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

• Applicant: Professor Dr. Miguel Angel Alejandre Alcázar, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 226463725

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Richard D. Bland