Hypoxia Inducible Factor: a breath of fresh air in lung development

Chapter 1 is a general introduction to normal and abnormal lung development. It outlines the current state of knowledge of the molecular basis of normal fetal lung development and then discusses the importance of these molecules in aberrant human lung development. It highlights the most important growth and transcription factors in each phase of lung development and describes where neonatal disease may arise and deals with the possible culprits. In chapter 2 an outline of the thesis is given. The role of HIF during basic murine lung development and the impact of the HIF pathway in the etiology of clinical diseases such as PPHN and ACD are important for understanding the effect HIF has on angiogenesis and pulmonary development. With these new insights innovative treatment strategies may be contemplated. Vessel formation in the lung is crucial for normal lung branching in the early embryonic phase as well as in the alveolar phase of lung development. In chapter 3 we demonstrate that in early fetal lung development over-expression of oxygen insensitive HIF-1a (HIF-1a .ODD) in mice leads to increased vascularization. This increase in vasculature seen in transgenic mice did not have an impact on branching. Low oxygen stimulated vessel growth in control and transgenic lungs as shown before. Pulmonary morphometric analyses of postnatal mice at various stages in alveolar development (postnatal days 2, 8, 14, 21) show an advancement of alveolarization in the HIF-1a .ODD lungs. Moreover, small vessel density was increased in HIF-1a .ODD lungs at E18.5 and postnatal days 2, 8 and 14. The HIF- 1a .ODD lungs had significantly higher VEGF mRNA expression than C57 control lungs on postnatal days 2, 8, and 14. The continuous activation of the HIF pathway and subsequent up-regulation of VEGF may account for this enhanced vascularization and subsequent alveolar formation.

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