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研究生:林慶政
研究生(外文):Lin Ching Cheng
論文名稱:探討敗血症小鼠餵予表皮生長因子之免疫調節反應
論文名稱(外文):The immuno-regulatory effects of rh-EGF on LPS-induced septic mice
指導教授:吳文勉
指導教授(外文):Wu wen-mein
口試委員:黃惠宇周秀慧吳文勉
口試委員(外文):Huang hui-yuChou shiu-hueyWu wen-mein
口試日期:2010-07-16
學位類別:碩士
校院名稱:輔仁大學
系所名稱:營養科學系
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:150
中文關鍵詞:敗血症脂多醣人類表皮生長因子發炎反應腸道免疫
外文關鍵詞:sepsislipopolysacchariderh-EGFinflammatoryintestinal immunity
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行政院衛生署公佈之 98 年國人死因統計排名結果顯示敗血症 (sepsis) 位居第十二位,同時也是加護病房中患者常見之併發症與死因。敗血症會導致體內免疫功能受損,致病機制為誘發免疫細胞過度凋亡、激活 Th2 免疫反應或 IL-10 不正常增加。先前研究指出,表皮生長因子 (epidermal growth factor, EGF) 具有抑制細胞凋亡、促進細胞增生之功效。因此本研究欲探討餵予敗血症小鼠人類基因重組之表皮生長因子 (recombinant human EGF, rh-EGF) 是否可促進細胞增生與組織修復,降低體內不平衡免疫反應。為建立合適之敗血症模式,將 BALB/c 小鼠分為控制組 (腹腔僅注射生理食鹽水)、低劑量組(單次腹腔注射LPS (lipopolysaccaride) 1.25 mg/kg Bw)、高劑量組 (LPS, 3.75 mg /kg Bw) 或連續三天注射低劑量LPS (1.25 mg /kg Bw/day) 組,注射後於特定時間點犧牲小鼠。結果顯示,不論注射低或高劑量 LPS 均會造成脾臟重量增加、脾臟 T 淋巴細胞數量降低,IL-2 與 IFN-γ 分泌量降低,腎臟組織出現空泡化等現象,上述病理反應支持以腹腔注射LPS是以模擬敗血症之合理性。進一步將 BALB/c 小鼠分別注射低或高劑量 LPS 後,餵予不同劑量之 rh-EGF (12.5 或 25 μg/kg Bw) 連續三天,於第四天犧牲小鼠並觀察腸道及全身性免疫反應。結果發現,餵予rh-EGF後可提升腸道培耶氏斑 (peyer’s patch, PP) 中的淋巴細胞總數、較高之 B、T 淋巴細胞總數、及顯著降低敗血症小鼠血清肌酸酐含量。以上結果顯示,rh-EGF 具有改善敗血症小鼠腎臟功能損傷,以及腸道免疫功能低下之功效,但對於全身免疫反應較無明顯作用。我們嘗試將 rh-EGF 進行奈米化後,餵予敗血症小鼠,結果顯示奈米化 rh-EGF 略為改善敗血症小鼠高死亡率情形,然而對於小鼠體重與腹腔注射 LPS 後四小時血清 IL-6 則無更顯著之改善效用。綜上所述,敗血症小鼠口服餵予 25 μg/kg Bw 之 rh-EGF 3 天後,具有減少或是緩解下列敗血症指標之功效,如:死亡率、急性發炎期血清 IL-6 含量、腎臟功能損傷,及腸道免疫功能低下等現象。未來值得進一步探討 rh-EGF 對腸道淋巴細胞、腸道組織細胞,以及發炎相關訊息傳遞之調控作用。
Sepsis is the 12th disease in the order of major death in Taiwan, and it also be the common complications and increase mortality in intensive care units (ICU). It was well documented that immunity were suppressed in sepsis which may induce lymphocytes apoptosis, tending to Th2 immune response and abnormally increased of IL-10. A few studies demonstrated that epidermal growth factor (EGF) play some roles on anti-apoptosis, improving cell proliferation and increase cell survival. In this study, we would like to confer the beneficial role of recombinant human EGF (rh-EGF) on the regulatory effect of immune response, or recovery tissues damage on LPS-induced sepsis animal model. In order to establish the appropriate animal model of sepsis, BALB/c mice were divided to four groups, including the control group (i.p. injected with saline), the low dosage of LPS group (single i.p. injected with LPS, 1.25 mg/kg Bw), the high dosage of LPS group (single i.p. injected with