Vitamin A in the treatment of neonatal necrotizing enterocolitis

描述(由申请人提供)： 坏死性小肠结肠炎(NEC)是新生儿，尤其是早产儿死于胃肠道疾病的主要原因。在工业化国家，早期诊断和新生儿重症监护方面的进展提高了存活率。在发展中国家，低出生体重儿存活率提高的同时，非传染性疾病病例也在增加，但由于资源限制，在管理方面却没有相应的改进。需要研究负担得起的干预措施，以改善NEC的结果。维生素A(VA)通常在早产儿中含量较低，是维持肠道完整性、免疫能力和其他宿主防御能力的必要营养物质。实验性VA缺乏症会导致肠道损伤和免疫变化，类似于NEC引起的变化。据南亚报道，在新生儿VA接受高效VA治疗后，早期婴儿死亡率的减少可能部分是通过加强对NEC的保护而起作用的。因此，一个相关的问题是，VA是否可以改善营养不良人群的NEC结局。为了解决这个问题，我们建议在孟加拉达卡的石树儿童医院进行一项随机、双盲、安慰剂对照的VA补充试验，这是一家全国性的儿科转诊中心。目的是评估补充维生素A在以下方面的有效性：1)减少炎性细胞因子的表达；2)改善症状的严重性和持续时间；3)降低NEC新生儿的疾病进展和死亡风险。量化VA的这些途径和影响可能有助于提高治疗效果，并为发展中国家预防NEC提供新的见解。这项研究建立在约翰·霍普金斯大学(JHU)和石树医院目前正在进行的临床试验研究的基础上。这项研究被提议作为K01奖项的一部分，以使PI成为营养免疫学的独立研究员。PI候选人将由JHU的West博士、Bream博士和Bourgeis博士指导，他们将通过组合定向阅读、课程作业、营养学、微生物学和免疫学的实验室培训、临床试验实施培训以及监督他的国际合作研究来与他合作。短期内，候选人将通过实验室和现场调查获得表征VA、感染和细胞因子表达相互作用的技能，同时这项研究将为VA在治疗和预防与营养不良相关的严重儿科疾病方面的潜在作用提供证据。

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in newborns, particularly in preterm infants. In industrialized countries, earlier diagnosis and advances in neonatal critical care have improved survival. In developing countries, improved survival of low birth weight infants is being accompanied by an increase in NEC cases without parallel improvement in management due to resource constraints. Research on affordable interventions to improve NEC outcomes is needed. Vitamin A (VA), typically low in preterm infants, is an essential nutrient for maintaining gut integrity, immune competence and other host defenses. Experimental VA deficiency produces lesions in the gut and changes in immunity similar to those caused by NEC. It is plausible that reductions in early infant death following newborn VA receipt of high-potency VA, as reported from South Asia, may have been mediated, in part, by enhanced protection against NEC. Thus, a relevant question is whether VA can improve NEC outcomes in undernourished populations. To address this question, we propose to conduct a randomized, double-blinded, placebo-controlled VA supplementation trial in Bangladesh, at the Shishu Children's Hospital in Dhaka, a national pediatric referral center. The aims are to evaluate the efficacy of VA supplementation in: 1) reducing inflammatory cytokine expression; 2) ameliorating severity and duration of symptoms; and 3) decreasing risks of disease progression and mortality in newborns with NEC. Quantifying these pathways and effects of VA may help to improve treatment efficacy and provide new insights to preventing NEC in developing countries. The study builds on clinical trial research currently underway between Johns Hopkins University (JHU) and Shishu Hospital. The study is proposed as part of a K01 award to prepare the PI as an independent investigator in nutritional immunology. The PI candidate will be guided by Drs. West, Bream, and Bourgeois at JHU, who will work with him through combined directed readings, coursework, laboratory training in nutrition, microbiology and immunology, training in clinical trial conduct, and supervising his international, collaborative research. In the short term, the candidate will gain skills to characterize interactions of VA, infection and cytokine expression through laboratory and field investigation, while the study contributes evidence on the potential roles of VA in treating and preventing severe pediatric diseases associated with malnutrition.