctions were exposed to normoxia (5% CO2 and 95 % air) or hypoxia (5 % CO2 and 95 % N2) for various time points. Cells exposed to 1, 2 and 4 hrs of hypoxia showed increase in transepithelial electrical resistance (TER), whereas 48 hrs of hypoxia caused TER to drop. Similarly, elevated TER was also seen in Caco-2 cells after treatment with hypoxic-mimetic agent (i.e. oligomycin A and rotenone) for 2-18 hrs, whereas TER decreased after treatment for 48 hrs. Furthermore, increased levels of occludin, ZO-1, claudin-1 and JAM1 proteins were seen in NP40-insoluble fractions of cellular extract after one hour of hypoxia, suggesting translocation of tight junctional proteins from cytosol to cytoskeleton-associated membranous region. The hypoxia-induced TER increase was diminished by pretreatment with PI3K inhibitors (i.e. Wortmannin and LY-294002) and PKCζ inhibitor (i.e. PKCζ pseudosubstrate), but not inhibitors to Akt and p38 MAPK. Membrane translocation of cytosolic PI3K and PKCζ was found after hypoxia for 1 hr. Besides, hypoxia for 1 hr reduced the phosphorylation of Akt and downstream signaling molecules such as mTOR, FoxO1/O3a and GSK3 in Caco-2 cells. In conclusion, HPC increases tight junctional assembly and enhances epithelial resistance through PI3K- and PKCζ-dependent signaling pathway, which may contribute to the protection against I/R-induced barrier dysfunction. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T17:24:34Z (GMT). No. of bitstreams: 1 ntu-100-R98441005-1.pdf: 12640331 bytes, checksum: 8ac694b4472a2aa5e6252f0114e395ff (MD5) Previous issue date: 2011 | en |
dc.description.tableofcontents | 致謝 I
摘要 II Abstract IV 一、前言 1 1. 腸道解剖構造 1 2. 腸道上皮細胞替換(Turnover)過程 2 3. 腸道組織修復(repair)及癒合能力(wound healing) 3 4. 腸道屏障功能 (Intestinal barrier function) 3 4.1 腸道物理性屏障 4 4.2緊密連接蛋白 4 4.3 緊密連接穿膜蛋白部分 5 4.4 緊密連接細胞內蛋白部分 7 4.5 細胞內圍連接肌動肌凝蛋白環調控緊密連接蛋白構造 7 5. 緊密連接蛋白調控及相關訊息傳遞路徑 8 5.1 PKCζ isoform在緊密連接蛋白調控中扮演的角色 9 6. Phosphatidylinositol 3-kinase/Akt訊息傳遞路徑概述 10 6.1 PI3K在細胞存活機制中扮演之角色 10 6.2 PI3K在緊密連結構造調節機制中扮演之角色 11 7. 腸道缺血再灌流 (ischemia/reperfusion;I/R) 12 7.1 臨床常見的腸道缺血再灌流成因 12 7.2 腸道缺血再灌流導致黏膜組織病理現象,腸道屏障功能失調和細菌轉移 12 8.低氧預處理 (hypoxic preconditioning;HPC) 13 8.1 低氧對臨床病患及實驗動物的保護功能 13 8.2 低氧對各器官可能的保護機轉 14 8.3 生理功能對低氧之適應 15 8.4 低氧對腸胃道功能之影響 15 9. 研究目的 15 二、材料與方法 17 A. 活體實驗 (In vivo) 17 1. 實驗動物 17 2.低氧預處理對大鼠生理功能影響之指標 19 3 腸道屏障功能分析 21 4 腸道組織型態分析 23 5. 免疫螢光染色(immunofluorescence staining, IF) : 上皮細胞訊息傳遞分子Akt 25 6. 免疫組織化學染色 (immunohistochemistry staining, IHC) : PCNA (proliferating cell nuclear antigen) 26 B. 體外實驗 (In vitro) 27 1. 人類腸道上皮細胞株 27 2. 常氧及低氧條件 27 3. 腸道上皮細胞屏障功能分析:跨上皮細胞電阻 (transepithelial electrical resistance, TER)之測量 28 4. 免疫螢光染色 29 5. 訊號傳遞分子抑制劑 (signaling molecular inhibitor) 30 6. 細胞蛋白萃取(protein extraction)及西方墨點法 (western blotting) 31 7. 免疫沉澱法(Immunoprecipitation):Akt 38 8. Trypan blue排除分析 39 9. TUNEL分析 39 10. Latate dehydrogenase (LDH)分析 40 11. 粒線體產生ATP能力分析 41 C. 數據統計分析 42 三、實驗結果 43 1. 低氧預處理(HPC)對Wistar大鼠生理之影響 43 2. 低氧預處理可部分避免腸道缺血再灌流導致的迴腸絨毛型態受損現象 44 3. 低氧預處理抑制腸道缺血再灌流導致的迴腸電導及HRP分子通透速率上升 45 4. 低氧預處理抑制腸道缺血再灌流造成的細菌轉移至肝臟及脾臟現象 45 5. 低氧預處理使腸道上皮細胞受缺血再灌流後傷口癒合能力仍得以維持 46 6. 以細胞株培養方式探討低氧對人類腸道上皮細胞屏障功能之影響 47 7. 低氧1小時使occludin、ZO-1、claudin-1及JAM1由細胞質轉移至細胞骨架 鄰近細胞膜部分及促進occludin磷酸化程度,此外p-MLC相對MLC比值顯著降低 49 8. 低氧1小時造成的Caco-2細胞TER上升的分子傳遞路徑為PI3K或PKCζ依賴性,而與Akt和p38MAPK無關 50 9. 低氧1小時促進PI3K訊息傳遞分子由細胞質轉移至細胞骨架鄰近細胞膜部位 51 10. 低氧1小時降低Akt及其下游訊息傳遞分子蛋白的磷酸化 51 11. 低氧1小時促進PKCζ之磷酸化和PKCζ轉移至細胞骨架鄰近細胞膜部位 52 12. 低氧1小時不影響PKCζ和Akt之間交互作用的程度 52 13. MAPKs (p38、ERK、JNK)和IκBα磷酸化程度在低氧1小時後顯著性提升 52 14. 低氧處理1小時不影響腸道上皮細胞存活和增生能力 53 四、討論 54 五、圖表 64 六、參考文獻 93 | |
dc.language.iso | zh-TW | |
dc.title | 低氧預處理引起之腸道上皮細胞緊密連接蛋白組合和屏障功能加強的訊息傳遞路徑探討 | zh_TW |
dc.title | Signaling pathways for tight junctional assembly and barrier enhancement in intestinal epithelial cells induced by hypoxic preconditioning | en |
dc.type | Thesis | |
dc.date.schoolyear | 99-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 林君榮(Chun-Jung Lin),沈麗娟(Li-Jiuan Shen),賴逸儒(I-Rue Lai) | |
dc.subject.keyword | 腸道缺血再灌流,低氧預處理,緊密連接蛋白,跨上皮細胞電阻,訊息傳遞路徑,PI3K,PKCζ,Akt, | zh_TW |
dc.subject.keyword | intestinal ischemia/reperfusion,hypoxic preconditioning,tight junction proteins,signaling pathway,PI3K,PKCζ,Akt, | en |
dc.relation.page | 108 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2011-07-14 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
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