進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-2008202007493500
論文名稱(中文) 新生兒免疫系統發展與氧化壓力,微生物菌相與營養的密切關係
論文名稱(英文) The close relationship between development of the immune system and oxidant stress, microbiota and nutrients in neonates
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 108
學期 2
出版年 109
研究生(中文) 林永傑
研究生(英文) Yung-Chieh Lin
學號 S98991160
學位類別 博士
語文別 英文
論文頁數 117頁
口試委員 指導教授-謝奇璋
指導教授-林其和
召集委員-許育祥
口試委員-齊嘉鈺
口試委員-黃昱瞳
口試委員-陳昌文
中文關鍵字 早產兒  母乳  微生物相  白血球  氧化壓力  發炎  免疫發育  自然類淋巴球  呼吸道過度反應  氣喘  誘發型相關淋巴組織 
英文關鍵字 Preterm birth  human milk  microbiota  ROS  Neutrophil  inflammation  innate lymphoid cell  airway hyperresponsiveness  asthma  iBALT 
學科別分類
中文摘要 背景
人類出生後免疫系統的發展,嬰幼兒期是關鍵,且仰賴許多的條件,如母乳、營養、微生物相、感染,出生前的自然免疫發展等。幼兒呼吸道的健康或氣喘等疾病,常是免疫系統發展後的指標,也和嬰幼兒期的早期暴露有關。新生兒的初期重要食物是母乳,人類母乳異於配方乳之處,是富含益生質與人類共生微生物相。母乳對嬰幼兒的免疫發展與呼吸健康,有著重要的角色。市售的配方乳在熱量或營養元素上雖可以調整,但無法取代是母乳中的微生物相。
另一種需要重視的嬰兒是早產兒,早產兒常因為感染而出生,住院中常常也會有營養不良、院內感染等問題。相對於足月兒,早產兒自然免疫的能力也較差,常暴露在抗生素之下而造成體內微生態失調,另因較常需要長期使用呼吸器,呼吸道表面黏膜被破壞,而使肺部發育受到影響。在嬰兒期受過這些特殊免疫事件影響的人,在學齡前期的免疫與呼吸健康,是需要被關注的。至他們的神經發展系統,也可能受到這些腸-肺軸線(gut-lung axis)、腸-腦軸線(gut-brain axis)、肺-腦軸線(lung-brain axis)的長期影響,這也是衛生假說( hygiene hypothesis)重要理論的一部份,因此使用兼顧營養提昇與母乳微生物相的新生兒營養品,可能是改善早產兒成長與發展的策略。
研究假說
本研究的假設是嬰幼時期,母乳或環境菌相、內毒系(LPS)等免疫刺激,會經由細胞氧化還原調控與代謝有關的機制長期影響學齡前期的幼童呼吸道的健康與疾病。
實驗方法與研究設計
實驗設計:本研究分成兩大部份:一、探討人類母乳的菌相、營養與早期感染等,對早產兒與足月兒呼吸道的影響,與營養與母乳微生物相介入早產兒照顧的成效 。 二、使用動物模型來了解衛生假說可能的機制,模擬人類嬰幼兒接受免疫反應刺激後,在幼童時期呼吸道健康與對過敏原的過度反應。
針對第一部份的研究方法:除了回顧本院加護病房的臨床照顧與追蹤成果外,探討嬰兒自然免疫對感染的反應,也以健保資料庫輔助,進行假設的驗證;此外我們收集母乳菌相、健康受乳者及住院早產兒口腔菌相、鼻腔菌相及腸道糞便菌相,以探討母子間菌相的互動性。最後,我們回顧「利用母乳與高熱量配方乳進行早產兒照顧的品質改善」的成果。
針對第二部份的研究方法:使用野生型與NCF1基因缺失型的新生小鼠,經鼻滴入內毒素(每2日一次共5次),模擬呼吸道的免疫刺激,4週後,再輔以過敏原誘發過敏後,測量呼吸道反應性(Airway hyperresponsiveness, AHR),並在各階段收集與分析肺部組織、自然免疫細胞群,與其組織表現之蛋白質與激素等。
研究結果
第一部份,顯示近年早產兒照顧提升,在邊緣存活者的明顯存活率上升,晚期菌血症每年百分率雖有下降,但慢性肺部疾病罹病率每年度仍停留在約20%左右。患有慢性肺部疾病的早產兒,在電腦斷層上的肺間質密度,明顯較低。在健保資料庫上,早產兒在出院後,患有呼吸道融合病毒感染的風險較高,且慢性肺部疾病病史會加重病情。為改善早產兒的預後,近年加護病房,對早產兒的呼吸照顧策略,在呼吸器的減少使用天數上,在妊娠週數26週與27 週的早產兒明顯下降。
早產兒出生時,患有感染時,長大後的免疫保護能力較差。在本院20年長期追蹤的資料顯示,加護病房中的感染,會對早產兒呼吸改善的進程,明顯有影響。而健保資料庫的追蹤也顯示,菌血症會讓學齡前期的下呼吸道感染機會,整體上升;顯示早期感染對幼童期的免疫發展,確實有影響。
人類母親母乳菌相,會影響嬰兒呼吸道中的鼻腔菌落與口腔菌落,但影響腸道菌落較慢。住院早產兒與健康足月兒在腸道菌的明顯差異性大,是可以介入的方向而長期持續使用母乳可能改變嬰兒的腸道菌相。而兼於母乳菌相與高熱量配方乳混合的營養措施,確實提昇了進行早產兒的成長與長期的神經預後發展。這些都是可以醫療介入的方向。
第二部份的結果顯示新生幼鼠時期,呼吸道接受內毒性免疫刺激後,會在肺部產生誘發型相關淋巴組織(iBALT),此機制需要藉由組織過氧自由基的媒介。野生型的幼鼠,若早期接受免疫刺激,在成長後遇過敏原時所產生呼吸道過度反應的現象,變得不明顯。
新生幼鼠時期接受反覆LPS刺激後,免疫調控的機制和定居肺部中的第二型ILC2s逐漸明顯減少有關,而且在接受過敏原後,抑制型的Treg 會明顯上昇,這個免疫機制可能是呼吸道反應在methacholine 刺激後,反應的變得不明顯的原因。
