臺灣博碩士論文加值系統

缺血­再灌注傷害引發嚴重全身發炎反應及造成組織器官病理變化。為了尋求解決臨床困境的可行醫療策略，我們設計了兩個研究如下：
第一部分：利用血管腔內汽球阻斷術阻斷活體幼豬腹主動脈不同時間後，再恢復腹主動脈血流灌注，隨著時間變化，觀察腹腔壓力與各種病、生理指標的改變。十二隻三個月大的肉豬，均等分成三組實驗。Ａ組動物被阻斷腹主動脈三十分鐘後，恢復供血；Ｂ組動物被阻斷腹主動脈六十分鐘後，恢復供血；Ｃ組動物被阻斷腹主動脈一百二十分鐘後，恢復供血。恢復供血後觀察二十小時，隨時間變化的腹腔壓力、血流動力參數、呼吸及腎功能、以及小腸、腎臟、肺臟組織切片染色，與未阻斷腹主動脈供血前之基準點參數作比較。我們發現：各組動物的腹腔壓力隨著恢復供血時間延長逐漸增加，但是並無組間差異。恢復供血四小時後，與基準點腹腔壓力比較差異明顯（p ＜ 0.001），甚至其中十隻豬腹腔壓力在觀察時間內逐漸超過22毫米汞柱。各組動物的心輸出量維持平穩，但是在恢復供血四小時後，與基準點比較，混合靜脈血氧氣飽和度明顯下降（p ＜ 0.05）。各組動物的血液酸鹼值在恢復供血十分鐘後明顯下降（p ＜ 0.001）。比較各組動物小腸、腎臟、肺臟組織切片染色無差異（p ＞ 0.05）。即使僅僅30分鐘腹主動脈被阻斷後再恢復供血，也會引發腹腔高壓症、多器官衰竭及混合靜脈血氧氣飽和度明顯下降。
第二部分：研究金絲桃對順鉑引發急性腎衰竭小鼠的保護作用。不同劑量的金絲桃給予小鼠三天後，施以順鉑引發急性腎衰竭。再將各組動物的腎臟及血液取出，分別組織切片染色並檢驗BUN、creatinine、reactive oxygen species 及malondialdehyde。另外利用ELISA方法檢測各組動物TNF-α、IL-1β及IL-6。磷酸化的NF-κB、Nrf2和HO-1的表現以西方點墨分析檢驗。結果顯示金絲桃能減少順鉑引發急性腎衰竭小鼠的傷害。金絲桃能減少順鉑引發 BUN、creatinine、reactive oxygen species及malondialdehyde的血中濃度。金絲桃能減少順鉑引發NF-κB活化。同時，金絲桃能提高增強Nrf2和HO-1的表現。總之，金絲桃能藉由抑制發炎、氧化反應，對順鉑引發急性腎衰竭小鼠發生保護作用。
總結以上，缺血­再灌注傷害會引發腹腔高壓症、多器官衰竭等嚴重全身發炎反應及造成組織器官病理變化。而金絲桃具抑制NF-κB活化、增強Nrf2和HO-1的表現。是否金絲桃能引進臨床治療需進一步的豬活體實驗證實。

