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系統識別號 U0026-1707201214220700
論文名稱(中文) 運動改善小鼠週邊發炎與閉鎖性頭部外傷的機制:MKP-1可能扮演的角色
論文名稱(英文) The Anti-inflammatory Effects of Exercise in Systemic Inflammation and Closed Head Injury Mouse Models:Possible Roles of MKP-1
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 100
學期 2
出版年 101
研究生(中文) 陳美鳳
研究生(英文) Mei-Feng Chen
學號 s58941353
學位類別 博士
語文別 英文
論文頁數 79頁
口試委員 指導教授-任卓穎
召集委員-陳洵瑛
口試委員-張明熙
口試委員-游一龍
口試委員-郭余民
口試委員-許勤
口試委員-王鐘賢
中文關鍵字 運動  免疫  發炎  閉鎖性頭部外傷 
英文關鍵字 exercise  cytokine  deconditioning  immunity  inflammation  LPS  MAPK  MKP-1  closed head injury  object recognition memory  BDNF  triptolid 
學科別分類
中文摘要 規律運動對於週邊免疫系統與大腦有許多益處,包括增強週邊免疫抵抗發炎相關疾病的能力,減緩大腦神經發炎相關疾病的病程。然而運動益處的詳細機制卻仍不清楚。
在週邊免疫方面,我們認為中度運動訓練,會增加巨噬細胞MKP-1的表現,進而避免過度發炎反應。成年C57BL/6公鼠分成運動實驗組與不運動對照組,給予運動實驗組為期8週的中度跑步機運動訓練。比較兩組的基礎免疫狀態,以及個體對於LPS所提引的免疫反應。運動訓練實驗組,跟不運動的控制組相比較,運動訓練組的in vivo實驗結果為: i)休息狀態腹腔巨噬細胞的MKP-1 mRNA增加,ii)休息狀態腹腔巨噬細胞的phospho-p38蛋白質減少,MKP-1蛋白質表現增加,iii)在腹腔LPS注射後,有較低的血清IL-6與TNF-α,較少的白血球浸潤到腹腔。另外,以LPS刺激腹腔巨噬細胞的in vitro實驗結果為: i)運動加速MKP-1蛋白質表現,ii) 運動減少phospho-p38表現,減少IL-6、MCP-1與TNF-α產生。若運動訓練8週後,停止訓練(deconditioning)8週,則不見運動訓練的效果(包括運動增加的MKP-1,與運動減少LPS提引的細胞激素)。
在中樞神經系統發炎方面,我們認為中度運動會增加大腦MKP-1的表現,避免產生過度神經發炎反應。利用ICR成年公鼠的閉鎖性頭部外傷模式,探討腦損傷後,運動是否具有大腦保護功能,包括神經細胞保護作用與抗神經發炎反應。閉鎖性頭部外傷小鼠,在early-phase(亦即腦傷後2天)立即增加神經功能缺損評分(neurological severity score, NSS),迅速缺失object recognition memory功能,漸進式損傷區域依賴性的神經細胞損失,在late-phase (亦即腦傷後9天)可以測得微小膠細胞活化。在頭部外傷後第2天(early post-injury exercise),給予連續7天或14天中度運動,能有效的回復object recognition memory功能,避免漸進式的神經細胞損失,減少微小膠細胞的活化。然而,若是頭部外傷後第9天(delay post-injury exercise),才施予連續7天中度運動,則無法回復object recognition memory功能。我們更進一步探討,BDNF與MKP-1在大腦保護中所扮演的角色。腦損傷後的運動,可以回復因為閉鎖性頭部外傷所減少的海馬迴BDNF與MKP-1表現,若在每次運動前給予MKP-1抑制劑(triptolide),則會阻斷運動所增加的MKP-1,亦阻斷運動對於腦損傷的保護功用,包括object recognition memory功能回復,神經細胞損失的減少。雖然單獨施予triptolide可以抑制腦損傷鼠的微小膠細胞活化,以及減少神經細胞損失,但是triptolide無法回復object recognition memory功能。由此可知,外傷後第2天(early post-injury exercise)開始運動,可藉由回復BDNF與MKP-1的表現,使得神經細胞修復,進而恢復object recognition memory功能。然而,在運動保護大腦的機制方面,運動促使神經細胞修復的重要性大於抑制神經發炎。
總括來說,在LPS提引的週邊發炎與頭部外傷的腦發炎模式,運動都可以藉由增加MKP-1的表現,來達到保護功能。但是,運動益處的機制,在週邊與中樞系統是截然不同的。如同預期的,這兩種實驗模式都可以藉由MKP-1來避免過度免疫反應。然而,在頭部外傷的模式之中,運動促使早期神經細胞修復的重要性,比減緩晚期神經發炎反應還要更重要。
英文摘要 Regular exercise is beneficial to systemic immunity and brain functions, e.g., promoting the defense against infectious diseases in the peripheral organs and neuro-inflammatory diseases in the brain. However, the mechanisms are unclear.