結論:
人類新生兒在新生兒時期的免疫刺激,會長期影響幼年時期的呼吸道的健康;而其機制可能受到呼吸道菌相與宿主肺部第二自然免疫淋巴球、 氧化還原系統,與後天免疫的TREG細胞共同調控。
母乳微生物相扮演重要的角色,會早期影響嬰兒的口鼻等呼吸道菌相,因此可作為介入肺部照顧的手段。這些以配方奶與母奶餵食的新知識可與近年發展的呼吸照顧技術,共同用來扭轉早產兒在住院過程中,肺部受到的傷害。透過呼吸道菌相與肺部自然免疫細胞等調控機制,進而提昇出院後長期的發展預後,預防幼兒接觸過敏原後,產生的過度反應,改善幼兒長期呼吸道健康。
英文摘要 Background
Early infancy is a key stage for human immune system ontogeny. This process depends on many conditions, including human milk, nutrition, microbiota, infection, and the development of innate immunity before birth. Young children's respiratory diseases, including asthma and other diseases, are often indicators of the development of the immune system and are also related to early exposure in infancy. The first important food for a newborn is human milk. Human milk is different from formula milk in that it is rich in natural prebiotics and human symbiotic microorganisms. Although commercial formula milk can be adjusted in calories or nutritional elements to mimic human milk, it cannot replace the microbiota in human milk.
Another subject regarding human immune development that requires special attention in premature babies is the exposure to microorganisms. Premature babies are often born due to infections. Malnutrition and nosocomial infections often occur in hospitals. Compared with full-term infants, premature infants have poor innate immunity and are often exposed to antibiotics, which cause dysbiosis in the body. In addition, because of the frequent need to use the respirator for a long time, the mucosa of their respiratory tract surface may be damaged, which affects the development of the lungs. People who have been affected by these special immunologic events in their infancy need to be concerned about the immune and respiratory health in young childhood. Their neural system development may also be affected by the gut-lung axis, gut-brain axis, and lung-brain axis in the long run. This is also part of the important theory of the hygiene hypothesis. Therefore, the use of neonatal nutrients that take into account the factors of nutritional enhancement and the microbes of human milk may be a strategy to improve the growth and development of premature infants.
Study hypothesis
The hypothesis of this study is that immune stimulations in infants such as human milk or environmental microbiota and endotoxins affect the health and disease of the respiratory tract of preschool children through cellular redox regulation and metabolism-related mechanisms.
