臺灣博碩士論文加值系統

背景與目的：系統性低氧所造成的益處和壞處，可能是藉由氧氣本身濃度的改變所產生，或者是在系統性低氧後循環中所產生的氧化還原反應的改變所造成。當在發炎或病菌感染時，局部微環境的狀態就像是處於低氧一樣。而系統性低氧能藉由低氧的反應去調節多形核性白血球（PMN）相關的先天免疫與發炎等重要功能，然而，補體系統在發炎反應時也扮演著不或缺的重要角色。系統性低氧也會造成血液中血液凝固反應和氧化還原狀態的改變，但在目前尚未有明確的研究指出，系統性低氧所引發的氧化壓力是否會影響血液凝固的反應。可知系統性低氧和氧化還原的狀態能控制感染組織中先天免疫的反應，而這樣也表示可以利用其增加宿主防禦方式，來做為一種新的治療方法。因此，本實驗主要研究在不同的系統性低氧介入下，能影響1.多形核性白血球中低氧誘發因子-1的生物活性。2.多形核性白血球毒殺病菌的能力和補體系統的活化。3.內在路徑和外在路徑的血液凝固反應以及在血漿中內生性凝血酶原的產生。
方法：四十二位健康且靜態生活習慣的男性，分為服用安慰劑和服用vitamin E (1000IU)的兩組，並分別接受劇烈低氧（12%的氧濃度），中度低氧（15%的氧濃度）以及輕度低氧（18%的氧濃度）各二個小時的常壓低氧。在接受低氧的之前和之後，去測量PMN中HIF-1的表現量，以及利用大腸桿菌去測量PMN的吞噬作用、呼吸氧爆作用、黏著分子表現和補體活化等反應，最後使用流氏細胞儀作為測定。
結果：（1.）劇烈低氧和中度低氧能增加PMN中HIF-1轉錄表現，而抗氧化劑（N-Acetylcysteine; NAC），能夠減少系統性低氧所增加PMN的HIF-1表現。（2.）在劇烈低氧下能提升血漿中凝血因子Ⅷ的活性以及內生性凝血酶原的產生。在血漿中先利用FⅧ的抗體，將凝血因子Ⅷ阻斷，之後發現劇烈低氧下提升內生性凝血酶原產生的現象被抑制。當在服用vitamin E後，劇烈低氧下提升之凝血因子Ⅷ活性的增加以及內生性凝血酶原產生的現象會被抑制。此外，在中度低氧和輕度低氧下，不管是在安慰組和vitamin E組的氧化還原狀態、凝血因子Ⅷ的活性以及內生性凝血酶原的產生等的反應是沒有變化的。（3.）在劇烈低氧下能提升PMN的細胞移行、吞噬作用、呼吸氧爆作用、補體受器和黏著分子的表現，並伴隨著PMN的總抗氧化能力的下降。而且在服用vitamin E後也會有明顯的改變抑制。相反的，在中度低氧和輕度低氧下，不管是在安慰組和vitamin E組的細胞移行、吞噬作用、呼吸氧爆作用、補體受器和黏著分子的表現等的反應是沒有變化的。
結論：劇烈低氧和中度低氧能增加PMN中HIF-1轉錄表現、劇烈低氧下能提升血漿中凝血因子Ⅷ的活性以及內生性凝血酶原的產生以及劇烈低氧下能提升PMN的細胞移行、吞噬作用、呼吸氧爆作用、補體受器和黏著分子的表現，並伴隨著PMN和血漿中的總抗氧化能力的下降。因此，中度低氧的影響是有著較少血栓發炎的危險性。
臨床意義：期望這樣的發現能夠提供一個安全而有效的低氧治療策略，來增進人體的先天免疫反應。

