跳到主要內容

臺灣博碩士論文加值系統

(18.97.14.82) 您好!臺灣時間:2025/02/18 23:09
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

: 
twitterline
研究生:王藍浣
研究生(外文):Lan-WanWang
論文名稱:探討缺氧性缺血及發炎對未成熟腦部白質傷害的影響 ─ 臨床及基礎研究
論文名稱(外文):The Effects of Hypoxic-Ischemia and Inflammation on White Matter Injury in the Immature Brain — Clinical and Experimental Approaches
指導教授:黃朝慶黃朝慶引用關係
指導教授(外文):Chao-Ching Huang
學位類別:博士
校院名稱:國立成功大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:101
語文別:英文
論文頁數:100
中文關鍵詞:極低出生體重早產兒腦性麻痺腦室周邊白質傷害缺氧性缺血發炎/感染lipopolysaccharidec-Jun N-terminal kinases
外文關鍵詞:very low-birth-weight infantcerebral palsycerebral white matter injuryhypoxic-ischemiaInflammation/infectionlipopolysaccharidec-Jun N-terminal kinases
相關次數:
  • 被引用被引用:0
  • 點閱點閱:262
  • 評分評分:
  • 下載下載:5
  • 收藏至我的研究室書目清單書目收藏:0
極低出生體重(〈 1500公克)早產兒是神經發展障礙的高危險群,其中主要的發展障礙為腦性麻痺,而腦室周邊白質傷害是早產兒最主要的腦傷,也是影響神經發展預後最重要的決定因素。造成白質傷害及腦性麻痺的危險因子依其致病機轉來分類,主要為缺氧性缺血或發炎/感染。缺氧性缺血及發炎/感染除了單獨發生,也有可能接連或合併發生,彼此產生交互或加成作用而加重白質傷害,增加腦性麻痺的機率。然而目前尚未有研究系統性的探討這個可能性,因此我們分別由模擬早產兒白質傷害的動物實驗及臨床早產兒資料分析,來驗證這個假設。
研究目標
臨床研究:探討在周產期及新生兒期的缺氧性缺血及感染因子是否對極低出生體重早產兒發生腦性麻痺的風險有聯合作用。
基礎研究:探討低劑量的lipopolysaccharide (LPS) 是否在未成熟腦部,藉由局部在白質活化神經發炎反應及破壞血腦障壁,來加重缺氧性缺血所產生的白質傷害;若確實如此,c-Jun N-terminal kinase (JNK)訊息傳遞路徑是否為連結神經發炎反應、血腦障壁破壞、及寡樹突膠質原始細胞凋亡的共同橋樑。
研究設計
臨床研究:我們由台灣早產兒追蹤醫療網,前瞻性收集從1995年到2005年間6318個住入台灣22家醫學中心新生兒加護病房的極低出生體重早產兒。我們以早產兒在兩歲時是否被診斷出有腦性麻痺作為預後變項,分析在周產期及新生兒期的缺氧性缺血及感染因子是否有交互或加成作用。
基礎研究:我們以出生兩天大,相當於早產兒好發白質傷害年齡(懷孕週數〈 30週)的Sprague-Dawley老鼠為實驗對象,將低劑量(0.05 mg/kg)的LPS注射到新生鼠的腹腔來模擬臨床感染,之後再予以腦部缺氧性缺血(HI) 90分鐘。我們比較單獨注射生理食鹽水(NS)的控制組、單獨注射LPS組、注射生理食鹽水及缺氧性缺血組(NS+HI),及注射LPS及缺氧性缺血組(LPS+HI),這四組腦部傷害、神經發炎反應、血腦障壁破壞,及寡樹突膠質原始細胞凋亡的程度。我們以免疫組織化學染色及螢光染色來偵測JNK活化的程度及表現的細胞,並用藥劑及基因抑制的方式來降低JNK的活性。
結果
臨床研究:有接受兩歲神經學檢查的3946人中,腦性麻痺患者有466位(11.8%),2238人(56.7%)動作發展正常,1242人(31.5%)有輕微或其他神經動作發展障礙。有腦性麻痺的早產兒在周產期及新生兒期發生缺氧性缺血因子,以及新生兒期發生敗血症的機率,遠較預後正常的早產兒來得高。出生急救、慢性肺疾病及重度呼吸暫停/心跳遲緩是預測腦性麻痺最具影響力的因子。相對於沒有缺氧性缺血或感染的早產兒,有出生急救、慢性肺疾病或重度呼吸暫停/心跳遲緩的早產兒發生腦性麻痺的機率分別增加1.91倍、2.22倍及5.07倍;而在合併有新生兒敗血症的情況下,發生腦性麻痺的機率分別增加3.05倍、3.10倍及7.11倍。以出生急救、慢性肺疾病、重度呼吸暫停/心跳遲緩及新生兒敗血症作為主要加成因子,則早產兒在這4個因子中全無,或有1、2、3個或4個全有時,腦性麻痺的發生率分別為10.3%、18.5%、28.0%、41.3%及55.6%。
基礎研究:在出生後第11天(實驗後第9天)的病理切片檢查發現只有LPS+HI組有明顯的白質傷害,四組在灰質均無明顯傷害。在實驗後24小時免疫組織化學染色發現,LPS+HI組與其他組相比,在白質區域有顯著的微小膠質細胞活化所引起的發炎反應、血腦障壁破壞,以及寡樹突膠質原始細胞的凋亡。白質腦傷伴隨有早期發生且持續性JNK活化,主要的表現細胞為微小膠質細胞、微血管內皮細胞及寡樹突膠質原始細胞,尤其在血管週邊有許多JNK活化細胞聚集。在LPS+HI前後注射藥劑或antisense oligodeoxynucleotides來抑制JNK活化,可降低神經發炎反應及血腦障壁破壞,減少寡樹突膠質原始細胞及血管內皮細胞凋亡,以及減少血管週邊JNK活化細胞的聚集,進而對白質腦傷產生神經保護作用。
