Magnetic resonance imaging; Lung development; X-ray tomography; Pneumonectomy; Pulmonary acinus; Lung regeneration; Three-dimensional imaging; Alveolarization; Tenascin-C
Lovric Goran, Mokso Rajmund, Arcadu Filippo, Vogiatzis Oikonomidis Ioannis, Schittny Johannes C., Roth-Kleiner Matthias, Stampanoni Marco (2017), Tomographic in vivo microscopy for the study of lung physiology at the alveolar level, in Scientific Reports
, 7(1), 12545-12545.
Schittny Johannes C (2017), Development of the lung., in Cell and tissue research
, 367(3), 427-444.
Vogiatzis Oikonomidis I., Cremona T.P., Lovric G., Stampanoni M., Schittny J.C. (2017), Effective segmentation of fresh post-mortem murine lung parenchyma in phase contrast X-ray tomographic microscopy images, in IOP Conference Series: Journal of Physics: Conf. Ser.
, 849, 012006.
I. Vogiatzis Oikonomidis, G. Lovric, T.P. Cremona, F. Arcadu, A. Patera, J.C. Schittny, M. Stampanoni (2017), Imaging samples larger than the field of view: the SLS experience, in IOP Conference Series: Journal of Physics: Conf. Ser.
, 849, 012004.
Woods Jason C., Schittny Johannes C. (2016), Lung structure at preterm and term birth, in Jobe A.H. (ed.), Cambridge University Press, New York, 126-140.
Modregger Peter, Cremona Tiziana P, Benarafa Charaf, Schittny Johannes C, Olivo Alessandro, Endrizzi Marco (2016), Small angle x-ray scattering with edge-illumination., in Scientific reports
, 6, 30940-30940.
Barre Sebastien F, Haberthür David, Cremona Tiziana P, Stampanoni Marco, Schittny Johannes C (2016), The Total Number of Acini Remains Constant throughout Postnatal Rat Lung Development., in American journal of physiology. Lung cellular and molecular physiology
Roth Christian J, Ehrl Andreas, Becher Tobias, Frerichs Inéz, Schittny Johannes C, Weiler Norbert, Wall Wolfgang A (2015), Correlation between alveolar ventilation and electrical properties of lung parenchyma., in Physiological measurement
, 36(6), 1211-26.
Dénervaud Valérie, Gremlich Sandrine, Trummer-Menzi Eliane, Schittny Johannes C, Roth-Kleiner Matthias (2015), Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation., in Pediatric research
, 78(6), 641-9.
Barré Sébastien F, Haberthür David, Stampanoni Marco, Schittny Johannes C (2014), Efficient estimation of the total number of acini in adult rat lung., in Physiological reports
, 2(7), e12063.
Roth-Kleiner Matthias, Berger Thomas M, Gremlich Sandrine, Tschanz Stefan A, Mund Sonja I, Post Martin, Stampanoni Marco, Schittny Johannes C (2014), Neonatal steroids induce a down-regulation of tenascin-C and elastin and cause a deceleration of the first phase and an acceleration of the second phase of lung alveolarization., in Histochemistry and cell biology
, 141(1), 75-84.
Tschanz Stefan A, Salm Lilian A, Roth-Kleiner Matthias, Barré Sebastien F, Burri Peter H, Schittny Johannes C (2014), Rat lungs show a biphasic formation of new alveoli during postnatal development., in Journal of applied physiology (Bethesda, Md. : 1985)
, 117(1), 89-95.
Ackermann Maximilian, Houdek Jan P, Gibney Barry C, Ysasi Alexandra, Wagner Willi, Belle Janeil, Schittny Johannes C, Enzmann Frieder, Tsuda Akira, Mentzer Steven J, Konerding Moritz A (2014), Sprouting and intussusceptive angiogenesis in postpneumonectomy lung growth: mechanisms of alveolar neovascularization., in Angiogenesis
, 17(3), 541-51.
Schittny Johannes C. (2014), Strukturelle Entwicklung – von der Anlage zur adulten Lunge, in von Mutius E. (ed.), Springer, Berlin, 3-16.
Hendaoui Ismaïl, Tucker Richard P, Zingg Dominik, Bichet Sandrine, Schittny Johannes, Chiquet-Ehrismann Ruth (2014), Tenascin-C is required for normal Wnt/β-catenin signaling in the whisker follicle stem cell niche., in Matrix biology : journal of the International Society for Matrix Biology
, 40, 46-53.
Gremlich S, Damnon F, Reymondin D, Braissant O, Schittny J C, Baud D, Gerber S, Roth-Kleiner M (2014), The long non-coding RNA NEAT1 is increased in IUGR placentas, leading to potential new hypotheses of IUGR origin/development., in Placenta
, 35(1), 44-9.
