Mechanical ventilation (MV) with O2-rich gas offers life-saving treatment for premature infants with respiratory failure, but often leads to chronic lung disease (CLD), characterized by impaired alveolarization and excess, disordered lung elastin. The goal of this research is to improve understanding of mechanisms that cause these abnormalities, and to formulate effective treatment strategies. In recent studies of newborn mice, in which lung septation and matrix organization occur mainly after term birth, we found that MV with 40% O2 for 24h led to dysregulated alveolar formation and elastin assembly, yielding lung structural defects similar to those seen in CLD. This proposal applies to mutant neonatal mice a novel experimental approach to help define mechanisms by which prolonged cyclic stretch of the developing lung, with or without modest hyperoxia, can impair alveolarization and elastin assembly, and to test a novel strategy for inhibiting these structural defects.
Specific Aim 1 will determine (a) if neonatal mutant mice that over-express the specific elastase inhibitor elafin show greater alveolar and lung capillary formation and less deposition of disordered elastin than non-transgenic pups show after 24h of MV with 40% O2;and (b) if early postnatal treatment with elafin given directly into the lungs will preserve normal alveolar and lung capillary formation, and prevent or reduce excess lung elastin during prolonged MV of newborn mice. If elafin treatment preserves lung structure in MV, we will test its benefit during MV of mutant mice described in Specific Aims 2 and 3.
Specific Aim 2 will determine if neonatal mice with elastin haploinsufficiency (Eln), which show abnormal lung growth after pneumonectomy or smoke inhalation, are more susceptible than non-mutant newborns to defective alveolar formation and lung elastin assembly after MV with either air or 40% O2 for 24h.
Specific Aim 3 will determine if neonatal mice deficient in fibulin-5 (Fbln5, Fbln5-/-), a matrix protein that plays a critical role in elastin assembly, exhibit an exaggerated lung phenotype, compared to non-mutant newborns, in terms of defective alveolar and elastic fiber formation after lengthy MV with either air or 40% O2. Molecular, biochemical and histological methods will be used to clarify how MV can disrupt alveolar septation and elastin assembly during lung growth, and also provide insight on how these adverse effects might be prevented in infants who require prolonged MV for respiratory failure. PROJECT NARRATIVE: This research proposal, which uses normal and genetically modified newborn mice, is designed to improve our understanding of how mechanical ventilation, as applied to premature infants with respiratory failure, often inhibits lung growth and causes disorganized assembly of elastic fibers in the lung, leading to a chronic form of neonatal lung disease called bronchopulmonary dysplasia (BPD). An important aim of the project is to test the potential benefit of delivering, directly into the lungs during mechanical ventilation, a drug called elafin that prevents the breakdown of elastic fibers, which we hope will preserve lung growth and provide effective treatment for newborn infants who are susceptible to BPD. Because BPD is similar to emphysema, this research also may lead to better understanding and treatment of chronic obstructive pulmonary disease (COPD) in adults.
