探討發炎性反應在新生兒疾病扮演的角色及其臨床啟示

Exploring the Role of Inflammatory Reaction in Neonatal Disease and Its Clinical Implication

陳倩儀(Chien-Yi Chen)

指導教授 ： 謝武勳 ； 符文美

國立臺灣大學/醫學院/臨床醫學研究所/博士(2015年)

https://doi.org/10.6342/NTU.2015.00275

摘要

近年新生兒研究及照護的進步大幅改善新生兒死亡率，進一步的研究大多專注在預防及早期治療早產及各式新生兒併發症，其中發炎性反應已被證實與早產、子宮內感染及新生兒腦部損傷等有很強的關聯性，本論文將探討發炎性反應在新生兒疾病扮演的角色並運用在改善臨床照護與預防層面。
周產期窒息造成的缺氧缺血腦病變是新生兒最常見腦部傷害的主因之一，常會造成永久性的神經後遺症，除低溫治療外，目前仍無臨床有效的藥物治療方式；有許多證據指出，在腦部缺氧時，不僅會對神經直接造成損傷，同時也會引發發炎反應，包括腦部微小膠細胞及星形膠細胞的活化、血液中性球及單核球的活化，以及發炎性細胞激素和活性氧物質等的釋放，進而加重其傷害程度，雖然有一些機制及分子已經被證實與缺氧前置處理的保護效果相關，但是發炎反應所扮演的角色卻未曾被提及，我們利用新生鼠腦部缺氧缺血的動物模式，以及細胞培養的體外研究方式，發現缺氧前置處理可藉由抑制微小膠細胞及星形膠細胞的活化，並抑制進一步的發炎反應的機制，來達到神經保護的效果，由此內生性抗發炎反應的神經保護作用研究可以了解，適當的使用具有抗發炎效果的藥物，對腦部缺氧造成的神經損傷可能會有治療效果。
因周產期窒息或其他原因造成腦損傷的新生兒，即使沒有發生腦性麻痺或智能障礙等嚴重神經後遺症，仍有很高的風險發生神經發展障礙，例如認知發展異常，情緒管理異常，學習障礙或過動兒等，造成長期的問題，其中大腦執行功能的異常為造成神經發展障礙的主要因素之一；已經有很多證據指出，執行功能的發展，與大腦額葉的成熟有緊密的相關性，而大腦額葉在兒童腦部發展中，是最晚完成髓鞘化並達成熟的區域，任何早期的腦部損傷，即使較為輕微，都有可能對這較不成熟的區域造成損傷，進而引起長期神經發展障礙，然而針對兒童及新生兒大腦額葉傷害的動物模式卻了解甚少，對其相關機制的探討亦較少被報告，因此我們發展一個新的單側局部前額葉腦部損傷的兒童動物模式，此局部損傷會引起明顯的局部發炎反應，在另外兩組小時候遭受過額葉損傷的老鼠，分別在成長到青春期和成年期後再測試其行為模式發現，此局部額葉損傷對焦慮表現，社交能力，空間學習和記憶並不會造成長期影響，然而在兩組的運動功能及學習對比於對照組有明顯的障礙，此結果與同側大腦額葉皮質體積的減少相吻合；此動物模式將有助於我們進一步研究新生兒疾病或治療對額葉損傷的影響，並可以藉由行為測試來驗證其長期功能的影響，對於進一步抗發炎藥物對新生兒腦部傷害的神經保護作用探討，有很大的幫助。
B型肝炎是台灣子宮內及周產期感染最常見的問題之一，只要能在新生兒時期進行早期預防措施即可有效降低感染率並減少慢性B型肝炎帶來的併發症，台灣自1984年開始實施全面新生兒接種B型肝炎疫苗計畫，於出生24 小時內、一個月及六個月大時各施打一劑B肝疫苗，不但使感染率明顯下降，同時也減少兒童猛爆性肝炎及肝癌的發生率；然而出生體重不足2000克的早產兒若是在出生時就施打第一劑B型肝炎疫苗，其後的追蹤發現並不能產生有效的血中保護抗體濃度，因此目前台大的早產兒B型肝炎疫苗注射是在體重滿2000或2200克時施打第一劑疫苗，這根據體重的策略與美國小兒科醫學會建議於體重滿2000克或一個月大時再施打第一劑建議更為延遲，雖然在臨床上更為方便執行，因為很多早產兒在一個月大時仍不夠穩定足以施打疫苗，然而此施打策略可能會有增加感染風險的疑慮。因此我們以台大醫院155位2至13歲之極低體重早產兒(出生體重低於1500克)為對象，評估目前延遲施打B型肝炎疫苗政策下之預防成效；我們發現所有的研究個案的B肝表面抗原(HBsAg)及核心抗體(anti-HBc)皆為陰性，儘管接受第一劑B肝疫苗的平均年齡大於55天大，且大多數（94％）遲於美國小兒科醫學會建議的30天大，沒有任何研究個案感染B型肝炎；其中有26位嬰兒的媽媽為B肝帶原者，產婦B肝帶原率在此研究中約為16.8%，與一般發生率相當，雖然並沒有給予美國小兒科醫學會建議於剛出生時給予第零劑B肝疫苗，沒有個案因而被感染。本研究成果顯示目前的早產兒B肝疫苗延遲施打政策並不會增加感染風險，且為臨床上可行的政策。

