背景
新生兒缺氧性缺血性腦病變為最常見的嬰兒腦病變之原因，而發炎為缺氧性缺血性腦病變可能之惡化因子。低溫治療是目前針對中度到重度新生兒缺氧性缺血性腦病變之標準療法，惟必須於出生內六小時實行。臨床上 目前只能靠臨床症狀來判斷缺氧性缺血性腦病變的嚴重度，缺乏實用的生物指標，利用它來判斷缺氧性缺血性腦病變的嚴重度或是否有像發炎等缺氧性缺血性腦病變可能之惡化因子來決定是否要施行低溫治療。骨橋蛋白(Osteopontin)是個存在於體液內的磷酸蛋白，已知它在缺氧窒息性腦傷後或組織發炎時會增加。而膠質纖維酸性蛋白在缺氧窒息性腦傷後也會被神經膠細胞釋放於血液中。所以我們假設可以利用骨橋蛋白和膠質纖維酸性蛋白來當作腦傷後的生物指標，利用它來判斷缺氧性缺血性腦病變的嚴重度以及分辨發炎加成的缺氧性腦傷。
方法
建立不同腦傷程度的缺氧性腦傷動物模式，分別再加成以發炎，並測試低溫對於不同腦傷程度的缺氧性腦傷或發炎加成缺氧性腦傷動物的效果。再進一步測試在血中的生物指標(骨橋蛋白、膠質纖維酸性蛋白)濃度與腦傷程度及預後的相關性。並將動物實驗之結果以缺氧性腦傷新生兒檢體來驗證。
結果
不同腦傷程度的動物模式建立後，我們發現腦傷前加成誘發發炎，不論在輕度或重度腦傷程度都會有加重腦傷之趨勢。低溫可以改善輕度或重度缺氧性腦傷，也可以改善誘發發炎的缺氧性腦傷。
在缺氧後90分鐘後，血中骨橋蛋白在缺氧性腦傷後會降低，而在加成發炎的缺氧性腦傷會顯著增加。另外膠質纖維酸性蛋白，其在缺氧性腦傷後會有微幅的上昇，在加成發炎的缺氧性腦傷會有很明顯的上昇。因此我們可以得知，在動物血中結合此兩個生物指標可區分其是否具有發炎加成之缺氧性腦傷。
在人體試驗中，預後跟腦傷之嚴重度有相關，在中度到重度腦傷的病人有較高的死亡率和嚴重併發症。而其比起未有腦傷和輕微腦傷不需低溫的族群，血中骨橋蛋白有明顯的上升。
結論
在動物模式中，透由結合兩種生物指標可以區分是否有發炎加成的腦傷。而在人類新生兒中，在中到重度腦傷之病患，檢測骨橋蛋白可以發現其升高的現象。所以缺氧性缺血性腦傷後，血中骨橋蛋白可能可以做為低溫治療的指標。

Background: Neonatal hypoxic–ischemic encephalopathy (HIE) is the most common cause of neurological disability in infancy. Superimposed inflammation may further worsen the outcomes. Clinicians need reliable biomarkers, besides clinical symptoms, to distinguish HIE from inflammation-sensitized HIE within a limited therapeutic window in order to start hypothermia as soon as possible, also, to early identity those patients who may have worse outcome due to additional injury caused by inflammation.
Methods: We tested plasma osteopontin (OPN) and glial fibrillary astrocytic protein (GFAP) within the reported therapeutic window (90 minutes after hypoxic-ischemic (HI) injury) in neonatal rats with different HI severity and inflammation. Moreover, we prospectively enrolled patients with different HIE severity, and their serum samples within hypothermia therapeutic window (6 hours) were tested.
Results: Two different HI severity groups (75 minutes hypoxia in mild-HI and 150 minutes hypoxia in severe-HI) were established. Inflammation-sensitized HI brain injury induced by lipopolysaccharide (LPS) further increased apoptotic neurons and infarct volumes. In HI alone groups, OPN significantly decreased (p < 0.001) but GFAP slightly increased (p < 0.05) at 90 minutes after HI either in mild-HI or severe-HI compared with naïve group. In LPS-sensitized HI groups, both OPN and GFAP were significantly increased either in LPS-mild-HI or LPS-severe-HI groups compared with naïve group (all p < 0.001).Despite hypothermia is still protective in inflammation-sensitized HI, inflammation-sensitized HI had poorer long term neurological outcome than those without. Human samples were classified into mild (Sarnat stage 1 HIE) and moderate/severe (Sarnat stage 2/3 HIE) HI. We found osteopontin increased in HI group, compared with normal group, moreover, correlation with severity was observed.
Conclusions: In this animal model using the blood panel test of OPN and GFAP, it is possible to differentiate HI alone groups from LPS-sensitized HI groups or naïve group. In human, elevated blood OPN may be an indicator of hypothermia therapy.

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