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系統識別號 U0026-1301201116140700
論文名稱(中文) 探討上皮細胞轉型成間質細胞之機制在單層奈米碳管誘發肺部纖維化過程中所扮演的角色
論文名稱(英文) The Role of Epithelial-to-Mesenchymal Transition in Single-Walled Carbon Nanotube Induced Pulmonary Fibrosis
校院名稱 成功大學
系所名稱(中) 環境醫學研究所
系所名稱(英) Institute of Environmental and Occupational Health
學年度 99
學期 1
出版年 100
研究生(中文) 黃惠淳
研究生(英文) Hui-Chun Huang
學號 S7697108
學位類別 碩士
語文別 中文
論文頁數 61頁
口試委員 指導教授-張志欽
口試委員-陳麗玉
口試委員-劉明毅
中文關鍵字 單層奈米碳管  上皮細胞-間質細胞轉型  肺部纖維化  轉化生長因子 
英文關鍵字 SWCNT  EMT  pulmonary fibrosis  TGF-β 
學科別分類
中文摘要 單層奈米碳管具有良好的導電性、韌性等特性,但先前研究指出單層奈米碳管可能會造成肺部的不良健康效應,如引發發炎反應、肉芽腫形成、形成肺部纖維化等病徵。然而,目前單層奈米碳管造成肺部纖維化之機制至今尚未明確,因此本研究將小鼠暴露單層奈米碳管後,探討單層奈米碳管誘發肺部纖維化之機轉。本研究將小鼠肺部以氣管內注入單層奈米碳管 (80 μg/mouse),分別在暴露1、7、14、28與42天犧牲,量測肺部沖洗液中肺部損傷與纖維化反應相關之蛋白,並利用螢光免疫染色法觀察肺部的纖維化機制。結果顯示小鼠暴露單層奈米碳管後,肺部沖洗液中的總蛋白量及乳酸脫氫酶活性顯著性上升,並且活化態之金屬基質蛋白分解酶-9和金屬基質蛋白分解酶-2的活性皆在暴露第1天顯著性增加;而鎖鏈素及羥脯胺酸表現量在暴露第7天有顯著性上升的情形;且轉化生長因子和血小板衍生生長因子表現量皆在暴露第1天及第7天顯著性增加,但到第42天的表現量則無顯著性差異。利用螢光免疫染色的方式觀察到小鼠暴露單層奈米碳管7天後,發現肺部上皮細胞及纖維母細胞會進行細胞增生,此時Masson’s trichrome染色結果觀察到大量細胞會包圍單層奈米碳管形成肉芽腫,並且隨著暴露時間增加,肺部纖維化也越來越嚴重。透過螢光免疫染色法觀察小鼠暴露單層奈米碳管14、28、42天後,表現間質細胞蛋白的細胞數各約有20 %、37 %、44 %是從上皮細胞轉型而來,其中有部分上皮細胞會轉型成肌纖維母細胞,並具有分泌第一型膠原蛋白的能力,此結果顯示暴露單層奈米碳管所誘發纖維化的過程中,透過上皮細胞-間質細胞轉型之機制促進纖維母細胞的增加,且此機制是透過活化TGF-β/p-Smad2的訊息傳遞路徑所調控。本研究首次驗證小鼠暴露單層奈米碳管是經由上皮細胞-間質細胞轉型的機制,使纖維母細胞生成,造成肺部纖維化反應。
英文摘要 Single-walled carbon nanotube (SWCNT) is an engineered nano-sized material. A few in vivo studies suggest that SWCNT exposure causes interstitial fibrosis and alveolar wall thickness. However, the mechanism remains ill-defined. The objective of this study is to investigate the mechanism of SWCNT-induced pulmonary fibrogenic response. In this study, C57BL6 female mice were intratracheally instilled with SWCNT at 80 μg/mouse for 1, 7, 14, 28 and 42 days. SWCNT caused significant increases of total proteins and lactate dehydrogenase (LDH) in bronchoalveolar (BAL) fluid. In BAL fluid, MMP-9 and MMP-2 activities were significantly increased in SWCNT group at 1 day post-exposure, compared with those in PBS group. BAL desmosine and hydroxyproline were found to be significantly increased in SWCNT group at 7 days post-exposure. There were significantly early increases of transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF) in BAL fluid. Alveolar type II cell and fibroblast proliferation started at 7 days. The ensuring formation of granuloma contained proliferating epithelial cells and fibroblasts. Trichrome staining demonstrated the existence of blue bundles of fibrous connective tissues within fibrotic loci. Significantly, 20 %, 37 %, 44 % of N-cadherin-positive cell were derived from hyperplastic epithelial cells at 14, 28, 42 days, respectively, indicative of EMT. Epithelial-derived epithelial cells were functional, in term of collagen production. Furthermore, TGF-β/p-Smad2 or β-catenin signaling were activated in hyperplastic epithelial cells. Our study demonstrates that SWCNT exposure results in EMT, contributing significantly to fibroblast expansion and fibrosis.
