Miguel A Alejandre Alcazar - CAP 10

Molecular Mechanisms of pulmonary alveolar and vascular development

Abstract

Oxygen (O2) and mechanical ventilation (MV) are life-saving treatments for premature infants, but they also promote lung injury, resulting in bronchopulmonary dysplasia (BPD), affecting 50% of the very premature infants. Lungs with BPD are marked by reduced microvascular and alveolar growth beyond infancy, yielding structural changes seen in emphysema and pulmonary hypertension. The high incidence of BPD and the lack of pharmaceutical therapy emphasize the need of unravelling the underlying molecular mechanisms. Recently, we found that impaired angiogenesis and alveolarization in lungs of newborn mice exposed to high O2 is linked to macrophage influx and polarization. While M2-macrophage markers were not changed, we found an up to 15-fold induction of inflammatory M1 markers (IL-6, CXCL10, macrophage elastase). These findings were coupled with decreased expression of Krüppel-like factor 4 (Klf4), a DNA-binding Zinc-finger transcription factor. Klf4 has been identified to be a key regulator of cell pluripotency, cell survival and macrophage differentiation. However, the mechanistic role of Klf4 in normal and aberrant lung development has not been addressed to date. Therefore we aim to identify the functional role of Klf4 in alveolarization using cell-specific ablation of Klf4 and cell culture models of hyperoxia and cell-stretch; and to define M1-cytokines as new targets for O2- or MV-induced lung injury. Finally, we will translate our findings to lungs of human fetuses or infants evolving BPD. The ultimate research goal is to identify novel mechanisms of alveolarization to enable lung growth. Understanding the role of Klf4 in lung growth will offer new targets to define innovative therapeutical strategies for BPD.

Clinical/medical relevance and sustainability in disease understanding

Bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease, is characterised by inflammation and lung growth arrest. The lack of therapies emphasizes the need to define new therapeutical strategies. We aim to decipher the mechanistic function of Klf4 – a regulator of cell pluripotency and inflammation – in lung angiogenesis, macrophages and alveolar growth. Identification of Klf4 as a novel target to promote alveolarization could define new avenues to enable lung growth and regeneration.


Jun.-Prof. Dr. med. Dr. nat. med. Miguel A Alejandre Alcazar

Dept. of Children and Adolescent Medicine

Jun.-Prof. Dr. med. Dr. nat. med. Miguel A Alejandre Alcazar

Work +49 221 478 96876

Dept. of Children and Adolescent Medicine
Kerpener Str. 62
50937 Cologne

https://kinderklinik.uk-koeln.de/forschung/pneumologie/experimentelle-pneumologie/

Publications - Miguel A Alejandre Alcazar

Link to PubMed