Background and Purpose: The beneficial or detrimental effects of systematic hypoxia may vary substantially with the concentration of air O2 exposure and the subsequent change in the circulatory redox status under the systematic hypoxia. Hypoxia is a characteristic feature of the tissue microenvironment during inflammation or bacterial infection. Systematic hypoxia regulates several important polymorphonuclear leukocyte (PMN) functions relevant to innate immune and inflammation during hypoxia. Additionally, complement cascade is one of the integral buttresses of the inflammatory response. Systemic hypoxia also causes alterations of coagulation and redox status in blood, no studies have investigated whether oxidative stress induced by systemic hypoxia affects endogenous thrombin generation. Systematic hypoxia and redox status control of innate immune response in infected tissues could represent a novel therapeutic target for enhancing host defense. Therefore, this study was to investigate how various systemic hypoxic interventions can affect 1) HIF-1 bioavailability of PMN; 2) Cytotoxicity of PMN and complement activation; and 3) Intrinsic and extrinsic coagulant activities and endogenous thrombin generation in plasma. Methods: In a normobaric hypoxia chamber, 42 healthy sedentary men were exposed to severe hypoxia (SH, 12% O2), moderate hypoxia (MH, 15% O2), and light hypoxia (LH, 18% O2) for 2 hours following vitamin E (1000 IU) or placebo treatment. Before and immediately hypoxic exposure, HIF-1 expression in PMNs as well as phagocytosis, respiratory burst, adhesion molecule and complement activation of PMNs to E-coli were measured by flow cytometer and ELISA. Results: 1) SH and MH enhanced HIF-1 translocation of PMNs, N-Acetylcysteine (NAC), an antioxidant, attenuated the effect of systematic hypoxia expression of HIF-1 in PMNs. 2) Exposure of SH enhanced plasma FVIII antigen/activity and endogenous thrombin potential (ETP), accompanied by decreased total antioxidant level in plasma. Depleted FVIII by incubation with anti-FVIII antibody in plasma suppressed the extent of ETP enhanced by SH hypoxia. Following vitamin E treatment, exposure of SH did not significantly change to total antioxidant levels, as well as FVIII antigen/activity and EPT in plasma. Additionally, plasma redox status, FVIII antigen/activity, and ETP were unaltered in response to MH and LH following either placebo or vitamin E treatment. 3) Exposure of SH enhanced PMNs migration, phagocytosis, respiratory burst, complement receptor and adhesion molecule expression, accompanied by decreased total antioxidant level in PMNs. Following vitamin E treatment, exposure of SH was also significantly changed. Conversely, PMNs redox status, migration, phagocytosis, respiratory burst, complement receptor and adhesion molecule were unaltered in response to MH and LH following either placebo or vitamin E treatment. Conclusion: SH and MH enhanced HIF-1 translocation of PMNs, SH enhanced plasma FVIII antigen/activity and ETP, SH enhanced PMNs migration, phagocytosis, respiratory burst, complement receptor and adhesion molecule, accompanied by decreased total antioxidant level in plasma and PMNs. However, MH minimizes the risk of thrombo-inflammation. Clinical Relevance: These findings may provide a safe and effective hypoxia strategy for improving innate immune response in human.

第一章 緒論（Introduction） 1
第一節 研究背景及目的 1
第二節 研究假設 4
第二章 文獻回顧（Literature Review） 5
第一節 低氧的分類 5
第二節 低氧環境下的生理適應反應 6
第三節 低氧誘發因子-1之分子機制 9
第四節 低氧與氧化壓力的相關性 11
第五節 低氧與發炎反應的相關性 13
第六節 噬菌細胞在發炎反應中的角色 15
第七節 補體與噬菌細胞在發炎反應中的關聯 17
第八節 血液凝固與血小板活化在發炎反應中的作用 19
第三章 實驗設計（Experimental Design） 23
第一節 實驗材料 23
第二節 實驗方法 28
受試者 28
實驗流程 28
血小板的置備 29
多形核性白血球萃取 29
細胞質中之蛋白質測定 29
細胞膜上補體受器與黏著分子的測定 30
細胞核與細胞質分離 31
噬菌性白血球的吞噬作用測定 33
噬菌性白血球的氧爆作用測定 34
血漿中補體活化的測定 35
尿液中氧化反應的測定 35
統計分析 36
第四章 實驗結果（Results） 38
第一節 受試者基本資料、身體狀況和活動情形調查 38
第二節 不同低氧濃度對於心跳、血壓、血氧飽和度之影響 38
第三節 不同低氧濃度對於白血球及其次組成之數目影響 39
第四節 不同低氧濃度對於PMN內HIF-1、vHL、Ub以及Ub-conjugate蛋白質的改變 39
第五節 不同低氧濃度對於氧化還原反應（redox ststus）之影響 42
第六節 不同低氧濃度對於血栓活化的影響 42
第七節 不同低氧濃度對於噬菌細胞的行為影響 45
第八節 不同低氧濃度對於白血球黏著分子之影響 47
第九節 不同低氧濃度對於補體活化以及白血球的抗原受器及補體受器之影響 50
第五章 討論（Discussion） 55
低氧對於基本生理的影響 55
低氧對於HIF-1分子機制的影響 57
低氧對於血液凝固反應的影響 58
低氧對於先天免疫反應的影響 60
第六章 結論（Conclusion） 64
圖表附錄 65
參考文獻（References） 108

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96.林宏昱，（間歇性低氧對於健康男性運動表現與血栓發炎調節因子之影響），長庚大學，碩士論文，民國九十五年。