根據流行病學的研究顯示，感染所引起的發炎反應以及缺氧窒息傷害，是造成早產兒腦傷的兩個重要且危險的因子。在臨床上卻發現，這兩個危險因子非常容易一併發生在早產兒身上，是否將導致更嚴重的腦部傷害則為現今迫切需要釐清的議題。為了研究這兩種因子在發育中大腦所扮演的角色，科學家建立動物模式，利用細菌細胞壁上的脂多醣 (LPS) 來模擬感染所引起的發炎反應，或以單側頸動脈結紮合併缺氧來模擬缺氧窒息所造成的腦部傷害。文獻紛紛指出，感染或是缺氧窒息事件的刺激之下，將容易誘發神經發炎，血腦屏障的破壞以及細胞凋亡的情形，進而讓發育未成熟的大腦受到嚴重的波及。本實驗室過去也建立了大鼠的幼鼠動物模式，發現給予低劑量 (0.05 mg/kg) 脂多醣的處理後，原本受到缺氧窒息所呈現的腦部傷害卻更加的惡化。然而，目前在發育未成熟大腦中探討由感染與缺氧窒息所誘發的神經發炎，血腦屏障破壞以及細胞凋亡等機制的研究並不是很多，倘若欲更深入於治療，則需更進一步了解其機轉。因此，建立一有利於機轉探討的小鼠幼鼠動物模式更是個刻不容緩的課題。臨床上發現，腫瘤壞死因子 (TNF-) 與受到感染或者是缺氧窒息傷害的早產兒息息相關。腫瘤壞死因子會透過腫瘤壞死因子受體1 (TNFR1) 以及腫瘤壞死因子受體2 (TNFR2) 來傳遞其訊息路徑。然而，此兩種受體所引領的訊息路徑卻可能造成細胞存活或者是細胞死亡兩種迥然不同的結果。過去研究顯示，在感染或缺氧窒息所引發的腦部傷害當中，腫瘤壞死因子及其受體可能部分參予了神經發炎，血腦屏障破壞以及細胞凋亡的機轉，但在於幼鼠腦傷的角色中有些機轉卻未多做著墨。另外，在感染或缺氧窒息的刺激之下，腫瘤壞死因子兩種受體在於幼鼠腦傷的個別作用仍有待釐清。
過去的文獻指出，在腦部神經細胞的表現上，腫瘤壞死因子受體1相較於腫瘤壞死因子受體2更加明確。也因此，我們大膽假設腫瘤壞死因子受體1的訊息傳遞路徑，會透過神經發炎，血腦屏障破壞以及細胞凋亡的機轉，在感染所惡化的缺氧窒息幼鼠腦傷當中，扮演著一關鍵性的角色。本實驗利用出生後五天的小鼠(腦部發育情形相當於人類小於三十二週大的早產兒)，在缺氧後第12天，確實發現低劑量 (0.05 mg/kg) 的脂多醣更加惡化了灰質以及白質的傷害。並且，在缺氧後的24小時，神經發炎，血腦屏障破壞以及細胞凋亡的情形都受到低劑量脂多醣的惡化。本實驗接續比較了野生型 (wild-type)，腫瘤壞死因子受體1基因剔除型 (TNFR1-knockout)，腫瘤壞死因子受體2基因剔除型 (TNFR2-knockout) 的幼鼠在缺氧後12天的腦傷情形，發現在合併脂多醣以及缺氧窒息刺激之下，腫瘤壞死因子受體1基因剔除型的幼鼠，不論是在皮質或者是白質都呈現比較保護的趨勢。而在缺氧後24小時也觀察到神經發炎，血腦屏障破壞以及細胞凋亡情形在腫瘤壞死因子受體-1基因剔除型幼鼠中受到了保護。爾後，本實驗利用聚合酶連鎖反應陣列 (PCR array) 掃描84個與腫瘤壞死因子配體和受體超家族 (TNF- ligand and receptor superfamily) 相關的基因。結果顯示，經過脂多醣和缺氧窒息的刺激之下，野生型以及腫瘤壞死因子受體-2基因剔除型幼鼠在缺氧後6小時，TWEAK-R的mRNA表現量皆有顯著上升 (P<0.05); 但此現象在腫瘤壞死因子受體1基因剔除型幼鼠卻受到了抑制。而在蛋白質表現量的評估上，我們同樣也觀察到腫瘤壞死因子受體-1基因剔除型幼鼠即使受到了脂多醣和缺氧窒息的刺激，其TWEAK-R的表現量仍無顯著上升。總而言之，本實驗成功建立了脂多醣惡化缺氧窒息幼鼠腦傷的小鼠動物模式，並證實腦傷情形是透過腫瘤壞死因子受體1的訊息傳遞路徑引起神經發炎，血腦屏障破壞以及細胞凋亡的機轉所致。另外，腫瘤壞死因子受體1可能亦參與著TWEAK-R的調控。因此，本研究首次證實腫瘤壞死因子受體1在感染合併缺氧窒息的幼鼠腦傷中扮演著關鍵性的角色。

Epidemiological studies have shown that hypoxic-ischemia (HI) and infection/inflammation are the two major risk factors for brain injury in preterm infants. Inflammation might predispose to or act in concert with HI in premature infants. Substantial evidence has documented that neuroinflammation, blood-brain barrier (BBB) damage and neuronal apoptosis, which triggered from lipopolysaccharide (LPS) or HI, account for the vulnerability of the developing brain. Our lab has demonstrated that LPS could sensitize HI injury in immature rat brain. However, it is necessary to establish a mice model to elaborate the detail mechanism. Moreover, little is known about the combined effects of LPS and HI on neuroinflammation, BBB damage and neuronal apoptosis in the immature brain. Tumor necrosis