我們得到的結論是缺氧性缺血及發炎/感染對早產兒發生腦性麻痺的機率,以及對未成熟腦部的白質傷害有聯合作用。臨床上,在周產期及新生兒期的缺氧性缺血因子以及新生兒敗血症,對極低出生體重早產兒腦性麻痺的發生率有累積加成作用。因此改善出生急救、慢性肺疾病、重度呼吸暫停/心跳遲緩及新生兒敗血症的危險因子,可有效降低腦性麻痺的發生率。動物實驗顯示低劑量的LPS可在不成熟腦部,藉由局部在白質增強神經發炎反應、破壞血腦障壁及寡樹突膠質原始細胞凋亡,來加重缺氧性缺血所引起的白質傷害;而JNK傳導路徑是寡樹突膠質血管網內,神經發炎反應、血腦障壁破壞及細胞凋亡共同的訊息傳遞橋樑。未來我們可藉此動物模型及其致病機轉,進一步探討可能的治療策略。希望能藉由降低臨床危險因子及治療策略的研發,來改善早產兒的神經發展預後。

Very low-birth-weight (VLBW, 〈 1500 g) premature infants have high risk of neurodevelopmental impairment, and cerebral palsy (CP) is the major disability in very preterm survivors. Cerebral white matter injury is the principal brain injury leading to CP in VLBW infants. Hypoxic-ischemia (HI) and inflammation/infection are the two major pathogenic factors of white matter injury and CP. From both experimental and clinical approaches, we examined whether HI and inflammation/infection have joint effects on the risk of CP in very preterm infants, and white matter injury in the immature brain.
Objective:
Clinical Study: To examine the joint effects of HI and infectious events in the perinatal and neonatal periods on CP risk in VLBW preterm infants.
Experimental Study: To investigate whether low-dose lipopolysaccharide (LPS) sensitizes HI-induced white matter injury in the immature brain by selectively up-regulating neuroinflammation and blood-brain barrier (BBB) damage in the white matter; and if so, whether c-Jun N-terminal kinases (JNK) signaling is the shared pathway linking neuroinflammation, BBB leakage and oligodendroglial apoptosis in the white matter injury.
Study Design:
Clinical Study: From 1995 to 2005, prospective registry of 6318 VLBW preterm infants admitted to Taiwan hospitals was conducted. CP was diagnosed at corrected age 24 months. The cumulative effects of HI and infectious events during the perinatal and neonatal periods on CP risk were analyzed.
Experimental Study: Postpartum (P) day 2 rat pups received LPS (0.05 mg/kg) (LPS+HI) or normal saline (NS+HI) followed by 90-minute HI. LPS and NS group were the pups that had LPS or NS only. Immunohistochemistry and immunoblotting were used to determine microglia activation, tumor necrosis factor-alpha (TNF-α), BBB damage, cleaved caspase-3, JNK and phospho-JNK (p-JNK), myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) expression. Immunofluorescence was performed to determine the cellular distribution of p-JNK. Pharmacological and genetic approaches were used to inhibit JNK activity.
