Stymieing infant mortality: effects of manipulating oxygen tension on lung development and lung vascular plasticity

In preterm infants, hypoxia occurs subsequent to functional lung insufficiency especially deficient surfactant system and lung structure. Consequently, lungs react with increased permeability, development of hyaline membranes, consequent inflammation leading to respiratory distress syndrome (RDS), the leading cause of death in preterm infants). Mechanical ventilation, supplemental oxygen and surfactants, are the preferred therapeutic approaches. A clear relationship between hyperoxia, and development of severe systemic lesions such as retinopathy and chronic lung disease (CLD) has been observed. Preliminary data indicate that there is robust angiogenesis and accelerated blood-gas barrier (BGB) formation and thinning in chick chorioallantoic membranes (CAM) exposed to short-term hypoxia.Main questionsThis project will focus on the following fundamental aspects:i) Does the oxygen tension influence lung (and other organ) development in an age-dependent manner (within a plasticity window)?ii) What signaling molecules influence lung maturation resulting from the fusion of the capillary networks and could artificial intervention rebound the effects of hyperoxia and induce postponed vascular maturation?iii) Can manipulation of oxygen precociously shift lung developmental process, resulting in early BGB formation and early maturation of the surfactant system? Approach and objectivesA familiarization meeting for the lead investigators will crystallize strategies for training of researchers and technicians, review log frames and important time lines. The objective will be to enhance capacity building while at the same time interrogating novel scientific ideas. There will be skills enhancement, infrastructure refurbishment and purchase of equipment. These approaches aim to establish a well prepared infrastructure and team ready to take on the experimental part. Activities and outputsInitial activities will involve infrastructure and skills enhancement by purchasing or refurbishing equipment and training. For the southern partners, this will result in important foundations for future units of research excellence. Animal experiments will be started in the four institutions with a judicious sharing of the tasks. Young rats and CAMs will be exposed to different oxygen concentrations during targeted developmental stages. Subsequently, qualitative and quantitative morphological analysis as well as molecular investigations will be performed to unearth the changes engendered by altered oxygen tensions. RDS will be mitigated in an unconventional way, by enhancing precocial lung maturation, including surfactant sufficiency and BGB maturation. At the end of the project we expect to have identified potential molecular targets that can be used for prophylaxis against RDS in addition to enhanced infrastructure and research skills.