論文目次 中文摘要 ………………………………………………………………………… I
英文摘要 ………………………………………………………………………… II
英文縮寫對照表 ………………………………………………………………… III
研究內容
第一章 序論………………………………………………………………………1
1.1 前言………………………………………………………………………… 1
1.2 研究目的…………………………………………………………………… 3
第二章 文獻探討…………………………………………………………………4
2.1 奈米微粒…………………………………………………………………… 4
2.1.1 奈米產業與奈米毒理學的興起 …………………………………… 4
2.1.2 奈米微粒對健康的危害 …………………………………………… 5
2.2單層奈米碳管 ………………………………………………………………6
2.2.1 單層奈米碳管特性 ………………………………………………… 6
2.2.2 單層奈米碳管的暴露途徑與毒理研究 …………………………… 7
2.2.3 單層奈米碳管造成肺部損傷 ……………………………………… 9
2.2.4 肺部纖維化反應 …………………………………………………… 9
2.2.5 Epithelial-mesenchymal transition機制 …………………………… 11
第三章 研究材料與方法 ……………………………………………………… 14
3.1 實驗架構 ……………………………………………………………14
3.2 實驗材料 ……………………………………………………………15
3.3 實驗方法 ……………………………………………………………15
第四章 結果 …………………………………………………………………… 21
4.1 暴露單層奈米碳管造成肺部損傷 ………………………………………21
4.1.1 小鼠暴露單層奈米碳管後肺沖洗液中總蛋白質表現量 …………21
4.1.2 小鼠暴露單層奈米碳管後肺部巨噬細胞與嗜中性白血球數量 … 21
4.1.3 小鼠暴露單層奈米碳管後肺沖洗液中乳酸去氫酶 (LDH) 活性…21
4.2 暴露單層奈米碳管造成肺部細胞外基質破壞及金屬基質蛋白 (MMPs)
分解酶活性上升……………………………………………………………… 22
4.2.1 小鼠暴露單層奈米碳管後肺沖洗液中金屬基質蛋白 (MMPs)
分解酶之活性 ……………………………………………………… 22
4.2.2 小鼠暴露單層奈米碳管後肺沖洗液之鎖鏈素(desmosine) 之含量22
4.2.3 小鼠暴露單層奈米碳管後肺部之羥脯胺酸 (hydroxyproline)
之含量 ……………………………………………………………… 22
4.3暴露單層奈米碳管引發與纖維化相關之蛋白表現 ……………………… 23
4.3.1 小鼠暴露單層奈米碳管後肺沖洗液中TGF-β之表現量 …………23
4.3.2 小鼠暴露單層奈米碳管後肺沖洗液中PDGF之表現量 ………… 23
4.4暴露單層奈米碳管誘發肺部上皮細胞及纖維母細胞增生 ……………… 23
4.4.1 小鼠暴露單層奈米碳管誘發肺部上皮細胞增升的情況 ………… 23
4.4.2小鼠暴露單層奈米碳管誘發肺部纖維母細胞增升的情況…………23
4.5暴露單層奈米碳管誘發肺部纖維化反應 ………………………………… 24
4.6暴露單層奈米碳管誘發上皮細胞轉型成間質細胞 ……………………… 25
4.6.1肺部組織中第二型上皮細胞及N-cadherin之時序性表現及量化圖25
4.6.2肺部組織中第二型上皮細胞及α-SMA之時序性表現…………… 25
4.6.3肺部組織中第二型上皮細胞及第一型膠原蛋白之時序性表現……26
4.6.4肺部組織中第二型上皮細胞及TGF-β之表現情形 ……………… 26
4.6.5小鼠暴露單層奈米碳管誘發第二型上皮細胞中的Smad2
磷酸化作用 ………………………………………………………… 26
4.6.6小鼠暴露單層奈米碳管誘發第二型上皮細胞的β-catenin增加 … 27
第五章 討論……………………………………………………………………… 28
第六章 結論……………………………………………………………………… 33
第七章 參考文獻………………………………………………………………… 34
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