Results:
Clinical Study: Of the 3946 infants who had completed 24-month neuromotor examinations, 466 (11.8%) had CP, 2238 (56.7%) normal outcomes, and 1242 (31.5%) minor or other impairment. CP group had significantly higher incidences of HI events in the perinatal and neonatal periods, and sepsis in the neonatal period than normal group. Three HI events, including birth cardiopulmonary resuscitation, chronic lung disease and severe apnea/bradycardia, were the most significant predictors for CP. Relative to CP risk for infants with neither HI nor sepsis, the CP odds increased 1.91-fold, 2.22-fold and 5.07-fold for infants with birth cardiopulmonary resuscitation, chronic lung disease, and severe apnea/bradycardia, respectively; while the combination with sepsis increased the odds by 3.05-fold, 3.10-fold and 7.11-fold, respectively. Using the three HI events plus sepsis, CP rates were 10.3%, 18.5%, 28.0%, 41.3% and 55.6% for infants with none, one, two, three and four events, respectively.
Experimental Study: Myelin basic protein immunohistochemistry on P11 showed white matter injury in LPS+HI group, but not in NS+HI, LPS and NS groups. In contrast, no gray matter injury was found in the four groups. In the white matter, increases of activated microglia, TNF-α expression, BBB leakage and cleaved caspase-3-positive oligodendrocyte progenitors were much more prominent in LPS+HI group than in the other three groups 24 hours post-insult. Immunoblotting and immunohistochemical analyses showed early and sustained JNK activation in the white matter at 6 and 24 hours post-insult. Immunofluorescence demonstrated up-regulation of p-JNK in activated microglia, vascular endothelial cells and oligodendrocyte progenitors, and also showed perivascular aggregation of p-JNK-positive cells around the vessels 24 hours post-insult. JNK inhibition by AS601245 or by antisense oligodeoxynucleotides significantly reduced microglial activation, TNF-α immunoreactivity, IgG extravasation, and cleaved caspase 3 in the endothelial cells and oligodendrocyte progenitors, and also attenuated perivascular aggregation of p-JNK-positive cells 24 hours post-insult. The AS601245 or JNK antisense oligodeoxynucleotide group had significantly increased MBP and decreased GFAP expression in the white matter on P11 than the vehicle or scrambled oligodeoxynucleotides group.
Conclusions: We concluded that HI and inflammation/infection have joint effects on CP risk in very preterm infants, and on the pathogenesis of white matter injury in the immature brain. Clinically, HI events and sepsis across the perinatal and neonatal periods exert cumulative effects on CP risk in VLBW premature infants. Experimentally, low-dose LPS sensitizes HI-induced white matter injury in the immature brain by selectively up-regulating neuroinflammation and BBB damage in the white matter, and JNK signaling is the shared pathway linking neuroinflammation, BBB leakage and oligodendroglial apoptosis in the white matter injury. The clinical and experimental studies may help reduce significant risk factors and develop effective therapeutic strategies against white matter injury to improve neurodevelopmental outcomes of very preterm infants.

中文摘要……………………………………………………1
英文摘要……………………………………………………3
誌謝……………………………………………………6
Table Contents………………………………………………10
Figure Contents……………………………………………11
Abbreviations…………………………………13
Introduction………………………………………14
Methods
Part I: Clinical Study……………………………………18
Part II: Experimental Study………………………………23
Results
Part I: Clinical Study………………………………………30
Part II: Experimental Study…………………33
Discussion……………………………38
References…………………………………………………52
Tables……………………………………………………65
Figures……………………………………………………74
Published Articles………………………………………98

1.Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol 2009; 8: 110-124.
2.Khwaja O, Volpe JJ. Pathogenesis of cerebral white matter injury of prematurity. Arch Dis Child Fetal Neonatal Ed 2008; 93: F153-161.
3.O’Shea TM. Cerebral palsy in very preterm infants: new epidemiological insights. Ment Retard Dev Disabil Res Rev 2002; 8: 135-45.
4.O’Shea TM, Klinepeter KL, Dillard RG. Prenatal events and the risk of cerebral palsy in very low birth weight infants. Am J Epidemiol 1998; 147(4): 362-369.
5.McElrath TF, Allred EN, Boggess KA, Kuban K, O’Shea TM, Paneth N, et al. Maternal antenatal complications and the risk of neonatal cerebral white matter damage and later cerebral palsy in children born at an extremely low gestational age. Am J Epidemiol 2009; 170 (7): 819-828.
