臺灣博碩士論文加值系統

大腦周腦室白質軟化症是一種好發於早產兒的神經性疾病，主要由大腦白質和寡突觸膠前驅細胞受損所引起的腦傷，導致引發雙下肢腦性麻痺。周腦室白質軟化症患者腦中常可發現大量活化的微神經膠細胞，他們能夠釋放大量的發炎細胞激素(像是甲型腫瘤壞死因子)而去毒殺寡突觸膠前驅細胞。這些藉由感染或是缺氧而產生的發炎細胞激素最後都能夠造成周腦室白質軟化症，然而研究中發現大概只有10%早產兒會得到周腦室白質軟化症所引起的腦性麻痺，由此可知周腦室白質軟化症的易受性為何到目前為止仍未釐清。
在我的研究中將從生化易受性及基因易受性兩點切入:在生化易受性方面，探討正常早產兒小孩及周腦室白質軟化症所引起的早產兒腦性麻痺小孩中，是否在體內存在著甲型腫瘤壞死因子及其第一型受體的表現量差異，並且觀察這兩組小孩子體內負責免疫功能的細胞，在遭受到發炎攻擊的情況下，其免疫反應是否有所不同；而在基因易受性方面，則是藉由單核酸多行性研究在正常及得病這兩組早產兒小孩，在甲型腫瘤壞死因子及其第一型受體基因的單核酸多行性是否有差異。
我們收集了29位正常早產兒小孩及28位由核磁共振證實的確罹患周腦室白質軟化症引起腦性麻痺的早產兒小孩，這兩組小孩不論是在懷孕周數或是出生體重均無差異。我們發現，相較於正常早產兒小孩組(mean ± SEM, 9.7 ± 3.5 pg/ml)，周腦室白質軟化症所引起腦性麻痺組的小孩在體內血液循環中有較高量(60.8 ± 17.3 pg/ml)的甲型腫瘤壞死因子(P<0.01)；而游離的腫瘤壞死因子第一型受體含量，在這兩組中並沒有統計上的差異。為了研究除了甲型腫瘤壞死因子外，是否仍有其它細胞激素及趨化激素在這兩組小孩中的表現量是存在著差異，我們利用蛋白質微陣列式晶片來進行分析，結果發現除了甲型腫瘤壞死因子外，還有十九種不同的細胞激素及趨化激素在得到周腦室白質軟化症小孩血液中的表現量是比較高的。
接下來為了研究正常早產兒小孩和罹患周腦室白質軟化症引起腦性麻痺的早產兒小孩其體內負責免疫功能的細胞，在遭受到發炎攻擊的情況下，免疫反應是否有所不同(生化易受性)，我們利用由全血中分離出周邊血單核球細胞並且搭配體外刺激脂多醣體的方式，想要觀察控制組及實驗組的免疫反應，結果發現在處理脂多醣體後，相較於正常早產兒小孩組(mean ± SEM, 963.2 ± 133.5 pg/ml)，周腦室白質軟化症所引起腦性麻痺組的小孩會釋放較高量(1612 ± 263.9 pg/ml)的甲型腫瘤壞死因子(P<0.05)，而在釋放游離的腫瘤壞死因子第一型受體含量方面，不論是在脂多醣體刺激前後，在這兩組中並沒有統計上的差異。另外我們也發現周腦室白質軟化症所引起腦性麻痺組的小孩在周邊血單核球細胞處理脂多醣體後，細胞內的甲型腫瘤壞死因子含量明顯增多(P<0.05)，而正常組的小孩反而有減少的趨勢(P<0.05)。
從過去研究中已經發現，在基因內的單核酸多行性將會影響到基因的訊息核醣核酸及蛋白質的表現(基因易受性)。我們實驗室在先前的單核酸多行性研究中已發現甲型腫瘤壞死因子基因上的-1031 C/T和該疾病的發生率有關聯。因此我們檢視87位正常早產兒小孩和40位周腦室白質軟化症所引起腦性麻痺組的小孩，這兩組小孩之間腫瘤壞死因子第一型受體基因內的單核酸多行性，包含rs4149573(C/G)、rs4149576(A/G)、rs4149577(C/T)、rs4149579(A/G)、和 rs4149584(A/G)，結果顯示不論是在周腦室白質軟化症的嚴重度或是發生率，都和這些單核酸多行性的點無直接的相關性。
總結我們的研究成果，我們發現得到周腦室白質軟化症引起腦性麻痺的早產兒小孩，在血液中除了甲型腫瘤壞死因子外，還有十九種不同的細胞激素及趨化激素的表現量是比較高的，並且在面對發炎感染時，是能夠引起較強烈的免疫反應。我們認為此實驗結果在研究早產兒周腦室白質軟化症的易受性方面，可提供新的切入觀點。