Ischemia-reperfusion injury (IRI) induced complicated inflammation and pathology of vital organs. For seeking possible strategies to treat IRI, we conduct two studies.
Part I: Using a porcine model, we evaluated the influence of different endovascular balloon occlusion (EBO) time periods on intra-abdominal pressure (IAP) and the association between various pathophysiologic indicators and reperfusion time. Twelve healthy 3-month-old domestic piglets were subjected to ischemia-reperfusion injury using EBO within the abdominal aorta. Animals were grouped as A, B, and C based on 30, 60, or 120 minutes, respectively, of ischemic time. Changes in IAP, hemodynamic data, respiratory and renal function, and histology after reperfusion were compared with baseline measurements. All pigs gradually developed intra-abdominal hypertension after ischemia-reperfusion injury. IAP increased significantly after 4 hours of reperfusion in all three groups (all P < 0.001) with maximal IAP reaching > 22 mmHg in 10 pigs. However, no significant intergroup differences were found. Cardiac output remained stable but mixed venous oxygen saturation decreased significantly at 4 h after reperfusion (P < 0.05). The pH decreased significantly at 10 min in all three groups (all P < 0.001). Histological changes in small intestine, lung, and kidney occurred secondary to aortic ischemia, however, no significant differences were noted between groups (P > 0.05). EBO within the abdominal aorta induced ischemia-reperfusion injury which led to intra-abdominal hypertension, pathological changes within multiple organs, and decreased mixed venous oxygen saturation after only 30 minutes of abdominal aortic ischemia.
Part II: we investigated the effects of hyperin on cisplatin-induced acute kidney injury (AKI) in mice. The renal tissue damage induced by cisplatin was detected by H&E staining. Blood urea nitrogen (BUN), creatinine, reactive oxygen species (ROS), and malondialdehyde (MDA) were also detected. Further, the effects of hyperin on cisplatin-induced TNF-α, IL-1ß and IL-6 were detected by ELISA. In addition, the phosphorylation of nuclear factor kappa B (NF-κB) and the expression of nuclear factor E2-related factor-2 (Nrf2) and HO-1 were detected by western blot analysis. The results showed that hyperin attenuated histological changes of kidney induced by cisplatin. The levels of BUN, creatinine, ROS, MDA, TNF-α, IL-1ß and IL-6 induced by cisplatin were also inhibited by hyperin. Cisplatin-induced NF-κB activation was inhibited by hyperin. Additionally, hyperin was found to up-regulate the expression of Nrf2 and HO-1. In conclusion, the results suggest that hyperin protects against cisplatin-induced AKI by inhibiting inflammatory and oxidant response.
In conclusion, IRI of abdomen aorta could induced severe systemic inflammatory response and even distal organ injury. Nevertheless, hyperin could inhibit NF-κB activation, and up-regulate the expression of Nrf2 and HO-1. Further experiment should be conducted to examine hyperin protective effect in porcine model.

Contents
Certificate & statements
Abstract in Chinese..................... I
Abstract................................ III
Acknowledgements in Chinese............. VI
Acknowledgements........................ VII
Contents................................ VIII

1. Introduction 1

2. Porcine model intra-abdominal vital organ inflammation induced by abdominal aorta Ischemia-reperfusion injury
2.1 Introduction 8
2.2 Materials and methods 11
2.2.1 Animal preparation 11
2.2.2 Measurements 15
2.2.3 Data Analysis 19
2.3 Results 20
2.3.1 Baseline characteristics and survival time 20
2.3.2 IAP after reperfusion 30
2.3.3 Hemodynamic data after reperfusion 32
2.3.4 Respiratory function after reperfusion 38
2.3.5 Renal function after reperfusion 42
2.3.6 Biochemical findings 46
2.3.7 Histopathologic findings 48
2.4 Discussion 50
2.5 Summary 57

3. The anti-inflammation mechanism of hyperin
3.1 Introduction 58
3.2 Materials and methods 60
3.2.1 Animal preparation 60
3.2.2 Reagents 60
3.2.3 Acute kidney injury model 61
3.2.4 Renal function 61
3.2.5 Histological analysis 61
3.2.6 Cytokines measurements 62
3.2.7 ROS and MDA assay 62
3.2.8 Western blot analysis 63
3.2.9 Cell culture and treatment 63
3.2.10 Data Analysis 64
3.3 Results 64
3.3.1 Hyperin attenuates CP-induced BUN and creatinine levels
64
3.3.2 Effects of hyperin on CP-mediated kidney histopathology
66
3.3.3 Hyperin inhibits CP-induced TNF-α, IL-6 and IL-1β production
68
3.3.4 Effects of hyperin on ROS and MDA levels 70
3.3.5 Hyperin inhibits CP-induced NF-κB activation 72
3.3.6 Effects of hyperin on Nrf2 and HO-1 expression 73
3.4 Discussion 76
3.5 Summary 78

4. Conclusion 79

References 83

List of Tables
Table 2-1 22
Table 2-2 23
Table 2-3 24
Table 2-4 26
Table 4-1 81
Table 4-2 81

List of Figures
Figure 1-1 2
Figure 1-2 4
Figure 1-3 6
Figure 2-1 14
Figure 2-2 17
Figure 2-3 18
Figure 2-4 21
Figure 2-5 31
Figure 2-6 (A) 33
Figure 2-6 (B) 34
Figure 2-6 (C) 35
Figure 2-6 (D 36
Figure 2-6 (E) 37
Figure 2-7 (A) 39
Figure 2-7 (B) 40
Figure 2-7 (C) 41
Figure 2-8 (A) 43
Figure 2-8 (B) 44
Figure 2-8 (C) 45
Figure 2-9 47
Figure 2-10 49
Figure 3-1 59
Figure 3-2 65
Figure 3-3 67
Figure 3-4 69
Figure 3-5 71
Figure 3-6 73
Figure 3-7 74
Figure 3-8 75


Appendix
1. Pictures in laboratory 100
2. Author related articles 108

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