LPS, 3.75 mg/kg Bw), and the triple Low-LPS group which mice been injected of lower dosage LPS for consecutive 3 days. The animals were scarified at different time points post LPS injection. Our data shown that as compared to the control group, whether mice been injected with low or high dosage of LPS, its weights of spleen were increased, the total number of splecinic T lymphocytes were decreased combined with lower cytokine secretion (such as IL-2, IFN-γ), and pathological finding represent vacuolation in the proximal epithelium of kidney. Accumulated data suggested that the LPS injection could mimic sepsis in BALB/c mice. Therefore, we fed BALB/c mice with different dosage (12.5 or 25 μg/kg Bw) of rh-EGF as mice been i.p. injected with low (1.25 mg/kg Bw) or high (3.75 mg/kg Bw) dosage of LPS. We found that total cell numbers of B or T lymphocytes were increased in Peyer’s patch than high dosage LPS only group. In addition, the levels of creatinine in the serum were significant decreased than high dosage LPS only group. These data indicated that rh-EGF could attenuate renal dysfunction and improve the intestinal immunity in septic mice. However, rh-EGF could not ameliorate the systemic immunity in septic mice. Furthemore, in order to amplify the biological function of rh-EGF by reconstruct it as a EGF- nanocapsules. By the way, we fed septic BALB/c mice with different dosage EGF- nanocapsules. Our results indicated that EGF- nanocapsules could improve the high mortality slightly but its could not improved the body weight and the levels of serum IL-6 post 4 hours LPS injection. In conclusion, our data demonstrated that septic mice administrated with rh-EGF could ameliorated the survival rate, reduced the levels of IL-6 in the acute inflammatory phase, attenuated renal dysfunction and improve the intestinal immunity. It will need more studies to elucidate the effect of rh-EGF on regulating the lymphocytes in the intestine, the intestinal tissue cell, and the inflammatory signaling pathway in future.
中文摘要………..………………………………………………………………………… I
英文摘要………..………………………………………………………………………… III
縮寫表…………..………………………………………………………………………… V
總目錄…………..………………………………………………………………………… VIII
表目錄…………..………………………………………………………………………… XIV
圖目錄…………..………………………………………………………………………… XV

第一章 前言…………………………………………………………………………………… 1
第二章 文獻回顧……………………………………………………………………………… 3
第一節 敗血症之簡介………………………………………………………………… 3
2.1.1 敗血症………………………………………………………………… 3
2.1.2 常見敗血症動物模式………………………………………………… 4
2.1.3 敗血症引發之免疫反應……………………………………………… 8
2.1.4 治療敗血症方法……………………………………………………… 9
