Novel mechanism for synergistic responses to systemic maternal inflammation and neonatal hyperoxia exposure on lung development and therapies to improve pulmonary function and reduce bronchopulmonary dysplaisa (BPD)

母体炎症是早产的一个主要原因，也是早产儿出现并发症的原因之一。此外，早产儿通常需要支持性护理，包括机械通风和暴露在高氧环境中。不幸的是，这些疗法也会增加肺部的炎症反应，并导致诸如支气管肺发育不良(BPD)等疾病的发病。BPD的特征是肺发育停滞和肺纤维化，导致气体交换受损。重要的是，较小和更脆弱的婴儿在过去几年中存活了下来，但他们早产和临床干预的长期后果尚不清楚。给怀孕的啮齿动物注射脂多糖会导致后代肺部炎症。此外，暴露在高氧中的啮齿动物表现出与患有BPD的婴儿相似的肺部发育受阻。全身性母体炎症和新生儿高氧暴露合并肺发育受损的机制尚不清楚。对新生小鼠的初步研究表明，联合侮辱会导致肺部发育受阻，并以类似BPD的模式弥漫性纤维化。具体目标1将检验这一假设，即全身性母体炎症和新生儿高氧暴露相结合会导致纤维化，损害肺部发育，并且比任何一种侮辱都更严重。具体目标2将测试这一假设，即补充母体膳食DHA将减少肺纤维化，减轻出生在脂多糖处理的母鼠和暴露于高氧环境中的小鼠的肺功能缺陷，并通过减少炎症来做到这一点。这些研究的总体目标是确定与肺发育和功能受损有关的分子图谱，并确定与炎症相关的预防策略和治疗方法，通过减少炎症反应来减少肺损伤和长期的肺病理，从而导致在婴儿中可能开发出保护婴儿不患BPD的策略。

Maternal inflammation is a major cause of preterm birth and contributes to complications that develop in premature infants. Furthermore, preterm infants often require supportive care including mechanical ventilation and exposure to hyperoxia. Unfortunately, these therapies can also add to the lung inflammatory responses and contribute to the pathogenesis of diseases such as bronchopulmonary dysplasia (BPD). BPD is characterized by arrested lung development and pulmonary fibrosis resulting in impaired gas exchange. Importantly, smaller and more fragile infants have survived in the last several years but the long term consequences of their prematurity and clinical interventions are not known. LPS injection to pregnant rodents leads to pulmonary inflammation in the offspring. Further, rodents exposed to hyperoxia demonstrate arrested lung development similar to that observed in human infants with BPD. The mechanisms associated with impaired pulmonary development in combined systemic maternal inflammation and neonatal hyperoxia exposure remains to be elucidated. Preliminary studies in newborn mice indicate that the combined insults result in arrested lung development and diffuse fibrosis in patterns that mimic BPD. Specific Aim 1 will test the hypothesis that the combination of systemic maternal inflammation and neonatal hyperoxia exposure induces a fibrotic profile that impairs pulmonary development and is more severe than either insult. Specific Aim 2 will test the hypothesis that maternal dietary DHA supplementation will decrease pulmonary fibrosis and lessen the pulmonary function deficits observed in mouse pups born to LPS-treated dams and exposed to hyperoxia and does so by decreasing inflammation.The overall objective of these studies is to identify the molecular profiles involved in impaired pulmonary development and function and to identify inflammation related prevention strategies and therapies that would diminish lung injury and long term lung pathology by decreasing inflammatory responses and in so doing lead to the possible development of strategies in infants that protect infants from developing BPD.