6.Vincer MJ, Allen AC, Joseph KS, Stinson DA, Scot H, Wood E. Increasing prevalence of cerebral palsy among very preterm infants: a population-based study. Pediatrics 2006; 118(6): e1621-e1626.
7.Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, Higgins RD, for the National Institute of Child Health and Human development Neonatal Research Network. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004; 292:2357-2365.
8.Yanowitz TD, Jordan JA, Gilmour CH, Towbin R, Bowen A, Roberts JM, Brozanski BS. Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations. Pediatr Res 2002; 51:310-316.
9.Tsuji M, Saul JP, Plessis A, Eichenwald E, Sobh J, Crocker R, Volpe JJ. Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants. Pediatrics 2000; 106:625-632.
10.Kaukola T, Herva R, Perhomma M, Paakko E, Kingsmore S, Vainionpaa L, Hallman M. Population cohort associating chorioamnionitis, cord inflammatory cytokines and neurological outcome in very preterm, extremely low birth weight infants. Pediatr Res 2006; 59:478-483.
11.Jacobsson B, Hagberg G, Hagberg B, Ladfors L, Niklasson A, Hagberg H. Cerebral palsy in preterm infants: a population-based case-control study of antenatal and intrapartal risk factors. Acta Paediatr 2002; 91(8): 946-51.
12.Beaino G, Khoshnood B, Kaminski M, Pierrat V, Marret S, Matis J, et al. Predictors of cerebral palsy in very preterm infants: the EPIPAGE prospective population-based cohort study. Dev Med Child Neurol 2010; 52(6): e119-25.
13.Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. PNAS 2003; 100:8514-8519.
14.Eklind S, Mallard C, Leverin AL, Gilland E, Blomgren K, Mattsby-Baltzer I, Hagberg H. Bacterial endotoxin sensitizes the immature brain to hypoxic-ischemic injury. Eur J Neurosci 2001; 13: 1101-1106.
15.Wang X, Svedin P, Nie C, Lapatto R, Zhu C, Gustavsson M, Sandberg M, Karlsson JO, Romero R, Hagberg H, Mallard C. N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury. Ann Neurol 2007; 61:263-271.
16.Rousset CL, Chalon S, Cantagrel S, Bodard S, Andres C, Gressens P, Saliba E. Maternal exposure to LPS induces hypomyelination in the internal capsule and programmed cell death in the deep gray matter in newborn rats. Pediatr Res 2006; 59:428-433.
17.Paintlia MK, Paintlia AS, Barbosa E, Singh I, Singh AK. N-acetylcysteine prevents endotoxin-induced degeneration of oligodendrocyte progenitors and hypomyelination in developing rat brain. J Neurosci Res 2004; 78: 347-361.
18.Svedin P, Hagberg H, Savman K, Zhu C, Mallard C. Matrix metalloproteinase-9 gene knock-out protects the immature brain after cerebral hypoxia-ischemia. J Neurosci 2007; 27:1511-1518.
19.Back SA, Han BH, Luo NL, Chricton CA, Xanthoudakis S, Tam J, Arvin KL, Holtzman. Selective vulnerability of late oligodendrocyte progenitors to hypoxia-ischemia. J Neurosci 2002; 22:455-463.
20.Back SA, Luo NL, Borenstein NS, Levin JM, Volpe JJ, Kinney HC. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J Neurosci 2001; 21:1302-1312.
21.Craig A, Luo NL, Beardsley DJ, Wingate-Pearse N, Walker DW, Hohimer AR, Back SA. Quantitative analysis of perinatal rodent oligodendrocyte lineage progression and its correlation with human. Exp Neurol 2003; 181:231-240.
22.Fan LW, Mitchell HJ, Rhodes PG, Cai Z. α–phenyl-N-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain. Neurosci 2008; 151:737-744.
23.Ivacko JA, Sun R, Silverstein FS 1996 Hypoxic-ischemic brain injury induces an acute microglial reaction in perinatal rats. Pediatr Res 1996; 39:39-47.
24.Fan LW, Pang Y, Lin S, Rhodes PG, Cai Z. Minocycline attenuates lipopolysaccharide-induced white matter injury in the neonatal rat brain. Neurosci 2005; 133:159-168
25.Bona E, Anderson AL, Blomgren K, Gilland E, Puka-Sundvall M, Gustafson K, Hagberg H. Chemokine and inflammatory cell response to hypoxia-ischemia in immature rats. Pediatr Res 1999; 45:500-509.
26.del Zoppo GJ. Stroke and neurovascular protection. N Engl J Med 2006; 354: 553-555.