Study design and methodology
The study in this thesis is divided into two major parts. The first part was to explore the effects of human milk microbiota, nutrition and early infections on the respiratory tract of premature and full-term infants, and the effectiveness of nutrition and human milk microbiota intervention in the care of premature infants. The second part of this study was to use animal models to understand the possible mechanisms of the hygiene hypothesis, and to simulate infant receiving immune-stimulation and the airway hyperresponsiveness to allergens in childhood.
For the first part, in addition to reviewing the clinical care and follow-up results of the intensive care unit in this hospital, this study also explored the response of the infants’ innate immunity to infection, and also utilized the health insurance database to verify the hypothesis. Moreover, this study collected the microbiota of human milk, healthy recipients' and hospitalized premature infants' samples from the nasal canals, oral cavities, and the stool. This study explored the microbiota interaction between mothers and children. Finally, this study reviewed the results of a quality improvement project of preterm infant nutrition by mixing human milk and concentrated formula.
For the second part, this study used wild-type and gene-deficient neonatal mice, treated with intranasal endotoxin (5 times, every two days) as serial postnatal immunological stimulation. After four weeks, this study used an allergen-induced lung inflammation model and measured airway hyperresponsiveness. This study collected the lung tissues, innate lymphoid cells, expressed proteins, and cytokines from lung homogenates.
Results
Part I
This study found that the care of premature babies improved in recent years, and the apparent survival rate of marginal survivors increased. However, even though the annual percentage of late-onset bacteremia declined, chronic lung disease still stayed at about 20% per year. In preterm infants with chronic lung disease, the interstitial density of the lungs on the computed tomography was significantly lower. On the health insurance database, premature babies were at higher risk of respiratory syncytial virus infection after discharge, and the history of chronic lung disease deteriorated the condition. In order to improve the prognosis of premature babies, the respiratory care strategy for premature babies reduced the duration of use of the invasive ventilators in the intensive care unit in recent years. This duration of mechanical ventilation in premature babies (gestational ages: 26 to 27 weeks) decreased significantly.
Our results showed that premature babies with infections had weaker immune defense later in their lives. From the 20 years of follow-up data in our hospital, a bacterial infection in the intensive care unit obviously affected the progress of breathing improvement in premature infants. The health insurance database also showed that bacteremia increased the chance of lower respiratory tract infections in preschool age, showing that early infections did have an impact on immune development.
The human milk microbiota affected the nasal and oral colonization in the infant's respiratory tract but affected the intestinal colonies more slowly. There was a significant difference in intestinal microbiota between hospitalized premature infants and healthy full-term infants, which was a direction that could be intervened. Long-term continuous use of human milk might change the intestinal microbiota in infants. The nutritional intervention that was combined with the human milk microbiota and high-calorie formula milk indeed improved the growth and long-term neurodevelopment of premature infants.
Part II
Newborn pups, after the respiratory tract received endotoxin immune-stimulation, generated inducible bronchus-associated lymphoid tissues (iBALT) in the lungs. Wild-type pups that received early immune stimulation tended to have weaker allergen-induced airway hyperresponsiveness when they grew up. This mechanism was shown to be mediated by the redox system.
After receiving repeated LPS stimulations, newborn pups had lower numbers of type 2 ILCs and increased Treg in the lungs after allergen stimulations six weeks later. Those observations might explain the decreased respiratory response after methacholine stimulation in lung function measurement.
Conclusion
Immune stimulation of human newborns during the neonatal period affects the health of the respiratory tract in childhood. The mechanism may be regulated by the respiratory tract microbiota and the innate lymphoid cells, redox system, and acquired regulatory T cells.
Human milk microbiota plays an important role and early affects the infant's mouth, nose, and other respiratory tract bacteria. Hence, human milk may be a means of interventional lung care for preterm infants to reverse the damage during hospitalization. Through the regulatory mechanisms of respiratory tract microbiota and the lung's innate immune cells, this study may improve long-term developmental prognosis after discharge. This study may also prevent the hyper-responsiveness of young children induced by allergens and improve children's long-term respiratory health.