關鍵字

發炎反應 ； 新生兒腦部損傷 ； B型肝炎疫苗 ； 早產兒 ； 缺氧前置處理 ； 額葉損傷 ； 大腦執行功能

並列摘要

Numerous reports have identified the association between infection, inflammation, preterm birth and perinatal tissue injury. Exploring of the role of inflammatory reaction in neonatal diseases may further improve neonatal care and outcome. Firstly, we examine the role of inflammatory response in perinatal brain injury. By using the well-established Rice–Vannucci model of hypoxia-ischemia (HI) injury in p7 neonatal rat and primary glial culture and microglial cell line BV-2, we demonstrated that hypoxic preconditioning induced significant neuroprotection, possibly through suppression of glial activation and subsequent inflammatory responses after HI insults. Induction of endogenous anti-inflammatory response may be beneficial to protect neuron from HI-induced brain damage. These results further address the importance of anti-inflammatory strategies in preventing neonatal brain injury.
Perinatal brain injury increase the risk of cognitive and executive deficit in infants, and the development of executive function is related to the maturation of the frontal lobe, particularly the prefrontal cortex. Despite the clinical significance of injuries localized to this region during brain development, the mechanisms underlying secondary damage and long-term recovery are poorly understood. Here, we have characterized the first model of unilateral focal traumatic injury to the developing frontal lobe with local inflammatory response, and determine the long-term functional consequences in adolescence and adulthood. In both cohorts, brain-injured mice showed normal levels of anxiety, sociability, spatial learning and memory, but were deficits in motor function and motor learning, coincident with a reduction in ipsilateral cortical brain volumes. Based on consistent findings of region-specific cellular vulnerability, coupled with evidence of a clinically relevant motor impairment, the new model of unilateral frontal brain injury to the developing brain may be of use in the future investigation.
Secondly, we studied the Hepatitis B virus (HBV) immunization policy for preterm infants. HBV infection is one of the major intrauterine and perinatal infections in Taiwan. Perinatal transmission from infectious mother to infant is an important route for HBV infection, and passive and active immunization starting at birth is an extremely important preventive measure. All infants in Taiwan receive three doses of HBV vaccine, at birth and at 1 and 6 months of age, but preterm infants with birth weights less than 2,000 g delayed the first dose until their weight of 2,000–2,200 g has been reached, regardless of chronological age. This weight-based policy is different from the recommendation from American Academy of Pediatrics (AAP), which the first dose is given as early as 30 days of chronologic age. Thus we conducted a retrospective cross-sectional study to evaluate the efficacy and immunogenicity of hepatitis B vaccinations in preterm infants.
There were 155 very low birth weight preterm infants was recruited at age 2 to 13 years, and all of them were HBsAg and anti-HBc negative. The low prevalence of HBsAg (0%) is comparable to that of children born at term after universal vaccination began in Taiwan (0.9%), and is much lower than the rate among children born before the vaccination program began (10%). Although the children in our study received their first dose of vaccine at a mean age >55 days, with the majority (94%) starting the first dose after 30 days, which is much later than the current AAP recommendation, none of the children was seropositive for HBsAg or anti-HBc. The maternal HBV carrier rate in the present preterm population was approximately 16.8%, which is in accordance with that of the general population. Although we did not use the birth dose of hepatitis B vaccine as part of immunoprophylaxis in infants born to carrier mothers during study periods, none of the 26 infants was infected. This observation demonstrates that our weight-based policy of hepatitis B vaccination in preterm infants, in comparison to the age-based policy, did not increase the risk of HBV infection in an endemic area.

並列關鍵字

Neuroinflammation ； hepatitis B vaccine ； preterm ； perinatal brain injury ； hypoxic preconditioning ； frontal brain injury

參考文獻

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