27.Chew LJ, Takanohashi A, Bell M. Microglia and inflammation: impact on developmental brain injuries. Ment Retard Dev Disabil Res Rev 2006; 12:105-112.
28.Muramatsu K, Fukuda A, Togari H, Wada Y, Nishino H. Vulnerability to cerebral hypoxic-ischemic insult in neonatal but not in adult rats is in parallel with disruption of the blood-brain barrier. Stroke 1997; 28: 2281-2288.
29.Tu YF, Tsai YS, Wang LW, Wu HC, Huang CC, Ho CJ. Overweight worsens apoptosis, neuroinflammation and blood-brain barrier damage after hypoxic ischemia in neonatal brain through JNK hyperactivation. J Neuroinflammation 2011; 8: 40-54.
30.Tu YF, Lu PJ, Huang CC. Moderate dietary restriction reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia in neonatal brain. Stroke 2012; 43: 491-498.
31.Dammann O, Durums S, Leviton A. Do white cells matter in white matter damage? Trends Neurosci 2001; 24: 320-324.
32.Manning AM, Davis RJ. Target JNK for therapeutic benefit: from Junk to gold? Nat Rev Drug Discov 2003; 2: 554-565.
33.Cao J, Semenova MM, Solovyan VT, Han J, Coffey ET, Courtney MJ. Distinct requirements for p38alpha and c-Jun N-terminal kinase stress-activated protein kinases in different forms of apoptotic neuronal death. J Biol Chem 2004; 279: 35903-35913.
34.Varfolomeev EE, Ashkenazi A. Tumor necrosis factor: an apoptosis JuNKie? Cell 2004; 116: 491-497.
35.Gao Y, Signore AP, Yin W, Cao G, Yin XM, Sun F, Luo Y, Graham SH, Chen J. Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. J Cereb Blood Flow Metab 2005; 25: 694-712.
36.Kuan CY, Whitmarsh AJ, Yang DD, Liao G, Schloemer AJ, Dong C, Bao J, Banasiak KJ, Haddad GG, Flavell RA, Davis RJ, Rakic P. A critical role of neural-specific JNK3 for ischemic apoptosis. PNAS 2003; 100: 15184-15189.
37.Guan QH, Pei DS, Zong YY, Xu TL, Zhang GY. Neuroprotection against ischemic brain injury by a small peptide inhibitor of c-Jun N-terminal kinase via nuclear and non-nuclear pathways. Neurosci 2006; 139: 609-627.
38.Guan QH, Pei DS, Liu XM, Wang XT, Xu TL, Zhang GY. Neuroprotection against ischemic brain injury by SP600125 via suppressing the extrinsic and intrinsic pathways of apoptosis. Brain Res 2006; 1092: 36-46.
39.Uesugi M, Nakajima K, Tohyama Y, Kohsaka S, Kurihara T. Nonparticipation of nuclear factor kappa B in the signaling cascade of c-Jun N-terminal kinases and p38 mitogen activated protein kinase-dependent tumor necrosis factor-alpha induction in lipopolysaccharide-stimulated microglia. Brain Res 2006; 1073: 48-59.
40.Deng YY, Lu J, Sivakumar V, Ling EA, Kaur C. Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats. Brain Pathol 2008; 18: 387-400.
41.Yatsusshige H, Ostrowski RP, Tsubokawa T, Colohan A, Zhang JH. Role of c-Jun N-terminal kinase in early brain injury after subarachnoid hemorrhage. J Neurosci Res 2007; 85: 1436-1448.
42.Karahashi H, Michelsen KS, Arditi M. Lipopolysaccharide-induced apoptosis in transformed bovine brain endothelial cells and human dermal microvessel endothelial cells: the role of JNK. J Immunol 2009; 182: 7280-7286.
43.Pirianov G, Jesurasa A, Mehmet H. Developmentally regulated changes in c-Jun N-terminal kinase signaling determine the apoptotic response of oligodendrocyte lineage cells. Cell Death Differ 2006; 13: 531-533.
44.Repici M, Centeno C, Tomasi S, Forloni G, Bonny C, Vercelli A, Borsello T. Time-course of c-Jun N-terminal kinase activation after cerebral ischemia and effect of D-JNKI1 on c-Jun and caspase-3 activation. Neuroscience 2007; 150: 40-49.
45.Herdegen T, Claret FX, Kallunki T, Martin-Villalba A, Winter C, Hunter T, Karin M. Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. J Neurosci 1998; 18: 5124-5135.