In the study of peripheral immunity, we hypothesized that chronic exercise upregulated macrophage MKP-1 and thus prevented excessive inflammatory responses. Male C57BL/6 mice were divided into exercise and sedentary groups. The former but not the latter group underwent 8 week treadmill exercise at moderate intensity. Both basal immunity and lipopolysaccharide (LPS)-evoked immune responses were compared between groups. Although basal levels of TNF-andIL-6 were undetectable in the serum of both groups, the exercised mice showed the following immune adaptations in vivo: i) higher basal MKP-1 mRNA level in peritoneal macrophages, ii) lower basal p38 MAPK activity and enhanced MKP-1 immunostaining in macrophages, and iii) lower serum levels of IL-6 and TNF-and less leukocyte infiltration into peritoneal cavity after i.p. administration of LPS. When exposed to LPS in vitro peritoneal macrophages in the exercise group showed i) accelerated MKP-1 protein expression, and ii) low levels of p38 MAPK activity and cytokine secretion. Furthermore, 2 months of deconditioning completely reversed the exercise-enhanced basal MKP-1 immunostaining in macrophages and the exercise-suppressed cytokine secretion under LPS-evoked conditions.
In the study of the brain inflammation, we hypothesized that chronic exercise upregulated brain MKP-1 and thus prevented excessive neuroinflammatory responses. We investigated whether a post-impact exercise program was beneficial to ICR mice suffered closed-head injury (CHI), which involves both physical damage of neurons and subsequent neuroinflammation. That is, CHI caused immediately elevated neurological severity score, rapid loss of object recognition memory, and followed by progressive location-dependent brain damages (neuronal loss and microglia activation in the cortex and hippocampus). A moderate exercise paradigm (started 2 d post-impact and lasting for 7 or 14 days) effectively restored the object recognition memory, prevented the progressive neuronal loss and microglia activation. However, the exercise started 9 d post-impact was unable to recover recognition memory deficits. We further tested the possible involvement of brain-derived neurotrophic factor (BDNF) and MAP kinase phosphatase-1 (MKP-1) in the exercise-induced beneficial effects. Exercise partially restored the impact-abolished hippocampal expression of BDNF and MPK-1, while oral administration of triptolide (a synthesis inhibitor of MKP-1 and an antagonist of nuclear factor-κB) before each bout of exercise blocked the exercise-restoring effects of MKP-1 and recognition memory, and the exercise-retarded neuronal loss. Although triptolide treatment alone inhibited microglia activation and maintained the neuron number, it did not recover the injury-hampered recognition memory. Therefore, moderate exercise shortly after CHI reversed the deficits in recognition memory and prevented the progression of brain injury partially by upregulating BDNF and MPK-1. However, the major beneficial effect of exercise-induced MKP-1 in our CHI model was to facilitate neuron repair rather than to suppress neuroinflammation.
Take together, although the exercise-upregulated MKP-1 is beneficial to both LPS-evoked inflammation in peripheral organs and CHI-evoked inflammation in the brain, its beneficial effects are attributed to different mechanisms. As expected, MKP-1 prevented excessive immune responses in both models. However, in the CHI model it facilitated neuron repair in the early phase which led to reduced neuroinflammation in the late phase.
論文目次 Chinese Abstract IV
English Abstract VI
Contents VIII
Index of Introduction IX
Index of Materials and Methods X
Index of Discussions XI
Index of Figures XII
Index of Supplementary Figures XIV
Abbreviations XV
Introduction 1
Hypothesis and Experimental Design 12
Specific Aims 13
Materials and Methods 14
Results 24
Discussion 34
Conclusion 44
References 46
Figures 58
Supplementary Figures 74
Curriculum Vitae 79
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