論文目次 Contents XXII
Chapter 1 1
Introduction 1
1.2 Human milk, nutrition, probiotics, the microbiota of infants and their long-term impacts 5
1.3 The innate immunity, innate lymphoid cells and immune ontogeny 6
1.4 Immunological stimulation in early life may imprint to later life through innate immune and then adaptive immune systems 7
1.5 Thesis Aims 8
Chapter 2 Human milk, Nutrition, Microbiota, Infection and Airway Health in Preterm and Term Infants 10
2.1 Background and Aims 10
2.2Materials and Methods 13
2.3 Results 18
2.4 Discussion: 21
2.5 Figures and tables 24
Chapter 3 51
Neonatal mice and NOX2 are both critical for iBALT formation after neonatal nasal LPS instillation results in protection from the development of AHR in later life. 51
3.1 Background and Aims 51
3.2 Material and methods 52
3.3 Results 56
3.4 Discussion 60
3.5 Figure and tables 62
Chapter 4 76
NOX2 is required for the neonatal LPS exposure-induced increase of ILC2s in the lungs. 76
4.1 Background and Aims 76
4.2 Material and Methods 77
4.3 Results 80
4.4 Discussion 83
4.5 Figures and tables 85
Chapter 5 96
Conclusion, Discussion, and Prospects 96
5.1 Experimental findings and conclusions 96
5.2 Discussion 98
5.3 Prospects 100
Supplementary data 102
Publication lists 107
Conference abstract 111
Books 112
References 113
參考文獻 References
Abidi, A., Laurent, T., Beriou, G., Bouchet-Delbos, L., Fourgeux, C., Louvet, C., . . . Martin, J. (2020). Characterization of Rat ILCs Reveals ILC2 as the Dominant Intestinal Subset. Front Immunol, 11, 255. doi:10.3389/fimmu.2020.00255
Aron, J. L., & Akbari, O. (2017). Regulatory T cells and type 2 innate lymphoid cell-dependent asthma. Allergy, 72(8), 1148-1155. doi:10.1111/all.13139
Babior, B. M. (2004). NADPH oxidase. Curr Opin Immunol, 16(1), 42-47. doi:S0952791503001936 [pii]
Barman, M., Murray, F., Bernardi, A. I., Broberg, K., Bolte, S., Hesselmar, B., . . . Sandin, A. (2018). Nutritional impact on Immunological maturation during Childhood in relation to the Environment (NICE): a prospective birth cohort in northern Sweden. BMJ Open, 8(10), e022013. doi:10.1136/bmjopen-2018-022013
Bartemes, K., Chen, C. C., Iijima, K., Drake, L., & Kita, H. (2018). IL-33-Responsive Group 2 Innate Lymphoid Cells Are Regulated by Female Sex Hormones in the Uterus. J Immunol, 200(1), 229-236. doi:10.4049/jimmunol.1602085
Bartemes, K. R., Iijima, K., Kobayashi, T., Kephart, G. M., McKenzie, A. N., & Kita, H. (2012). IL-33-responsive lineage- CD25+ CD44(hi) lymphoid cells mediate innate type 2 immunity and allergic inflammation in the lungs. J Immunol, 188(3), 1503-1513. doi:10.4049/jimmunol.1102832
Cardenas, S., Scuri, M., Samsell, L., Ducatman, B., Bejarano, P., Auais, A., . . . Piedimonte, G. (2010). Neurotrophic and neuroimmune responses to early-life Pseudomonas aeruginosa infection in rat lungs. Am J Physiol Lung Cell Mol Physiol, 299(3), L334-344. doi:ajplung.00017.2010 [pii]10.1152/ajplung.00017.2010
Carstens, L. E., Westerbeek, E. A., van Zwol, A., & van Elburg, R. M. (2016). Neonatal antibiotics in preterm infants and allergic disorders later in life. Pediatr Allergy Immunol, 27(7), 759-764. doi:10.1111/pai.12614
Cederlund, A., Kai-Larsen, Y., Printz, G., Yoshio, H., Alvelius, G., Lagercrantz, H., . . . Agerberth, B. (2013). Lactose in human breast milk an inducer of innate immunity with implications for a role in intestinal homeostasis. PloS one, 8(1), e53876. doi:10.1371/journal.pone.0053876