Background. Pulmonary airways are formed by branching morphogenesis, which stops with the saccular stage. One stage earlier (canalicular stage) epithelial differentiation progressed so far that the conducting and gas-exchanging airways may be distinguished. The acinus, the gas-exchange area which is ventilated by the most distal generation of a purely conducting airway, is born. The acini are the functional units of the lung parenchyma. During the following stage of alveolarization the parenchymal volume of rat lungs increases ~10 times, the alveolar surface area ~20 times and the number of alveoli ~25 times. This is mainly achieved by the lifting off of new alveolar septa from existing ones resulting in a subdivision of the existing airspaces. Recently we and others showed that alveolarization continues until young adulthood. We even resolved the mechanism how it may take place after the maturation of the alveolar microvasculature. Due to the fact that individual acini may not be distinguished on lung section little is known of how the acinus develops and how much it may contribute to lung regeneration. Based on synchrotron radiation based X-ray tomographic microscopy (SRXTM) we recently developed 3-dimensional (3D) imaging and analysis tools. These tools now enable us to study the structure and function of the acini during development and regeneration. Working hypothesis and specific aims. First, we would like to understand how the 3D-structure of the acini develops and second, we would like to understand the functional consequences of it. Specifically, we would like to verify or falsify the following hypotheses. 1. Based on preliminary data we hypothesize that during alveolarization the number of acini stays con-stant and that the individual acini themselves are growing to the same extent as the lung parenchyma grows. We propose that the acinar growth is achieved by an elongation, widening, and alveolarization of the acinar airway, but not by the formation of new generations of gas-exchanging airways. 2. To a large extent lung regeneration resembles lung development. Therefore, we hypothesize that after pneumonectomy the compensatory growth and alveolarization does not increase the number of acini, but results in abnormally large acini. 3. We propose that the increasing size and structural changes of the acini (be it during development or regeneration) alters the acinar ventilation and alveolar gas-exchange. We speculate that the adult size of the acini is optimized and that smaller or larger acini work less efficient.4. Currently 3He magnetic resonance imaging (MRI) represents the only available method to indirectly detect structural alteration of the lung parenchyma in humans. Based on the measurement of diffusion times and on a structural model the mean linear intercept, alveolar density, and surface-to-volume ra-tio are calculated. We propose that the calculation may be verified and improved, if instead of the current, very simplified model, a model based on SRXTM (human and rodent data) will be used.Experimental design (in order of the hypotheses)1. High resolution 3D-SRXTM images of isolated rat lung lobes (day 0-90) will be obtained at the beam-line TOMCAT (Paul-Scherrer-Institut, Villigen, Switzerland). After reconstruction all transitional bron-chioles (transition from conducting to gas-exchanging airways) will be counted according to morpho-logical criteria by scrolling through the dataset of an entire lobe. Afterwards individual acini will be segmented and the acinar volume, surface area, length of free septal edge, and number of alveoli will be estimated applying classical stereology. In addition, we would like to develop new software based tools to analyze the skeleton of the acinar airways (length, diameter of segments, generations, etc.). 2. We would like to apply the same tools for the characterization of pneumonectomy and sham operation in mice and dogs. We expect that the quantitative data obtained under #1 and #2 will verify or falsify the first two hypotheses (in collaboration with Moritz Konerding, Mainz, Germany and Connie Hsia, Dallas, TX, USA).3. Numerical models of the lung ventilation and of the alveolar gas exchange can yield predictions on the efficiency of a given lung morphology. We will use such a model to test the efficiency of different acinar configurations. Lung morphologies with large and with small acini will be parameterized for our one-dimensional numerical model. Simulations of the different acinar configurations will allow us to verify (or falsify) hypothesis #3.4. 3He MRI will be applied to 7-60 days old live mice. Afterward their lungs will be scanned and analyzed according to #1. The morphological data obtained by MRI will be calculated based on the currently used model and on our SRXTM data and compared to the stereological estimations done as under #1. The same procedure will be repeated using adult human imaging data. A new realistic model will be established and verified (in collaboration with Jason Woods, Cincinnati Children's Hospital).Expected value of the proposed project. Structural lung diseases represent the fourth leading causes of death in Switzerland. Due to the existence of a strong correlation between development and regenera-tion, we expect that a better understanding of the functional acinus development will contribute to an improvement of the therapy of structural lung diseases. Furthermore, we would like to improve the clinical diagnosis (3He-MRI) of lung diseases by revising and verifying the structural model used for the translation of the measured diffusion times into structural parameters using our 3D-lung structures as basis.