急性腎損傷會造成住院病患死亡率上升與後遺症增加，因此發展偵測指標早期監測急性腎損傷與治療標的防止急性腎損傷的發生是刻不容緩。巨噬細胞遷移抑制因子是一促炎性細胞激素並表現在正常的腎小管細胞; 在腎發炎性疾病時，腎臟的巨噬細胞遷移抑制因子含量上升，且其上升與腎組織損害，白血球浸潤和腎功能異常呈正相關，故推測巨噬細胞遷移抑制因子可能是腎功能損傷的潛在生物指標與致病因子。雖然腎臟感染為臨床常見急性腎損傷原因，但巨噬細胞遷移抑制因子在感染導致的腎損傷之調控角色與與致病機制仍屬未明。我們的研究假設為:巨噬細胞遷移抑制因子為造成急性腎損傷的重要調節因子並參與急性腎損傷的產生，本論文目的即在探討巨噬細胞遷移抑制因子偵測腎感染病患之腎損傷存在與否的臨床應用角色，與急性腎損傷產生時是否為重要的致病因子。
泌尿道感染所致急性腎損傷與巨噬細胞遷移抑制因子之關聯目前尚不清楚，因此在我們論文特定目標一即利用前瞻性臨床研究去釐清巨噬細胞遷移抑制因子的變化、急性腎損傷、疾病嚴重性之間的關係。我們發現腎盂腎炎的病人中，急性腎損傷發生時會伴隨著尿液中巨噬細胞遷移抑制因子濃度上升，而此濃度與之前所知的腎損傷生物指標，含腎損傷因子1與細胞白介素1β的濃度呈正相關，故我們推論尿液中巨噬細胞遷移抑制因子可用來偵測腎盂腎炎患者中，是否併發急性腎損傷。接著我們利用小鼠上行性泌尿道感染的動物模式，發現伴隨腎功能異常，尿液中巨噬細胞遷移抑制因子上升時，腎臟的巨噬細胞遷移抑制因子在腎小管中的含量卻不明原因的明顯下降。為釐清此問題，我們利用尿路致病型大腸桿菌感染細胞實驗，發現在大腸桿菌感染造成了細胞壞死，並導致巨噬細胞遷移抑制因子由細胞釋放至胞外。腎感染會導致腎血管損傷而導致腎臟缺血性傷害，而腎臟缺血性傷害為造成急性腎損傷的重要原因，故在特定目標3中，我們利用了小鼠腎臟缺血-再灌流的動物模式進一步探討巨噬細胞遷移抑制因子在急性腎損傷中所扮演的致病角色。我們發現即使在腎功能尚未異常時，尿液中巨噬細胞遷移抑制因子可靈敏的偵測腎損傷的存在; 此外，抑制巨噬細胞遷移抑制因子的生物活性可產生腎保護的效果，包含減少腎功能異常、降低腎組織損傷與減緩腎發炎的功效，這樣的發現提供了一個腎保護的策略: 阻斷巨噬細胞遷移抑制因子可降低腎缺血所導致的腎損傷。
綜上所論，我們證實了偵測尿液中巨噬細胞遷移抑制因子的濃度是一個簡單又低侵襲性的檢查，即使在腎功能尚未異常時，它可靈敏的偵測腎損傷的存在; 我們亦提出了以巨噬細胞遷移抑制因子為治療標的之腎保護策略。

Acute kidney injury (AKI) is associated with increase in-hospital morbidity and mortality. Biomarkers to facilitate early identification of kidney injury and the strategies to prevent the development of AKI are of emergent needs. Macrophage migration inhibitory factor (MIF) is a potent pro-inflammatory cytokine and is constitutively expressed in renal tubules. Under inflammatory kidney disease, renal MIF upregulates, and the level of renal MIF is correlated to leukocyte infiltration, histopathological damage, and renal dysfunction, and is therefore considered as a potential marker and pathogenic participant for the development of renal injury. Although kidney infection is an important factor to AKI, the mechanism of renal MIF deregulation and pathogenic role of MIF during kidney infections remains unknown. We therefore hypothesize that MIF acts as a pathogenic regulator and participate in the development of AKI. The aim of our thesis is at investigating the clinical implication of aberrant MIF expression in detecting AKI and the pathogenic role of MIF in the development of AKI.
In Specific Aim 1 of this thesis, the correlation between deregulated MIF and renal dysfunction were investigated through prospective clinical study enrolling patients with pyelonephritis. We demonstrated that elevated levels of urine MIF accompanied the development of AKI. An elevated urine MIF level, along with elevated kidney injury molecule-1 and interleukin-1β levels, is speculated to be a biomarker for the presence of AKI in patients with pyelonephritis. To investigate the expression pattern of MIF during AKI, we used a mice model of ascending urinary tract infections. The urine MIF increased accompanying with the development of AKI and histological damage in mice model of kidney infections. Notably, the MIF storage of the renal cortical tubules diminished with AKI through unknown mechanism. In Specific Aim 2 of this study, we demonstrated that uropathogenic Escherichia coli infections caused necrotic cell death and accompanied with MIF release from intracellular storage. Kidney infections cause vasculature damage and produce ischemia injury to the kidney. Kidney ischemic injury is a major contributing factor to the development of AKI. For Specific Aim 3, we investigated the pathogenic role of MIF in the development of ischemia-evoked AKI through mice models of kidney ischemia-reperfusion injury (IRI). Elevation of urine MIF was found in subclinical kidney damage in which serum creatinine were within normal limit. Furthermore, MIF inhibitions protected kidney against renal IRI-induced AKI, tissue damage, and renal inflammation.
Taken together, the thesis demonstrated that measurement of urine MIF is a accessible assay for detect AKI and even subclinical kidney damage, and MIF-targeting strategy may be an effective target against the development of AKI.

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