Cephus, J. Y., Stier, M. T., Fuseini, H., Yung, J. A., Toki, S., Bloodworth, M. H., . . . Newcomb, D. C. (2017). Testosterone Attenuates Group 2 Innate Lymphoid Cell-Mediated Airway Inflammation. Cell Rep, 21(9), 2487-2499. doi:10.1016/j.celrep.2017.10.110
Cerdo, T., Dieguez, E., & Campoy, C. (2019). Early nutrition and gut microbiome: interrelationship between bacterial metabolism, immune system, brain structure, and neurodevelopment. Am J Physiol Endocrinol Metab, 317(4), E617-E630. doi:10.1152/ajpendo.00188.2019
Chan, T. Y., Yen, C. L., Huang, Y. F., Lo, P. C., Nigrovic, P. A., Cheng, C. Y., . . . Shieh, C. C. (2019). Increased ILC3s associated with higher levels of IL-1β aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase. Eur J Immunol, 49(11), 2063-2073. doi:10.1002/eji.201948141
Chang, J.-H., Hsu, C.-H., Tsou, K.-I., & Jim, W.-T. (2018). Outcomes and related factors in a cohort of infants born in Taiwan over a period of five years (2007–2011) with borderline viability. Journal of the Formosan Medical Association, 117(5), 365-373. doi:10.1016/j.jfma.2018.01.018
Chi, H., Chung, C. H., Lin, Y. J., & Lin, C. H. (2018). Seasonal peaks and risk factors of respiratory syncytial virus infections related hospitalization of preterm infants in Taiwan. PloS one, 13(5), e0197410. doi:10.1371/journal.pone.0197410
Cowardin, C. A., Ahern, P. P., Kung, V. L., Hibberd, M. C., Cheng, J., Guruge, J. L., . . . Gordon, J. I. (2019). Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition. Proc Natl Acad Sci U S A, 116(24), 11988-11996. doi:10.1073/pnas.1821770116
de Kleer, I. M., Kool, M., de Bruijn, M. J., Willart, M., van Moorleghem, J., Schuijs, M. J., . . . Lambrecht, B. N. (2016). Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung. Immunity, 45(6), 1285-1298. doi:10.1016/j.immuni.2016.10.031
de Medeiros, P., Pinto, D. V., de Almeida, J. Z., Rego, J. M. C., Rodrigues, F. A. P., Lima, A. A. M., . . . Oria, R. B. (2018). Modulation of Intestinal Immune and Barrier Functions by Vitamin A: Implications for Current Understanding of Malnutrition and Enteric Infections in Children. Nutrients, 10(9). doi:10.3390/nu10091128
Dzidic, M., Abrahamsson, T. R., Artacho, A., Collado, M. C., Mira, A., & Jenmalm, M. C. (2018). Oral microbiota maturation during the first 7 years of life in relation to allergy development. Allergy, 73(10), 2000-2011. doi:10.1111/all.13449
Eberl, G., Colonna, M., Di Santo, J. P., & McKenzie, A. N. J. (2015). Innate lymphoid cells: A new paradigm in immunology. Science, 348(6237), aaa6566. doi:10.1126/science.aaa6566
Eidelman, A. I. (2020). Cost-Effectiveness of an Exclusive Human Milk Diet. Breastfeed Med, 15(6), 353. doi:10.1089/bfm.2020.29154.aie
Ferretti, P., Pasolli, E., Tett, A., Asnicar, F., Gorfer, V., Fedi, S., . . . Segata, N. (2018). Mother-to-Infant Microbial Transmission from Different Body Sites Shapes the Developing Infant Gut Microbiome. Cell Host & Microbe, 24(1), 133-145.e135. doi:10.1016/j.chom.2018.06.005
Goedicke-Fritz, S., Härtel, C., Krasteva-Christ, G., Kopp, M. V., Meyer, S., & Zemlin, M. (2017). Preterm Birth Affects the Risk of Developing Immune-Mediated Diseases. Frontiers in Immunology, 8. doi:10.3389/fimmu.2017.01266
