Large parts of the airways are formed prenatally by branching morphogenesis. Postnatally during alveolarization the gas-exchange surface of the lungs is enlarged a second time by septation of the most distal airspaces. New septa are lifted off of pre-existing ones subdividing these airspaces. The alveolar septa mature by a reduction of their double layered capillary network to a single layered one (microvascular maturation). We reinvestigated both, alveolarization and microvascular maturation, and showed that alveolarization is not finished during early childhood as postulated, but continue until young adulthood, and that it is basically independent of the maturation of the alveolar capillary networks.
As every other developmental process lung development is governed by a large number of factors. E.g. extracellular matrix proteins like elastin, collagens, laminins and tenascin-C contribute to pre- and postnatal lung development. These proteins are recognized by specific receptors like integrins, a-dystroglycan and the two discoidin domain receptors (collagen receptors). Most likely all of these factors are part of (extra) cellular signaling networks which are orchestrating lung development.
In the wide field of lung development my lab is focusing on three main topics.
- Since years I am studying the role of extracellular matrix components like laminins, integrins and tenascin-C during pre- and postnatal lung development.
- Synchrotron Radiation based X-ray Tomographic Microscopy (SRXTM) allows us to follow the structural lung development by high resolution 3D-imaging. We are especially interested in the development of 3D-structure of the gas-exchanging area. However, we are not only interested in the normal development, but also in the influence of the extracellular matrix on the 3D-structure.
- SRXTM opens up a third avenue. Our structural data represent the basis for the simulation of the air-flow and of particle deposition in the gas-exchange area. Furthermore, we started to investigate the influence of particle depositions - be it nano-particles or ultrafine particles - on lung development.
Expected value of the current project
Lung failure represents the fourth leading reason of death Switzerland. In most cases structural alterations like emphysema and fibrosis are involved. A thorough structural and molecular characterization of lung development represents a prerequisite for the development of new therapies of structural lung diseases. Due to the lack of high resolution imaging methods little is known about the 3D-structure of the lung parenchyma - the area where an emphysema and a fibrosis develops. SRXTM enables us to generate skeletons of the acini and to perform a detailed characterization of the 3D-structure of the gas-exchange area. Since we are pioneering the use of SRXTM for the ultrahigh resolution, 3D visualization of the lung tissue, we will have to define and implement novel morphometric tools for its quantitative evaluation and interpretation. We expect that these data will serve as the starting point for our proposed investigations characterizing factors (e.g. extracellular matrix components, glucocorticoids, or retinoids) which are influencing the 3D-lung structure.
The negative health effects of inhaled particles are well documented especially on the cardiovascular and pulmonary system. Currently, environmental particles represent the most important category. But the rapid advances in nanotechnology will likely lead to an increasing exposure of designed nano-particles. In opposite to the importance of this health issue not much is known about the mechanism involved in the deposition of particles in the lungs. In terms of particle deposition in developing lung nearly nothing is known. Pulmonary particle deposition is directly linked to pulmonary airflow and the airflow itself is directly linked to the pulmonary 3D-structure. However, the 3D-structure of the pulmonary gas-exchange area - especially during lung development - is still poorly characterized. We would like to generate the basic structural 3D-data of the developing lung parenchyma as a basis for further studies on particle deposition.