Regulation of neonatal inflammation by myeloid-derived suppressor cells

项目摘要 超过四分之一的极早产儿在出生后的头几个月内死亡。炎症失调 异常的宿主-微生物相互作用在三种最常见的 导致新生儿死亡的因素：支气管肺发育不良（BPD）、坏死性小肠结肠炎（NEC）和 败血症近年来，出现了一种新的范式，确定了髓源性的重要作用， 抑制细胞（MDSC）在新生儿炎症的调节。我们假设短暂的 MDSC的扩增可能是提供抗感染性粘膜损伤保护的机制之一 在新生儿中。我们发现新生小鼠的MDSC具有更高的抗菌和抗真菌作用 活性高于成人中性粒细胞和单核细胞。这可能会提供一个关键的，额外的保护层， 新生儿我们的数据表明MDSC的出现与妊娠成熟度密切相关， 在极早产儿中观察到显著较低的表达，这些极早产儿处于BPD、NEC和 败血症本研究的总体目标是确定MDSC的机制和临床意义 在早产新生儿中的积累，并表征这些细胞在预防中的治疗潜力 以及从BPD、NEC和败血症中恢复。 为了实现这一目标，我们提出了三个具体目标。 具体目标1：描述自然史的特征，并确定调节过渡期的机制 MDSC在出生后第一周的积累。 具体目标2：确定MDSC在支气管肺发育不良发生中的意义 (BPD)、坏死性小肠结肠炎（NEC）和极低出生体重儿的败血症。 具体目标3：确定MDSC控制新生小鼠炎症的潜在治疗效果。

Project Summary Over one quarter of extremely preterm infants die during the first months of life. Dysregulation of inflammation and aberrant host-microbial interactions play a central role in the development of the three most common contributors to neonatal mortality: bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and sepsis. In recent years, a novel paradigm has emerged that identifies the important role of myeloid-derived suppressor cells (MDSC) in the regulation of newborn inflammation. We hypothesize that transitory expansion of MDSC may be one the mechanisms that provides protection against infectious mucosal injury in newborns. We found that MDSC observed in newborn mice have much higher antibacterial and anti-fungal activity than neutrophils and monocytes in adults. This may provide a crucial, additional layer of protection in newborns. Our data indicate that the appearance of MDSC is closely connected to gestational maturity, with significantly lower expression observed in very premature babies who are at high risk for BPD, NEC, and sepsis. The overall goal of this study is to determine the mechanism and clinical significance of MDSC accumulation in preterm newborns and characterize the therapeutic potential of these cells in the prevention and recovery from BPD, NEC, and sepsis. To achieve this goal we propose three specific aims. Specific aim 1: To characterize the natural history and identify the mechanisms regulating transitory accumulation of MDSC during first weeks of life. Specific aim 2: To determine the significance of MDSC in the development of bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), and sepsis in very low birth weight infants. Specific aim 3: To identify the potential therapeutic effect of MDSC to control inflammation in newborn mice.