第二節 表皮生長因子………………………………………………………………… 11
2.2.1 表皮生長因子之簡介………………………………………………… 11
2.2.2 表皮生長因子應用於各類疾病之療效……………………………… 13
2.2.3 表皮生長因子對腸道免疫之效用…………………………………… 16
2.2.4 表皮生長因子應用在敗血症治癒之成效…………………………… 16
第三節 腸道免疫系統………………………………………………………………… 18
2.3.1 腸道黏膜相關免疫系統……………………………………………… 18
2.3.2 腸道免疫系統活化之作用…………………………………………… 18
2.3.3 敗血症對腸道免疫之影響…………………………………………… 19

第四節 奈米的簡介…………………………………………………………………… 20
2.4.1 奈米的定義與應用…………………………………………………… 20
2.4.2 奈米科技的發展……………………………………………………… 20
2.5.3 奈米於食品科技上的應用…………………………………………… 21
第三章 研究動機與目的……………………………………………………………………… 23
第四章 建立合適之敗血症動物模式………………………………………………………… 25
第一節 實驗動物……………………………………………………………………… 25
第二節 LPS 之腹腔注射劑量與分組………………………………………………… 25
第三節 實驗流程……………………………………………………………………… 26
第四節 實驗試劑的配製……………………………………………………………… 29
4.4.1 腹腔注射之LPS 溶液………………………………………………… 29
4.4.2 細胞培養液…………………………………………………………… 29
4.4.3 HBSS 緩衝溶液……………………………………………………… 30
4.4.4 10 倍 PBS 溶液之配製……………………………………………… 30
4.4.5 紅血球溶解緩衝溶液………………………………………………… 31
4.4.6 有絲分裂劑…………………………………………………………… 31
第五節 實驗分析方法………………………………………………………………… 32
4.5.1 血液樣本之取得……………………………………………………… 32
4.5.2 白血球計數…………………………………………………………… 32
4.5.3 脾臟細胞……………………………………………………………… 33
4.5.4 脾臟細胞培養上清液之收集………………………………………… 33
4.5.5 測定細胞增生實驗…………………………………………………… 34
4.5.6 淋巴細胞次群分析…………………………………………………… 34
4.5.7 病理組織切片………………………………………………………… 35
4.5.8 分析細胞激素分泌之情形…………………………………………… 37
第六節 統計分析……………………………………………………………………… 38
第七節 結果…………………………………………………………………………… 38
4.7.1 不同劑量 LPS 對小鼠體重之影響………………………………… 38
4.7.2 不同劑量 LPS 對小鼠存活率之影響……………………………… 39
4.7.3 不同劑量 LPS 對小鼠 i.p. 後 4 小時血清 IL-6 濃度之影響…… 39
4.7.4 不同劑量 LPS 與犧牲時間點對小鼠臟器重量之影響…………… 39
4.7.5 不同劑量 LPS 與犧牲時間點對小鼠臟器組織病理變化之影響… 40
4.7.6 不同劑量 LPS 與犧牲時間點對小鼠脾臟細胞總數之影響……… 41
4.7.7 不同劑量 LPS 與犧牲時間點對小鼠脾臟細胞增生反應之影響… 41
4.7.8 不同劑量 LPS 與犧牲時間點對小鼠脾臟淋巴細胞次群之影響… 42
4.7.9 脾臟細胞培養上清液之 IL-2 分泌情形…………………………… 42
4.7.10 脾臟細胞培養上清液之 IL-6 分泌情形…………………………… 43
4.7.11 脾臟細胞培養上清液之 IFN-γ 分泌情形…………………………… 43
第八節 討論…………………………………………………………………………… 44
4.8.1 注射不同劑量 LPS 對小鼠生理反應之影響………………………… 44
4.8.2 注射不同劑量 LPS 對小鼠多重器官之影響………………………… 45
4.8.3 注射不同劑量 LPS 對細胞激素及全系統免疫反應之影響………… 46
第九節 總結…………………………………………………………………………… 49
第五章 餵予表皮生長因子之敗血症小鼠的腸道與全身性免疫反應變化………………… 69
第一節 基因重組人類 EGF 劑量之決定…………………………………………… 69
第二節 實驗動物……………………………………………………………………… 70
第三節 實驗分組……………………………………………………………………… 70
第四節 實驗流程……………………………………………………………………… 71
第五節 實驗試劑的配製……………………………………………………………… 73
5.5.1 腹腔注射之LPS 溶液配製…………………………………………… 73
5.5.2 人類 EGF 溶液配製…………………………………………………… 73
5.5.3 ET/AO 螢光染劑配製………………………………………………… 73
第六節 實驗分析方法…………………………………………………………………… 74
5.6.1 血清生化值檢測……………………………………………………… 74
5.6.2 腸道淋巴細胞之收集………………………………………………… 74
5.6.3 計數腸道淋巴細胞…………………………………………………… 75