factor-alpha (TNF-), a pleiotropic cytokine mediating inflammation and cell death, has been demonstrated to play an important role in immature brain injury. TNF- exerts its biological functions mainly through binding to its two cell-surface receptors, the p55/p60 TNF receptor-1 (TNFR-1) and the p75/p80 (TNFR-2). Whereas most of the biological effects induced by TNF- have been attributed to TNFR-1 and TNFR-2, the individual effect of TNFR-1 or TNFR-2 is still unclear after LPS and HI injury in the immature brain.
Previous studies have shown that TNFR-1 is more dominant than TNFR2 in neurons. We, therefore, hypothesized that TNFR-1 signaling plays the major role in LPS-induced sensitization of HI injury in the immature brain through upregulation of neuroinflammation, BBB damage and neuronal apoptosis. Using postnatal day-5 mouse pups, we found that LPS significantly worsened HI injury in the cortex, striatum and white matter 12-day post-insult. The HI injury in the cortex was associated with increases of microglia activation and BBB damage, and upregulation of TNF-α and activated caspase-3 levels. Compared with wild-type mouse pups, TNFR1-knockout pups, but not TNFR2-knockout ones, had significantly less damage from LPS sensitization of HI injury in the cortex and white matter. The protective effect of TNFR-1 knockout was associated with attenuation of HI-induced microglia activation, BBB damage, and neuronal apoptosis. Furthermore, we analyzed changes of gene expression post-insult among wild-type, TNFR1-knockout and TNFR2-knockout mouse pups by profiling 84 genes of TNF ligand and receptor superfamily with polymerase chain reaction (PCR) microarray. HI induced significant upregulation of c-Jun and TWEAK-R (tumor necrosis factor-like weak inducer of apoptosis receptor). mRNA levels in wild-type and TNFR2-knockout group (P<0.05), but not in TNFR1-knockout group. In addition, TWEAK-R protein was inhibited in TNFR1-knockout pups compared to wild-type and TNFR2-knockout pups after HI insult. In conclusion, this study indicates that LPS sensitizes HI injury in the immature brain through TNFR-1 signaling-induced neuroinflammation, BBB disruption and neuronal apoptosis. TNFR-1 may play a role in TWEAK-R pathway. Selective inhibition of TNFR-1 signaling may represent a new approach to reduce LPS plus HI-induced neuronal damage in the immature brain.

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