46.Wang LW, Wang ST, Huang CC. Preterm infants of educated mothers have better outcome. Acta Paediatr 2008; 97(5): 568-573.
47.Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio: Psychological Corporation, 1993.
48.Kuban K, Allred EN, O’Shea M, Paneth N, Pagano M, Leviton A. An algorithm for identifying and classifying cerebral palsy in young children. J Pediatr 2008; 153(4): 466-472.
49.Lin CY, Chang YC, Wang ST, Lee TY, Lin CF, Huang CC. Altered inflammatory responses in preterm children with cerebral palsy. Ann Neurol 2010; 68(2): 204-212.
50.Shennan AT, Dunn MS, Ohlsson A, Lenox K. Abnormal pulmonary outcomes in premature infants: prediction from oxygen requirement in the neonatal period. Pediatrics 1988; 82(4): 527-532.
51.Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin N Am 1986; 33(1): 179-201.
52.Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular haemorrhage: a study of infants with birth weights less than 1500 gm. J Pediatr 1978; 92(4): 529-534.
53.An international classification of retinopathy of prematurity. Pediatrics 1984; 74(1): 127-133.
54.Babson SG, Benda GI. Growth graphs for the clinical assessment of infants of varying gestational ages. J Pediatr 1976; 89(5): 814-820.
55.HMSO. Classification of occupation. In: Office of population censuses and surveys. London: HMSO, 1980.
56.Leviton A, Kuban KC, Pagano M, Allred EN, Van Marter L. Antenatal corticosteroids appear to reduce the risk of postnatal germinal matrix haemorrhage in intubated low birth weight newborns. Pediatrics 1993; 91(6): 1083-1088.
57.Schmidt B, Asztalos EV, Roberts RS, Robertson CMT, Sauve RS, Whitfield MF. Impact of bronchopulmonary dysplasia, brain injury and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months. JAMA 2003; 289(9): 1124-1129.
58.Chang YC, Huang CC, Hung PL, Huang HM. Rolipram, a phosphodiesterase type IV inhibitor, exacerbates periventricular white matter lesions in rat pups. Pediatr Res 2008; 64: 234-239.
59.Paxinos G, Watson C. The rat brain in stereotaxic coordinates. New York: Academic, 1986.
60.Lee HT, Chang YC, Tu YF, Huang CC. VEGF-A/VEGFR-2 signaling leading to cAMP response element-binding protein phosphorylation is a shared pathway underlying the protective effect of preconditioning on neurons and endothelial cells. J Neurosci 2009; 29:4356-4368.
61.Manning SM, Talos DM, Zhou C, Selip DB, Park HK, Park CJ, Volpe JJ, Jensen FE. NMDA receptor blockade with memantine attenuates white matter injury in a rat model of periventricular leukomalacia. J Neurosci 2008; 28:6670-6678.
62.Lin HY, Huang CC, Chang KF. Lipopolysaccharide preconditioning reduces neuroinflammation against hypoxic ischemia and provides long-term outcome of neuroprotection in neonatal rat. Pediatr Res 2009; 66: 254-259.
63.Carboni S, Hiver A, Szyndralewiez C, Gaillard P, Gotteland JP, Vitte PA. AS601245 (1,3-Benzothiazol-2-yl (2-{[2-(3-pyridinyl) ethyl] amino}-4 pyrimidinyl) Acetonitrile): a c-Jun NH2-terminal protein kinase inhibitor with neuroprotective properties. J Pharmacol Exp Ther 2004; 310: 25-32.
64.Lin HY, Wu CL, Huang CC. The Akt-endothelial nitric oxide synthase pathway in lipopolysaccharide preconditioning-induced hypoxic-ischemic tolerance in the neonatal rat brain. Stroke 2010; 41: 1543-1551.
65.Wang LW, Chang YC, Lin CY, Hong JS, Huang CC. Low-dose lipopolysaccharide selectively sensitizes hypoxia-ischemia-induced white matter injury in the immature brain. Pediatr Res 2010; 68: 41-47.
66.Wang LW, Tu YF, Huang CC, Ho CJ. JNK signaling is the shared pathway linking neuroinflammation, blood-brain barrier disruption, and oligodendroglial apoptosis in the white matter injury of the immature brain. J Neuroinflammation 2012; 9: 175-191.
67.Chau V, Poskitt KJ, McFadden DE, Bowen-Roberts T, Synnes A, Brant R, et al. Effect of chorioamnionitis on brain development and injury in premature newborns. Ann Neurol 2009; 66(2): 155-164.