Periventricular leukomalacia (PVL), a form of cerebral white matter damage and pre-oligodendrocyte (pre-OL) injury, is the most common neuropathological lesion that underlies most of the neurological sequelae in preterm infants who develop diplegic cerebral palsy (CP). PVL is characterized by the marked presence of activated microglia that is fully capable of producing toxic pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-a), which have the potential to induce pre-OL cell death. These cytokines may form a “final common pathway” leading to PVL whether triggered by infection or hypoxia. Despite the developmental vulnerability, only about 10% of preterm infants develop PVL-related CP. Therefore, the susceptibility to PVL in preterm infants remains unclear.
Here, we investigated biochemical and genetic susceptibility of PVL in children with premature birth and explored whether there are differences in immune responses of TNF-a/TNF receptor-1 (TNFR1) expression and in TNFA and TNFRSF1A genetic polymorphism between the preterm with PVL-related CP and the preterm with normal development.
There were 29 normal preterm children and 28 preterm children with PVL-related CP, both diagnosed by neurodevelopmental and magnetic resonance imaging examination. There was no significant difference in the gestation age and birthweight between the two groups. The plasma levels of sTNF-a,�nbut not sTNFR1, in the preterm CP group (mean ± SEM, 60.8 ± 17.3 pg/ml) were significantly (P<0.01) higher than those in the normal preterm group (9.7 ± 3.5 pg/ml). In addition, cytokines/chemokines antibody array showed 19 other cytokines/chemokines, such as CXCR2 ligands (IL-8, ENA-78, GRO-a, GRO), CCR3 ligands (MCP-1, MCP-2, MCP-3, RANTES, Eotaxin-2), CCR4 ligand (MDC), growth factors (PDGF-BB, Angiogenin, VEGF, EGF, IGF-1), and others (IL-6sR, Oncostatin M, Leptin, IL-4), were also significantly increased in CP preterm group than in normal preterm group.
Using an in-vitro model of lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs), we found that the CP preterm group (mean ± SEM, 1612 ± 263.9 pg/ml) had significantly (P<0.05) higher levels of sTNF-a but not sTNFR1 in the supernatants of cultured PBMCs after LPS stimulation compared with the normal preterm group (963.2 ± 133.5 pg/ml). Furthermore, flow cytometry showed that after LPS stimulation the PBMCs from preterm CP patients contained significantly (P<0.05) higher intracellular TNF-a levels, in contrast, those from the normal preterm had decreased intracellular TNF-a levels.
Our previous study found that TNFA-1031 was associated with the severity of PVL-related CP in preterm infants. Here, we compared TNFRSF1A SNPs, including rs4149573 (C/G), rs4149576 (A/G), rs4149577 (C/T), rs4149579 (A/G), and rs4149584 (A/G), between 40 CP preterm and 87 normal preterm children. The result showed that there was no significant difference in the SNPs polymorphism measured in the TNFRSF1A among the two groups.
In conclusion, the findings that CP preterm children had increased LPS sensitivity in their PBMCs compared with normal preterm children might underlie the biochemical susceptibility to PVL in preterm infants.

INTRODUCTION. . . .1
Cerebral palsy and periventricular leukomalacia in preterm infants. . . . 1
Risk factors and pathogenesis of PVL. . . . .2
The relationship between infection/inflammation and PVL. . . . .2
TNF-a�nand TNF receptors. . . . .4
White blood cells involve in the course of cerebral white matter damage . . . .6
Immune cells can reflect the neurological dysfunction . . . . 7
Propose of our study. . . .7
MATERIAL AND METHODS . . . . .10
Subjects. . . . .10
Neuroimaging by Magnetic Resonance Imaging. . . . . .10
Enzyme-Linked Immunosorbent Assay. . . . . 11
Isolation of Peripheral Blood Mononuclear Cells . . . . .11
ex vivo Study of Pro-inflammatory Cytokine Protein Expression Profile. . . . . 12
Flow Cytometry . . . . . .12
RNA Extraction . . . . .13
RNA Extraction by Commercialize Kit. . . . .13
TaqMan Real-time PCR SNP Genotyping. . . . .14
RT-PCR. . . . . .15
Statistics. . . . .16
RESULTS . . . . . .17
Maternal and neonatal characteristics of normal preterm children and preterm with PVL-related CP. . . . .17
Preterm children with CP had poorer performance in motor and cognitive function than normal preterm children. . . . .17
Preterm children with CP had higher plasma levels of TNF-a than normal preterm children. . . . . .18
Preterm children with CP had higher plasma levels of cytokines/chemokines than normal preterm. . . . .19
Establishing an in-vitro LPS-stimulated PBMCs model CP. . . . .20
LPS-stimulated PBMCs secreted higher levels of TNF-a instead of sTNFR1 in preterm children with CP than in normal preterm. . . . .20
Preterm children with CP had increased intracellular TNF-a�nlevels in the PBMCs after LPS stimulation. . . . . .21
No association of SNPs in TNFRSF1A between preterm CP and normal preterm children. . . . . .22
DISCUSSION. . . . .24
REFERENCES. . . . .30
APPENDIX. . . . . .38


INDEX OF TABLES

Table 1. Characteristics of the normal preterm and PVL-related CP preterm children . . . . .38
Table 2. Cognitive and neurodevelopmental outcome of normal preterm and CP preterm cohorts 39
Table 3. Gene list of antibody arrays 40
Table 4. 19 cytokines/chemokines were significantly higher in the CP preterm group than in the normal preterm group. . . . .43
Table 5. The occurrence of PVL-related CP is not associated with SNPs in TNFRSF1A. . . . . .50

INDEX OF FIGURES

Fig 1. Significantly high plasma levels of TNF-a in CP group than in normal group. 41

Fig 2. Plasma level of sTNFR1 showed no difference between PVL-related CP preterm group and normal preterm group. 42

Fig 3. ENA-78 but not GRO-a was higher in the CP preterm group compared with normal preterm group. 44

Fig 4. An in-vitro LPS-stimulated PBMCs model. 45

Fig 5. PBMCs secreted higher levels of TNF-a after LPS stimulation in preterm children with CP than in normal preterm. 46

Fig 6. The sTNFR1 levels showed no difference before or after LPS administration in the CP preterm group or in the normal preterm group. 47

Fig 7. The levels of intracellular TNF-a were decreased in the normal preterm group but increased in CP preterm group after LPS stimulation. 48

Fig 8. There are no difference in the level of membrane-bound form of TNFR1 on PBMCs before or after LPS stimulation for 3 hours in the normal preterm group and in the CP preterm group. 49

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