TGF-beta inhibition to promote lung growth in mechanically ventilated newborn mice: a novel strategy to prevent ventilator-induced lung injury

TGF-β抑制促进机械通气新生小鼠肺生长：预防呼吸机引起的肺损伤的新策略

• 批准号: 226463725
• 负责人: Professor Dr. Miguel Angel Alejandre Alcázar, Ph.D.
• 金额: --
• 依托单位: Division of Pediatric Cardiology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/226463725?language=en
• 关键词: TGF; beta; inhibition; promote; lung

Prolonged mechanical ventilation with O2-rich gas (MV-O2) of premature infants leads to failed formation of alveoli and pulmonary micro-vessels, resulting in lung growth arrest. This form of neonatal lung injury is a variant of a condition initially described as bronchopulmonary dysplasia, now more aptly called neonatal chronic lung disease (CLD) and is the leading cause of long-term hospitalization and recurrent respiratory disorders among prematurely born infants. Moreover, there is an emerging concern that the risk of pulmonary emphysema could be increased in adults. Recent studies of infants evolving CLD treated with MV-O2 after premature birth, and animal models of CLD, provide compelling evidence that dysregulated signaling of two important growth factors - TGF-beta and VEGF - can undermine survival of lung epithelial and endothelial cells and thereby disrupt alveolar septation and angiogenesis in the developing lung exposed to lengthy MV-O2.However, the molecular mechanisms that link dysregulated TGF-beta and VEGF signaling to failed lung growth in CLD still remain unclear. The overall goal of this research proposal is to test the hypothesis that MV-O2 of the developing lung activates TGF-beta, which in turn down-regulates VEGF signaling, resulting in increased apoptosis and in lung growth arrest. We will test this hypothesis using a unique animal model featuring MV-O2 (MV with 40% O2) of newborn mice for up to 48 hours. The research plan has 3 specific aims: First (Aim 1), I will determine whether inhibiting TGF-beta signaling preserves normal growth of alveoli and micro-vessels as well as restores VEGF signaling and decrease apoptosis in lungs of neonatal mice exposed to MV-O2. 5d-old mice will be treated with either a TGF-beta neutralizing antibody (TGF-beta-Nab) or an angiotensin-2 receptor antagonist (Losartan), which has been shown to inhibit TGF-beta signaling, after which they will receive MV-O2 for 24h or 48h. Unventilated pups breathing 40% O2 will serve as controls, and treated mice will be compared to those given placebo (TGF-beta-Nab or Losartan vehicle). Next (Aim 2), I will analyze the effects of inhibiting TGF-beta signaling on lung matrix protein metabolism, specifically elastin. Finally (Aim 3), I will determine the effects of TGF-beta inhibition on lung function in newborn mice subjected to MV-O2. By inhibiting TGF-beta signaling in this unique model of MV-O2, I pursue the overall goal to restore VEGF signaling and thereby to preserve formation of alveoli and vessels. The long-term benefits of this clinically translational project include the evaluation of a promising innovative therapy for CLD and improvement of quality of life for children who were born with immature lungs.

早产儿长时间机械通气富氧(MV-O2)会导致肺泡和肺微血管形成障碍，导致肺生长停滞。这种形式的新生儿肺损伤是一种最初被描述为支气管肺发育不良的疾病的变体，现在更恰当地被称为新生儿慢性肺病(CLD)，是导致早产儿长期住院和反复发生呼吸系统疾病的主要原因。此外，出现了一个新的担忧，即成人患肺气肿的风险可能会增加。最近对早产后应用MV-O2治疗的婴儿发生CLD的研究，以及CLD的动物模型，提供了令人信服的证据，表明两种重要的生长因子-转化生长因子-β和血管内皮生长因子的信号失控可以破坏肺上皮细胞和内皮细胞的生存，从而扰乱暴露于长时间MV-O2的发育中的肺的肺泡间隔和血管生成。但是，将失控的转化生长因子-β和血管内皮生长因子信号与慢性阻塞性肺疾病肺生长失败联系起来的分子机制仍不清楚。这项研究计划的总体目标是检验这一假说，即发育中的肺的MV-O2激活转化生长因子-β，转化生长因子-β反过来下调血管内皮生长因子信号，导致细胞凋亡增加和肺生长停滞。我们将使用一种独特的动物模型来验证这一假设，该模型以新生小鼠长达48小时的MV-O2(含40%O2的MV)为特征。该研究计划有三个具体目标：第一个目标(目标1)，我将确定抑制转化生长因子-β信号是否能维持MV-O2暴露的新生小鼠肺泡和微血管的正常生长，以及恢复血管内皮生长因子信号和减少细胞凋亡。5d龄小鼠将接受转化生长因子-β中和抗体(转化生长因子-β-NAB)或血管紧张素-2受体拮抗剂(氯沙坦)的治疗，后者已被证明可抑制转化生长因子-β信号转导，之后它们将接受MV-O2 24或48小时。呼吸40%氧气的未通风幼鼠将作为对照，并将处理的小鼠与给予安慰剂(转化生长因子-β-NAB或氯沙坦载体)的小鼠进行比较。接下来(目标2)，我将分析抑制转化生长因子-β信号对肺基质蛋白代谢的影响，特别是弹性蛋白。最后(目标3)，我将确定抑制转化生长因子-β对MV-O2所致新生小鼠肺功能的影响。通过抑制这种独特的MV-O2模型中的转化生长因子-β信号，我追求恢复血管内皮生长因子信号的总体目标，从而保护肺泡和血管的形成。这一临床翻译项目的长期好处包括评估一种有前景的CLD创新疗法，并改善出生时肺部未成熟的儿童的生活质量。