68.van Iersel PAM, Bakker SCM, Jonker AJH, Hadders-Algra M. Does perinatal asphyxia contribute to neurological dysfunction in preterm infants? Early Hum Dev 2010; 86(7): 457-461.
69.Andrews WW, Cliver SP, Biasini F, Peralta-Carcelen AM, Rector R, Alriksson-Schmidt AI, et al. Early preterm birth: association between in utero exposure to acute inflammation and severe neurodevelopmental disability at 6 years of age. Am J Obstet Gynecol 2008; 198(4): 466.e1-e11.
70.Graham EM, Holcroft CJ, Rai KK, Donohue PK, Allen MC. Neonatal cerebral white matter injury in preterm infants is associated with culture positive infections and only rarely with metabolic acidosis. Am J Obstet Gynecol 2004; 191(4): 1305-1310.
71.Grether JK, Nelson KB, Walsh E, Willoughby RE, Redline RW. Intrauterine exposure to infection and risk of cerebral palsy in very preterm infants. Arch Pediatr Adolesc Med 2003; 157(1): 26-32.
72.Bassler D, Stoll BJ, Schmidt B, Asztalos EV, Roberts RS, Robertson CMT, et al. Using a count of neonatal morbidities to predict poor outcome in extremely low birth weight infants: added role of neonatal infection. Pediatrics 2009; 123(1): 313-318.
73.Poets CF, Stebbens VA, Richard D, Southall DP. Prolonged episodes of hypoxemia in preterm infants undetected by cardiorespiratory monitors. Pediatrics 1995; 95:860-863.
74.Mattia FR, deRegnier R-A O. Chronic physiologic instability is associated with neurodevelopmental morbidity at one and two years in extremely premature infants. Pediatrics 1998; 102:e35.
75.Billiards SS, Haynes RL, Folkerth RD, Trachtenberg FL, Liu LG, Volpe JJ, Kinney HC. Development of microglia in the cerebral white matter of the human fetus and infant. J Comp Neurol 2006; 497:199-208.
76.Haynes RL, Folkerth RD, Keefe RJ, Sung I, Swzeda LI, Rosenberg PA, Volpe JJ, Kinney HC. Nitrosative and oxidative injury to premyelinating oligodendrocytes in periventricular leukomalacia. J Neuropathol Exp Neurol 2003; 62: 441-450.
77.Kadhim H, Tabarki B, Verellen G, Prez C De, Rona AM, Sebire G. Inflammatory cytokines in the pathogenesis of periventricular leukomalacia. Neurol 2001; 56:1278-1284.
78.Stolp HB, Dziegielewska KM, Ek CJ, Potter AM, Saunders NR. Long-term changes in blood-brain barrier permeability and white matter following prolonged systemic inflammation in early development in the rat. Eur J Neurosci 2005; 22:2805-2816.
79.McColl BW, Rothwell NJ, Allan SM. Systemic inflammation alters the kinetics of cerebrovascular tight junction disruption after experimental stroke in mice. J Neurosci 2008; 28: 9451-9462.
80.Zoppo GJ, Milner R, Mabuchi T, Hung S, Wang X, Berg GI, Koziol JA. Microglial activation and matrix protease generation during focal cerebral ischemia. Stroke 2007; 38:646-651.
81.Eklind S, Hagberg H, Wang X, Savman K, Leverin AL, Hedtjarn M, Mallard C. Effect of lipopolysaccharide on global gene expression in the immature rat brain. Pediatr Res 2006; 60: 161-168.
82.Wang X, Stridh L, Li W, Dean J, Elmgren A, Gan L, Eriksson K, Hagberg H, Mallard C. Lipopolysaccharide sensitizes neonatal hypoxic-ischemic brain injury in a MyD88-dependent manner. J Immunol 2009; 183: 7471-7477.
83.Fan LW, Mitchell HJ, Tien LT, Zheng B, Pang Y, Rhodes PG, Cai Z. α-phenyl-n-tert-butyl-nitrone reduces lipopolysaccharide-induced white matter injury in the neonatal rat brain. Dev Neurobiol 2008; 68: 365-378.
84.Zacchigna S, Lambrechts D, Carmeliet P. Neurovascular signaling defects in neurodegeneration. Nat Rev Neurosci 2008; 9: 169-181.
85.Back SA, Volpe JJ. Cellular and molecular pathogenesis of periventricular white matter injury. Ment Retard Dev Disabil Res Rev 1997; 3: 96-107.