Goldenberg, R. L., Hauth, J. C., & Andrews, W. W. (2000). Intrauterine Infection and Preterm Delivery. New England Journal of Medicine, 342(20), 1500-1507. doi:10.1056/nejm200005183422007
Grases-Pinto, B., Torres-Castro, P., Abril-Gil, M., Castell, M., Rodriguez-Lagunas, M. J., Perez-Cano, F. J., & Franch, A. (2019). A Preterm Rat Model for Immunonutritional Studies. Nutrients, 11(5). doi:10.3390/nu11050999
Gueimonde, M., Laitinen, K., Salminen, S., & Isolauri, E. (2007). Breast milk: a source of bifidobacteria for infant gut development and maturation? Neonatology, 92(1), 64-66. doi:10.1159/000100088
Habas, F., Durand, S., Milesi, C., Mesnage, R., Combes, C., Gavotto, A., . . . Cambonie, G. (2020). 15-Year trends in respiratory care of extremely preterm infants: Contributing factors and consequences on health and growth during hospitalization. Pediatric pulmonology. doi:10.1002/ppul.24774
Hennet, T., Weiss, A., & Borsig, L. (2014). Decoding breast milk oligosaccharides. Swiss Med Wkly, 144, w13927. doi:10.4414/smw.2014.13927
Hsu, C. T., Chen, C. H., Lin, M. C., Wang, T. M., & Hsu, Y. C. (2018). Post-discharge body weight and neurodevelopmental outcomes among very low birth weight infants in Taiwan: A nationwide cohort study. PloS one, 13(2), e0192574. doi:10.1371/journal.pone.0192574
Hwang, J. Y., Randall, T. D., & Silva-Sanchez, A. (2016). Inducible Bronchus-Associated Lymphoid Tissue: Taming Inflammation in the Lung. Front Immunol, 7, 258. doi:10.3389/fimmu.2016.00258
Isolauri, E., Rautava, S., Salminen, S., & Collado, M. C. (2019). Early-Life Nutrition and Microbiome Development. Nestle Nutr Inst Workshop Ser, 90, 151-162. doi:10.1159/000490302
Jarvinen, K. M., Martin, H., & Oyoshi, M. K. (2019). Immunomodulatory effects of breast milk on food allergy. Ann Allergy Asthma Immunol, 123(2), 133-143. doi:10.1016/j.anai.2019.04.022
Jung, E., & Lee, B. S. (2019). Late-Onset Sepsis as a Risk Factor for Bronchopulmonary Dysplasia in Extremely Low Birth Weight Infants: A Nationwide Cohort Study. Scientific reports, 9(1), 15448. doi:10.1038/s41598-019-51617-8
Kim, C. J., Romero, R., Chaemsaithong, P., Chaiyasit, N., Yoon, B. H., & Kim, Y. M. (2015). Acute chorioamnionitis and funisitis: definition, pathologic features, and clinical significance. American Journal of Obstetrics & Gynecology, 213(4), S29-S52. doi:10.1016/j.ajog.2015.08.040
Kumar, S. K., & Bhat, B. V. (2016). Distinct mechanisms of the newborn innate immunity. Immunol Lett, 173, 42-54. doi:10.1016/j.imlet.2016.03.009
Kumova, O. K., Fike, A. J., Thayer, J. L., Nguyen, L. T., Mell, J. C., Pascasio, J., . . . Carey, A. J. (2019). Lung transcriptional unresponsiveness and loss of early influenza virus control in infected neonates is prevented by intranasal Lactobacillus rhamnosus GG. PLoS Pathog, 15(10), e1008072. doi:10.1371/journal.ppat.1008072
Levy, O. (2007). Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol, 7(5), 379-390. doi:10.1038/nri2075
Lin, C. Y., Hsu, C. H., Chang, J. H., & Taiwan Premature Infant Follow-up, N. (2020). Neurodevelopmental outcomes at 2 and 5 years of age in very-low-birth-weight preterm infants born between 2002 and 2009: A prospective cohort study in Taiwan. Pediatrics and neonatology, 61(1), 36-44. doi:10.1016/j.pedneo.2019.05.006
