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死亡。炎症调节失调 而异常的宿主-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，一种新的范式已经出现，它确定了髓系来源的重要作用 抑制细胞(MDSC)在调节新生儿炎症中的作用。我们假设那是暂时的 MDSC的扩增可能是保护粘膜免受感染性损伤的机制之一 在新生儿身上。我们发现，在新生小鼠体内观察到的MDSC具有更高的抗菌和抗真菌能力 成人的中性粒细胞和单核细胞的活性。这可能会在以下方面提供一层至关重要的额外保护 新生儿。我们的数据表明，MDSC的出现与妊娠成熟密切相关， 在BPD、NEC和BPD高危早产儿中观察到显著的低表达 败血症。本研究的总体目标是确定MDSC的机制和临床意义。 早产儿体内的蓄积及其在预防中的治疗潜力 以及从BPD、NEC和脓毒症中恢复。 为了实现这一目标，我们提出了三个具体目标。 具体目标1：描述自然历史并确定调节瞬变的机制 MDSC在生命的最初几周内积累。 特异性目标2：确定MDSC在支气管肺发育不良发生发展中的意义 极低出生体重儿的BPD、坏死性小肠结肠炎(NEC)和败血症。 具体目的3：确定MDSC对新生小鼠炎症的潜在治疗作用。

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.