5.6.4 腸道淋巴細胞增生實驗……………………………………………… 75
5.6.5 腸道淋巴細胞次群分析……………………………………………… 75
5.6.6 病理組織切片………………………………………………………… 76
第七節 統計分析………………………………………………………………………… 76
第八節 口服不同劑量 EGF 對敗血症小鼠生理變化之結果…………………………… 77
5.8.1 口服不同劑量 rh-EGF 對敗血症小鼠血清 rh-EGF 含量之影響…… 77
5.8.2 口服不同劑量 rh-EGF 對敗血症小鼠體重之影響…………………… 77
5.8.3 口服不同劑量 rh-EGF 對敗血症小鼠血清生化值之影響…………… 78
5.8.4 口服不同劑量 rh-EGF 對敗血症小鼠臟器病理組織切片影響……… 78
第九節 口服不同劑量 rh-EGF 對敗血症小鼠腸道免疫反應之結果………………… 80
5.9.1 口服不同劑量 rh-EGF 對敗血症小鼠培耶氏斑顆數之影響………… 80
5.9.2 口服不同劑量 rh-EGF 對腸繫膜淋巴結與培耶氏斑淋巴細胞
總數之影響……………………………………………………………… 80
5.9.3 口服不同劑量 rh-EGF 對敗血症小鼠腸道淋巴細胞增生反應……… 81
5.9.4 口服不同劑量 rh-EGF 對腸繫膜淋巴結與培耶氏斑淋巴細胞
次群之影響………………………………………………………………… 81
5.9.5 腸繫膜淋巴細胞分泌 IL-2 之情形……………………………………… 82
5.9.6 腸繫膜淋巴細胞分泌 IFN-γ 之情形…………………………………… 82
5.9.7 培耶氏斑培養上清液 IL-6 含量之情形………………………………… 82
5.9.8 培耶氏斑培養上清液 IgA 含量之情形………………………………… 83
第十節 口服不同劑量 rh-EGF 對敗血症小鼠全身性免疫反應之影響………………… 84
5.10.1 rh-EGF 對敗血症小鼠脾臟重量之影響………………………………… 84
5.10.2 脾臟細胞增生反應………………………………………………………… 84
5.10.3 脾臟淋巴次群百分比……………………………………………………… 84
5.10.4 脾臟細胞培養上清液之細胞激素分泌情形……………………………… 85
第十一節 討論……………………………………………………………………………… 87
5.11.1 不同劑量 rh-EGF 對敗血症小鼠生理變化之影響…………………… 87
5.11.2 不同劑量 rh-EGF 對敗血症小鼠腎、脾臟之影響…………………… 89
5.11.3 不同劑量 EGF 對敗血症小鼠腸道免疫反應之影響…………………… 90
5.11.4 不同劑量 EGF 對敗血症小鼠全身系統性免疫反應之影響…………… 92
第十二節 總結………………………………………………………………………… 93
第六章 奈米化 rh-EGF 對敗血症小鼠急性發炎反應之影響…………………………… 119
第一節 奈米 rh-EGF in vitro 試驗…………………………………………………… 119
6.1.1 奈米 rh-EGF 包覆率預試驗…………………………………………… 119
6.1.2 奈米 rh-EGF穩定性預試驗……………………………………………… 119
第二節 奈米 rh-EGF in vivo 試驗……………………………………………………… 120
6.2.1 實驗動物…………………………………………………………………… 120
6.2.2 實驗分組…………………………………………………………………… 120
6.2.3 實驗流程…………………………………………………………………… 121
第三節 實驗試劑配製……………………………………………………………………… 123
6.3.1 奈米 rh-EGF 之製備…………………………………………………… 123
6.3.2 腹腔注射LPS 溶液之製備……………………………………………… 123
6.3.3 林格氏液之製備………………………………………………………… 123
第四節 統計分析………………………………………………………………………… 123
第五節 奈米 rh-EGF in vitro 試驗結果…………………………………………… 124
6.5.1 奈米 rh-EGF 包覆率預試驗………………………………………… 124
6.5.2 奈米 rh-EGF 穩定性預試驗………………………………………… 124
第六節 奈米 rh-EGF in vivo 試驗結果…………………………………………… 124
6.6.1 奈米 rh-EGF 對敗血症小鼠體重之影響…………………………… 124
6.6.2 奈米 rh-EGF 對敗血症小鼠存活率之影響………………………… 125
6.6.3 奈米 rh-EGF 對敗血症小鼠血清 IL-6 含量之影響……………… 125
第七節 討論…………………………………………………………………………………… 126
6.7.1 奈米 rh-EGF 包覆率預測試…………………………………………………… 126
6.7.2 奈米 rh-EGF 穩定性預測試…………………………………………………… 126
6.7.3 奈米 rh-EGF in vivo 預試驗……………………………………………… 126
第八節 總結…………………………………………………………………………………… 128
第七章 總結…………………………………………………………………………………… 135
第八章 參考文獻……………………………………………………………………………… 137

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