Lin, Y.-C., Chen, Y.-J., Huang, C.-C., & Shieh, C.-C. (2020). Concentrated Preterm Formula as a Liquid Human Milk Fortifier at Initiation Stage in Extremely Low Birth Weight Preterm Infants: Short Term and 2-year Follow-up Outcomes. Nutrients, 12(8), 2229. doi:10.3390/nu12082229
Lin, Y. C., Lin, Y. J., & Lin, C. H. (2011). Growth and neurodevelopmental outcomes of extremely low birth weight infants: a single center's experience. Pediatr Neonatol, 52(6), 342-348. doi:10.1016/j.pedneo.2011.08.008
Liu, S. Y., Wang, W. Z., Yen, C. L., Tsai, M. Y., Yang, P. W., Wang, J. Y., . . . Shieh, C. C. (2011). Leukocyte nicotinamide adenine dinucleotide phosphate-reduced oxidase is required for isocyanate-induced lung inflammation. The Journal of allergy and clinical immunology, 127(4), 1014-1023. doi:10.1016/j.jaci.2010.12.008
Lo, J., Zivanovic, S., Lunt, A., Alcazar-Paris, M., Andradi, G., Thomas, M., . . . Greenough, A. (2018). Longitudinal assessment of lung function in extremely prematurely born children. Pediatr Pulmonol, 53(3), 324-331. doi:10.1002/ppul.23933
Marin, N. D., Dunlap, M. D., Kaushal, D., & Khader, S. A. (2019). Friend or Foe: The Protective and Pathological Roles of Inducible Bronchus-Associated Lymphoid Tissue in Pulmonary Diseases. J Immunol, 202(9), 2519-2526. doi:10.4049/jimmunol.1801135
Martin, R., Jimenez, E., Olivares, M., Marin, M. L., Fernandez, L., Xaus, J., & Rodriguez, J. M. (2006). Lactobacillus salivarius CECT 5713, a potential probiotic strain isolated from infant feces and breast milk of a mother-child pair. Int J Food Microbiol, 112(1), 35-43. doi:10.1016/j.ijfoodmicro.2006.06.011
Melville, J. M., & Moss, T. J. M. (2013). The immune consequences of preterm birth. Frontiers in Neuroscience, 7. doi:10.3389/fnins.2013.00079
Metcalfe, A., Lisonkova, S., Sabr, Y., Stritzke, A., & Joseph, K. S. (2017). Neonatal respiratory morbidity following exposure to chorioamnionitis. BMC Pediatr, 17(1), 128. doi:10.1186/s12887-017-0878-9
Mirzakhani, H., Al-Garawi, A. A., Carey, V. J., Qiu, W., Litonjua, A. A., & Weiss, S. T. (2019). Expression network analysis reveals cord blood vitamin D-associated genes affecting risk of early life wheeze. Thorax, 74(2), 200-202. doi:10.1136/thoraxjnl-2018-211962
Moossavi, S., Sepehri, S., Robertson, B., Bode, L., Goruk, S., Field, C. J., . . . Azad, M. B. (2019). Composition and Variation of the Human Milk Microbiota Are Influenced by Maternal and Early-Life Factors. Cell Host & Microbe, 25(2), 324-335.e324. doi:10.1016/j.chom.2019.01.011
Moro, K., Ealey, K. N., Kabata, H., & Koyasu, S. (2015). Isolation and analysis of group 2 innate lymphoid cells in mice. Nat Protoc, 10(5), 792-806. doi:10.1038/nprot.2015.047
Nolan, L. S., Parks, O. B., & Good, M. (2019). A Review of the Immunomodulating Components of Maternal Breast Milk and Protection Against Necrotizing Enterocolitis. Nutrients, 12(1). doi:10.3390/nu12010014
Nutritional composition of breast milk produced by mothers of preterm infants. (1980). Nutr Rev, 38(9), 312-313. doi:10.1111/j.1753-4887.1980.tb05970.x
Palmer, A. C. (2011). Nutritionally mediated programming of the developing immune system. Adv Nutr, 2(5), 377-395. doi:10.3945/an.111.000570
Rangel-Moreno, J., Carragher, D., & Randall, T. D. (2007). Role of lymphotoxin and homeostatic chemokines in the development and function of local lymphoid tissues in the respiratory tract. Inmunologia, 26(1), 13-28.