86.Kuno R, Wang J, Kawanokuchi J, Takeuchi H, Mizuno T, Suzumura A. Autocrine activation of microglia by tumor necrosis factor-α. J Neuroimmunol 2005; 162: 89-96.
87.Baud V, Karin M. Signal transduction by tumor necrosis factor and its relatives. Trends Cell Biol 2001; 9: 372-377.
88.Remmers M, Schmidt-Kastner R, Belayev L, Lin B, Busto R, Ginsberg MD. Protein extravasation and cellular uptake after high-dose human-albumin treatment of transient focal cerebral ischemia in rats. Brain Res 1999; 827:237-242.
89.Del Bigio MR, Deck JHN, Davidson GS. Glial swelling with eosinophilia in human post-mortem brains: a change indicative of plasma extravasation. Acta Neuropathol 2000; 100:688-694.
90.Jensen MB, Finsen B, Zimmer J. Morphological and immunophenotypic microglial changes in the denervated fascia dentata of adult rats: Correlation with blood–brain barrier damage and astroglial reactions. Exp Neurol 1997; 143:103-116.
91.Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem 2002; 71: 635-700.
92.Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett P, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T. The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 2002; 22: 2478-2486.
93.Dauphinee SM, Karsan A. Lipopolysaccharide signaling in endothelial cells. Lab Invest 2006; 86: 9-22.
94.Palsson-Mcdermott EM, O’Neill LAJ. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunol 2004; 113: 153-162.
95.Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia 2002; 39: 279-291.
96.Lucas R, Garcia I, Donati YRA, Hribar M, Mandriota SJ, Giroud C, Buurman WA, Fransen L, Suter PM, Nunez G, Pepper MS, Grau GE. Both TNF receptors are required for direct TNF-mediated cytotoxicity in microvascular endothelial cells. Eur J Immunol 1998; 28: 3577-3586.
97.De Boer AG, Breimer DD. Cytokines and blood-brain barrier permeability. Prog Brain Res 1998; 115: 425-451.
98.D’Mello C, Le T, Swain MG. Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factor-α signaling during peripheral organ inflammation. J Neurosci 2009; 29: 2089-2102.
99.Pang Y, Cai Z, Rhodes PG. Effects of lipopolysaccharide on oligodendrocyte progenitor cells are mediated by astrocytes and microglia. J Neurosci Res 2000; 62: 510-520.
100.Sherwin C, Fern R. Acute lipopolysaccharide-mediated injury in neonatal white matter glia: role of TNF-α, IL-1β and calcium. J Immunol 2005; 175: 155-161.
101.Pang Y, Cai Z, Rhodes PG. Effects of TNF-α on developing optic nerve oligodendrocytes in culture. J Neurosci Res 2005; 80: 226-234.
102.Volpe JJ. Systemic inflammation, oligodendroglial maturation and encephalopathy of prematurity. Ann Neurol 2011; 70: 525-529.
103.Baud O, Li J, Zhang Y, Neve RL, Volpe JJ, Rosenberg PA. Nitric oxide-induced cell death in developing oligodendrocytes is associated with mitochondrial dysfunction and apoptosis-inducing factor translocation. Eur J Neurosci 2004; 20: 1713-1726.
104.Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA. Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci USA 2005; 102: 9936-9941.
105.Back SA, Luo NL, Mallinson RA, O’Malley JP, Wallen LD, Frei B, Morrow JD, Petito CK, Roberts CT, Murdoch GH, Montine TJ. Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes. Ann Neurol 2005; 58: 108-120.
106.Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNF-α-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005; 120: 649-661.
107.Ventura JJ, Cogswell P, Flavell RA, Baldwin AS, Davis RJ. JNK potentiates TNF-stimulated necrosis by increasing the production of cytotoxic reactive oxygen species. Genes Dev 2004; 18: 2905-2515.
108.Shen HM, Liu ZG. JNK signaling is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radical Biol Med 2006; 40: 928-939.
109.Liu HN, Giasson, BI, Mushynski WE, Almazan G. AMPA receptor-mediated toxicity in oligodendrocyte progenitors involves free radical generation and activation of JNK, calpain and caspase 3. J Neurochem 2002; 82: 398-409.
110.Borsello T, Clarke PGH, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C. A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 2003; 9: 1180-1186.
111.Pirianov G, Brywe K, Mallard C, Edwards AD, Flavell RA, Hagberg H, Mehmet H. Deletion of the c-Jun N-terminal kinase 3 gene protects neonatal mice against cerebral hypoxic-ischemic injury. J Cereb Blood Flow Metab 2007; 27: 1022-1032.

連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top