臺灣博碩士論文加值系統

中文摘要
BPD(Bronchopulmonary dysplasia) 是發生在早產兒最常見的一種慢性肺部發育不全的疾病。 形成的原因錯綜複雜， 除了早產本身肺部不夠成熟之外 ，氧氣的使用或和呼吸器的機械性傷害，加上長時間住院諸多臨床疾病如感染、發炎等，再加上早產兒神經發育及腸胃道不夠成熟以致無法自行吸食及消化足夠母奶或配方奶，以致於營養素的缺乏也是造成此疾病的一樣重要的因素之一。 過去幾十年來認為營養因素中特別維他命A的不足是造成慢性肺部疾病的重要因素之一。 臨床的觀察研究中發現早產兒血液中維他命A的量比起足月而要來的低。在過去臨床上少量樣本曾經觀察到單獨一次血液中維他命 A低的早產兒會增加BPD慢性肺部疾病的機率，然而也有一些觀察研究持不同的結果或意見。其中原因之一是，當給與早產兒肌肉注射維他命 A時，並無法絕對有效預防BPD慢性肺部疾病的發生。另外原因也可能是影響早產兒BPD慢性肺部疾病及維他命A的因素眾多而且複雜，至今都尚未釐清，例如產前類固醇的使用，發炎疾病以及營養不良等因素。而這些因素同時也會影響早產兒維他命 A的代謝和濃度。
所以本研究目的是想看看產前施打得類固醇或出生後給的類固醇是否會影響維他命 A的濃度，還有臨床上還有哪些因子會跟血清低維他命 A濃度(retinol<20ug/dl)或是血清維他命 A缺乏(retinol<10ug/dl)相關連。以及連續多次追蹤血清中的維他命 A濃度，探討什麼時間點的低維他命 A濃度或是維他命A缺乏跟早產兒的一些預後如慢性肺部疾病、較長期氧氣依賴、或是中重度早產兒視網膜病變和腦室出血、以及神經發展預後是否有相關。
結果我們發現出生小於二十九週或體重小於1250公克的早產兒，血液中維
他A的濃度與孕母是否早期破水(>18 hr)、早產兒的懷孕週數、出生體重無關
以及男女性別也無關。 產前孕婦有施打類固醇所生的早產兒，他們48小時內
低維他命A濃度的機率比產前孕婦沒有施打類固醇所生的早產兒明顯比較高。
另外出生後有使用類固醇者，沒有明顯造成血液中低維他命A濃度或維他命
A濃度缺乏的機率升高。另外發現，剛出生48小時內如果血液中維他命A缺乏，
罹患中度及嚴重度早產兒呼吸窘迫症的機率明顯增加。也發現延長使用靜脈營養
(>3weeks) 的早產兒會明顯增加住院中維他命A缺乏的機率。在住院一星期之後，
若持續有低維他命A濃度的早產兒，會明顯增加new BPD的機率；若持續有維他
命A缺乏的早產兒，會明顯增加不良慢性肺部預後(adverse pulmonary outcome)
的機率，以及明顯增加在矯正年齡一歲和兩歲的貝利嬰兒神經發展評估有延遲的
現象。
已知血液中低維他命 A濃度和早產兒的慢性肺部疾病、及血液中維他命 A缺乏和早產兒較長期氧氣依賴有關。但是它們之間的詳細作用機轉，特別是氧氣和維他命 A之間的交互作用，都是重要卻懸而未決的問題。所以我們運用新生的小鼠高氧曝露15天，成功建立一個BPD的動物模式，當肺部發育受到停滯的過程中，運用Ki-67 組織染色，定量分析時序性肺部細胞增生受到抑制
的情況，結果發現在第四天(P4) 和第九天 (P9)的抑制最明顯；然後利用real rime PCR來定量肺部中維他命 A受體 (RARs and RXRs) 的mRNA在高氧曝露下造成BPD的同時，基因表現的時序性改變。結果發現RAR-α在第九天(P9) ；RXR-α和 RAR-γ在第四天 (P4)，第十五天(p15) ；RAR-β和RXR-γ在第九天(p9), 第十五天(p15) 的抑制最明顯。體外實驗結果也顯示在高氧環境下的肺細胞增生也受到明顯抑制，同時間肺泡細胞內RAR-α和RAR-γ的基因表現也明顯受到明顯抑制。但在高氧環境下加入維他命 A酸可以減弱細胞的受抑制，而RAR-α和RAR-γ的基因表現也恢復正常。高氧環境的長期曝露下也同時明顯改變了維他命 A在新生小鼠肝臟和肺臟的代謝。
從我們的臨床研究結果中發現血清中低維他命 A濃度，或是維他命 A缺乏，明顯會增加短期或長期的不良預後。所以要如何讓這些早產兒的體內在出生和住院中維持血液中足夠的維他命A濃度，比如改變投予的路徑，施與的劑型和劑量，這些是未來非常重要的課題。另外利用新生的小鼠曝露高氧十五天可以成功建立一個BPD 的動物模式，可應用於基礎研究BPD的詳細致病機轉，以及維他命 A，高氧hyperoxia和BPD之間的交互作用及詳細分子機轉，進一步研發出真正針對特定分子細胞的疾病治療策略。有助於我們預防和治療早產兒的BPD。同時也能發展出一個安全，有效率，以及方便投予維他命A的治療方式。