Rangel-Moreno, J., Carragher, D. M., de la Luz Garcia-Hernandez, M., Hwang, J. Y., Kusser, K., Hartson, L., . . . Randall, T. D. (2011). The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat Immunol, 12(7), 639-646. doi:10.1038/ni.2053
Rangel-Moreno, J., Carragher, D. M., de la Luz Garcia-Hernandez, M., Hwang, J. Y., Kusser, K., Hartson, L., . . . Randall, T. D. (2011). The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nature Immunology, 12(7), 639-646. doi:10.1038/ni.2053
Saroja, K. (1981). Breast milk is the best. Swasth Hind, 25(2), 46-47. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/12279196
Scholz, S. M., & Greiner, W. (2019). An exclusive human milk diet for very low birth weight newborns-A cost-effectiveness and EVPI study for Germany. PloS one, 14(12), e0226496. doi:10.1371/journal.pone.0226496
Segal, B. M. (2010). Th17 cells in autoimmune demyelinating disease. Semin Immunopathol, 32(1), 71-77. doi:10.1007/s00281-009-0186-z
Silva-Sanchez, A., & Randall, T. D. (2020). Role of iBALT in Respiratory Immunity. Curr Top Microbiol Immunol. doi:10.1007/82_2019_191
Simon, A. K., Hollander, G. A., & McMichael, A. (2015). Evolution of the immune system in humans from infancy to old age. Proceedings of the Royal Society B: Biological Sciences, 282(1821), 20143085. doi:10.1098/rspb.2014.3085
Stein, M. M., Hrusch, C. L., Gozdz, J., Igartua, C., Pivniouk, V., Murray, S. E., . . . Sperling, A. I. (2016). Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. New England Journal of Medicine, 375(5), 411-421. doi:10.1056/NEJMoa1508749
Tang, H. H., Teo, S. M., Belgrave, D. C., Evans, M. D., Jackson, D. J., Brozynska, M., . . . Inouye, M. (2018). Trajectories of childhood immune development and respiratory health relevant to asthma and allergy. Elife, 7. doi:10.7554/eLife.35856
Thorsen, J., Rasmussen, M. A., Waage, J., Mortensen, M., Brejnrod, A., Bonnelykke, K., . . . Bisgaard, H. (2019). Infant airway microbiota and topical immune perturbations in the origins of childhood asthma. Nat Commun, 10(1), 5001. doi:10.1038/s41467-019-12989-7
Tsai, Y. S., Liu, Y. S., Shih, Y. H., Chuang, M. T., Lin, Y. J., Lin, C. H., & Lin, Y. C. (2016). Lung density standard deviations obtained using high-pitch dual-source computed tomography are valid predictors of bronchopulmonary dysplasia in preterm infants. Clin Imaging, 40(4), 594-600. doi:10.1016/j.clinimag.2016.02.010
Turi, K. N., Shankar, J., Anderson, L. J., Rajan, D., Gaston, K., Gebretsadik, T., . . . Hartert, T. V. (2018). Infant Viral Respiratory Infection Nasal Immune-Response Patterns and Their Association with Subsequent Childhood Recurrent Wheeze. American journal of respiratory and critical care medicine, 198(8), 1064-1073. doi:10.1164/rccm.201711-2348OC
van den Berg, W. B., & Miossec, P. (2009). IL-17 as a future therapeutic target for rheumatoid arthritis. Nat Rev Rheumatol, 5(10), 549-553. doi:10.1038/nrrheum.2009.179
Vandenplas, Y., Carnielli, V. P., Ksiazyk, J., Luna, M. S., Migacheva, N., Mosselmans, J. M., . . . Wabitsch, M. (2020). Factors affecting early-life intestinal microbiota development. Nutrition, 78, 110812. doi:10.1016/j.nut.2020.110812
von Berg, A., Filipiak-Pittroff, B., Schulz, H., Hoffmann, U., Link, E., Sussmann, M., . . . Berdel, D. (2016). Allergic manifestation 15 years after early intervention with hydrolyzed formulas--the GINI Study. Allergy, 71(2), 210-219. doi:10.1111/all.12790
Walsh, V., & McGuire, W. (2019). Immunonutrition for Preterm Infants. Neonatology, 115(4), 398-405. doi:10.1159/000497332
Warner, J. O. (2007). Early life nutrition and allergy. Early human development, 83(12), 777-783. doi:10.1016/j.earlhumdev.2007.09.005
WHO. (2012). Born Too Soon: the global action report on preterm birth.
Yasuda, Y., Nagano, T., Kobayashi, K., & Nishimura, Y. (2020). Group 2 Innate Lymphoid Cells and the House Dust Mite-Induced Asthma Mouse Model. Cells, 9(5). doi:10.3390/cells9051178
Zaramella, P., Munari, F., Stocchero, M., Molon, B., Nardo, D., Priante, E., . . . Baraldi, E. (2019). Innate immunity ascertained from blood and tracheal aspirates of preterm newborn provides new clues for assessing bronchopulmonary dysplasia. PloS one, 14(9), e0221206. doi:10.1371/journal.pone.0221206

論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2023-07-24起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2023-07-24起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw