Leptin and the control of pulmonary maturation before birth

Normal development of the fetal lungs is essential for newborn babies to be able to breathe at delivery. Hormones produced by the fetus are important for a range of maturational changes that occur in the lungs of the fetus to prepare it for the transition from the womb to the outside world. Premature delivery before these maturational changes have taken place leads to respiratory disease in the newborn. Leptin is a hormone that is known to regulate appetite and metabolism in adult life, but its functions in the fetus are poorly understood. Leptin production is increased in the fetus after glucocorticoid treatment which is commonly used to promote lung maturation in fetuses at risk of preterm delivery. Furthermore, there is some evidence from laboratory studies on fetal lung tissue that leptin may influence lung development before birth. In an animal model, this project will investigate (a) the control of leptin activity in fetal lungs and (b) the effect of leptin on lung development. It will measure leptin production and receptor expression in fetal lungs at a range of gestational ages and after glucocorticoid treatment, and will determine several aspects of lung structure and function in animals treated with leptin before birth. The findings of this project will improve our understanding of the control of lung development in the fetus and will provide important information about the consequences of premature birth. Leptin may be a potential therapeutic agent in the treatment and prevention of respiratory disease in the premature infant at birth and in adult life.

Glucocorticoids are essential for normal pulmonary maturation in utero and respiratory function at birth, although the extent to which their actions are mediated by leptin is unknown. The hypothesis of this project is that developmental and glucocorticoid-dependent increments in circulating leptin are responsible for aspects of lung maturation in the fetus near term. Therefore, the project will ask three research questions: 1. What are the normal developmental changes in leptin and leptin receptor expression in fetal lungs during late gestation? 2. Is pulmonary leptin and leptin receptor expression in utero upregulated by endogenous and synthetic glucocorticoids? 3. What are the effects of leptin administration on indices of pulmonary development in the fetus? Blood and a variety of tissues, including lungs, will be collected from sheep fetuses after experimental manipulation of leptin and glucocorticoid concentrations during late gestation. Various indices of pulmonary structure and function will be determined including alveolar number, surface area and diffusion distance, and the gene and protein expression of surfactant proteins and vascular endothelial growth factors. The project will provide valuable information about the mechanisms responsible for the hormonal control of pulmonary development before birth, with important implications for fetal, neonatal and adult health. A greater understanding of the basic science underlying normal development of the fetal lungs is essential for the future progress of therapeutic and preventative strategies for the consequences of prematurity. Indeed, the findings may provide a novel mechanism for the maturational actions of antenatal glucocorticoid therapy. Furthermore, since the intrauterine environment influences the development of the lungs both before and after birth, these findings may provide a mechanism for the developmental programming of respiratory function in adult life.

The primary beneficiaries from the proposed research will include (a) researchers in fetal and neonatal physiology, intrauterine programming, mammalian endocrinology and respiratory physiology, (b) obstetricians and paediatricians caring for preterm pregnancies and infants, (c) premature babies and mothers at risk of preterm delivery, and (d) pharmaceutical organisations who may translate the findings into clinical practice. Furthermore, the economic and social consequences of prematurity mean that there are wider implications of the research for society in both the short and longer term. The project will provide valuable and novel information on the endocrine control of lung development before birth. A greater understanding of the basic science underlying normal development of the fetal lungs is essential for the future progress of therapeutic and preventative strategies for the consequences of prematurity. Indeed, the project may elucidate leptin as a mechanism by which endogenous and synthetic glucocorticoids promote lung maturation and as an important potential therapeutic agent for preterm infants. Lung development before birth also has long-term consequences for a number of adult pathologies, such as asthma and chronic lung disease. Therefore, understanding the mechanisms underlying the control of lung development will have significant implications not only for fetal and neonatal health, but also for the development of preventative strategies for respiratory diseases in adult life. Current collaborative links with members of the Departments of Obstetrics and Gynaecology, Clinical Biochemistry and Paediatrics, at Addenbrooke's Hospital, Cambridge will allow dissemination of results at local special interest groups and departmental seminars. For example, the applicant is a member of the local Perinatal Research group of clinicians and basic scientists who meet on a regular basis to discuss recent research and clinical findings. Furthermore, as an executive committee member of the Neonatal Society, Dr Forhead has links with a number of obstetricians and neonatalogists that will provide useful in the potential translation of these findings to clinical practice. The University of Cambridge has a department concerned specifically with the commercial exploitation of research findings (Cambridge Enterprise, part of the University Research Services Division) and they would be consulted where necessary. Due to the use of animals in this project, care needs to be taken when communicating detailed research information to the public. However, the applicant actively promotes understanding of physiology more generally and participates in the London International Youth Science Forum and the annual departmental open day as part of the University of Cambridge Science Festival. She is also involved in a number of college-based events which promote the Natural Sciences course to school children and pupils in higher education.