Abstract
Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease occurring in premature infants. The pathogenesis of BPD is complex and multi-factorial. Nutrient deficiency, especially deficiency of retinol, is one of the main causes of BPD in premature infants. Studies have reported that the retinol concentration in the blood of premature infants is lower than that in full-term infants, and the risk of BPD is increased in premature infants with a low retinol concentration. Although some studies have shown that BPD and could not be prevented by the administration of retinol intramuscularly. Moreover, many other factors may also have effects on serum retinol concentration in premature infants.
So, in this study we aimed to assess the effects of antenatal and postnatal steroid administration, and other clinical factors on the serum concentrations of vitamin A. Another way, we would like to determine whether low serum retinol increase the risk of developing BPD, long-term pulmonary sequelae, and other poor morbidity such ROP , IVH, and abnormality of neurological outcome because these chronic morbidities have much influence on later life of premature infants.
From these studies revealed neither antenatal nor postnatal steroid administration affected retinol concentrations. Retinol deficiency was associated with an increased risk for moderate-severe respiratory distress syndrome and adverse pulmonary outcome (death during 28 days of age and long-term oxygen dependence > 90 days); low retinol levels conferred an increased risk for bronchopulmonary dysplasia. Prolonged duration of total parenteral nutrition (> 21 days) was associated with serum retinol deficiency during hospitalization (P < 0.05). Retinol deficiency was associated with an increased risk for delayed neurological development in one year old and 2 year old.
We observed serum retinol concentration is correlated with acute and chronic respiratory outcomes, but the molecular and cellular events among hyperoxia exposure retinoids and BPD are still unresolved issues. We established a neonatal mouse model to investigate the effects of normobaric hyperoxia on retinoid metabolism and retinoid receptor expression.
Hyperoxia significantly reduced the body and lung weight of neonatal mice. Hyperoxic mice also showed a significant decrease in alveolar proliferation and alveolarization, accompanied by increased retinoid metabolism. Hyperoxia also downregulated expression of RAR-α, RAR-γ, RXR-α,RAR-βand RXR-γ in the lungs of neonatal mice. In vitro, hyperoxia inhibited proliferation and expression of retinoid receptors(RAR-α and RAR-γ) in A549 cells. Vitamin A treatment was sufficient to block the effects of hyperoxia in vitro.
Clinical results further indicate that maintaining adequate retinol levels in premature infants is critically important for promoting better life quality of premature
Infants. These insights of basic study may help in developing novel therapeutic and prevention strategies for premature infants who require oxygen therapy through genetic and pharmacological means in the future.

目 錄

誌謝………………………………………………………………………………..p.i
中文摘要……………………………………………………………………...….p.ii
英文摘要……………………………………………………………………...…p.v
目錄…………………………………………………………………………...…p.vii
表目錄………………………………………………………………………....p.ix
圖目錄………………………………………………………………………....p.x.
1緒論(INTRODUCTION)…………………………………………..…….. p.1.
1.1背景介紹及詳細文獻回顧(Background and literature review)…..……......p.2.
1.1.1維他命A對早產兒的重要性(The importance of vitamin A for preterm
infants)….…..………………………………………….……………...…..p.3
1.1.2維他命A的生物功能性(Biological effects of vitamin A)……….........p.5
1.1.3維他命A的吸收及代謝作用
(Uptake and metabolism of vitamin A)…………………………….....….p.9
1.1.4維他命A和肺部發育的關聯(Vitamin A and lung development)…….p.10
1.1.5 Bronchopulmonary dysplasia的病理和可能致病機轉
(Pathophysiology of Bronchopulmonary dysplasia)……..….....…….…p.15
1.1.6維他命A和Bronchopulmonary dysplasia的關聯
(Vitamin A and Bronchopulmonary dysplasia)………….………………p.17
….. .1.1.7氧氣和動物模式的建立(Oxygen and animal model)……….…...….…p.20
1.1.8新生小鼠的動物模式(The new born mice model)…….…..…………..p.21
1.2研究動機(Research motives)…………………………..……….....……….…p.23
. 1.3欲研究問題的重要性(Importance of the research)………………………….p.24
1.4研究的假(Hypothesis)………………………………………………….….….p.25
1.5研究的特定目的(Specific aims)…………………………………………...…p.26
2研究材料與方法(MATERIALS AND METHODS)..………………..p.27
3 結果(RESULTS)…………………………………...………………………....p.41
4討論 (DISCUSSION)………………………………………...……………p.51
5展望 (PROSPECTIVES)………………………..………………………..p.64
6參考文獻 (REFERENCES)…………………..………………………….p.76
7圖說 (FIGURES AND LEGENDS)……………….……...……………p.99
8主要論文…………………..……………………….…………...……...……….p.130

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