Factors influencing lung development: translational studies on animal and humans
In our laboratory, we developed several in vivo and in vitro models to study the molecular and physiological mechanisms underlying acute and chronic lung diseases and more specifically related to oxidative stress In most pulmonary diseases, such as asthma, tobacco exposure and respiratory distress syndrome (RDS), oxidant burden is central resulting from the concomitant direct effects of oxidants in the extracellular space as well as the increased release of reactive oxygen species (ROS) from inflammatory cells.
More recently, we focused on lung development and the possible injuries that can affect normal lung development and might be determinant in the occurrence of chronic lung disease later in life. During intrauterine life, lungs abnormalities could be due to toxic exposure, to premature birth or to abnormal architecture development.
We study lung development in two distinct areas: 1) the role of nicotine/cigarette smoke (CS) maternal exposure during gestation and lactation in mice and 2) the genesis of lung malformations such as congenital pulmonary airways malformations (CPAM) occurring during embryogenesis in humans.
Maternal smoke has been associated to elevated levels of oxidant in foetal and neonatal tissues and we recently reported that nicotine, one of the main components of CS responsible for its addiction, induces oxidative stress and triggers apoptosis in lung epithelial cells through a molecular pathway involving NOX1 and mitochondria (NADPH oxidase 1).
For the first project, we developed an in vivo mouse model of nicotine/CS exposure using wild type and transgenic mice and we study the lungs of pups born from exposed mother by several techniques: transciptomic, proteomic, immunohistochemistry and stereology.
The second project focused on human samples of CPAM and human embryonic lungs. CPAM belong to lung birth defects diagnosed prenatally in which the pathophysiology remains poorly understood to date. To date, inappropriate cellular interactions between different cell lung, including epithelial cells, endothelial cells, and fibroblasts are involved in the genesis of this abnormal lung development. We are currently studying and comparing these lung defects removed surgically post- natally with healthy lung tissue and lung fetal human embryos by immunohistocehmistry, transciptomic and proteomic. The analysis of this pathology should allow identifying some genes involved in lung organogenesis and by extension other types of malformations such as pulmonary emphysema or pulmonary sequestrations.
These studies will also allow a better understanding of lung embryogenesis.