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)

母体炎症是早产的主要原因，并会导致早产儿出现并发症。此外，早产儿通常需要支持性护理，包括机械通气和高氧暴露。不幸的是，这些疗法也会增加肺部炎症反应，并导致支气管肺发育不良（BPD）等疾病的发病机制。BPD的特点是肺发育受阻和肺纤维化，导致气体交换受损。重要的是，在过去的几年里，更小、更脆弱的婴儿存活了下来，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其后代出现肺部炎症。此外，暴露于高氧环境中的啮齿动物表现出与BPD婴儿相似的肺部发育停滞。与合并全身性母体炎症和新生儿高氧暴露的肺发育受损相关的机制仍有待阐明。对新生小鼠的初步研究表明，联合损伤导致肺发育停滞和弥漫性纤维化，其模式与BPD相似。特异性目的1将验证以下假设：母体全身性炎症和新生儿高氧暴露的结合导致纤维化，损害肺部发育，且比任何一种损害都更严重。特异性目标2将验证母体膳食DHA补充将减少肺纤维化和减轻肺功能缺陷的假设，这些假设在lps处理的小鼠和暴露于高氧环境中出生的小鼠幼崽中观察到，并通过减少炎症来实现。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特征，并确定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肺病理，从而可能开发出保护婴儿免受BPD影响的策略。

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.