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How does the 3-dimensional structure of the pulmonary acinus develop and regenerate and which functional consequences does it have?

English title How does the 3-dimensional structure of the pulmonary acinus develop and regenerate and which functional consequences does it have?
Applicant Schittny Johannes C.
Number 153468
Funding scheme Project funding (Div. I-III)
Research institution Institut für Anatomie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Structural Research
Start/End 01.09.2014 - 30.09.2017
Approved amount 464'288.00
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All Disciplines (3)

Discipline
Structural Research
Embryology, Developmental Biology
Physiology : other topics

Keywords (9)

Magnetic resonance imaging; Lung development; X-ray tomography; Pneumonectomy; Pulmonary acinus; Lung regeneration; Three-dimensional imaging; Alveolarization; Tenascin-C

Lay Summary (German)

Lead
Wie entwickelt und regeneriert sich die 3D-Struktur der Acini und welche funktionellen Konsequenzen haben diese Vorgänge?Bis jetzt ist wenig über die strukturelle Entwicklung und das Wachstum der funktionellen Einheiten der Gasaustauschregion der Lunge, der Acini bekannt. Im vorliegenden Projekt möchten wir erforschen, welche funktionellen Konsequenzen die strukturellen Veränderungen der Acini bedingen - insbesondere wie ändert sich die Belüftung der Acini während ihrer Entwicklung und auf Grund von Lungenerkrankungen.
Lay summary

Die Lunge enthält einem Baum luftleitender, sich ständig verzweigender Luftwege, die die Atemluft zur Gasaustauschregion transportieren. Die Gasaustauschregion ist in funktionelle Einheiten (Acini) unterteilt, die jeweils von einem Luftweg belüftet werden. Ein Acinus besteht seinerseits aus einem kleinen Baum von Luftwegen, die in ihren Wänden die Lungenbläschen (Alveolen) enthalten. Auf Grund ihrer 3-dimensionalen (3D) Struktur sind die Acini in Lungenschnitten nicht voneinander unterscheidbar und dementsprechend wenig ist über sie bekannt. Wir haben eine Methode entwickelt (tomographische Röntgenmikroskopie), mit der wir die 3D-Struktur der Acini untersuchen, sowie strömungsmechanische Simulationen (CFD) an Tiermodellen durchführen können.

  • Nach der Geburt nimmt das Lungenvolumen um das ca. 10-fache zu. Verzehnfacht sich auch die Anzahl der Acini oder vergrössern sich „nur“ die Acini?
  • Welche funktionellen Konsequenzen hat die eine oder andere Verzehnfachung auf die Belüftung der Acini und den Gasaustausch?
  • Es gibt Lungenerkrankungen (z.B. Broncho-pulmonaler-distress (BPD), chronisch obstruktive Lungenerkrankung (COPD), Pneumonektomie), bei denen sich die Struktur der Acini verändert. Wie sehen diese Veränderungen aus und welche funktionellen Konsequenzen folgen daraus?

Wir möchten verstehen, wie die Struktur der Gasaustauschregion die Funktion der Lunge beeinflusst. Hierdurch können erwartungsgemäss bestehende und neue Behandlungsmethoden struktureller Lungenerkrankungen verbessert werden. Ausserdem stellen die erwarteten Ergebnisse eine Grundlage für das Verständnis von umweltbedingter oder therapeutischer Partikeldeposition in der Lunge dar.

Direct link to Lay Summary Last update: 14.07.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Tomographic in vivo microscopy for the study of lung physiology at the alveolar level
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.
Development of the lung.
Schittny Johannes C (2017), Development of the lung., in Cell and tissue research, 367(3), 427-444.
Effective segmentation of fresh post-mortem murine lung parenchyma in phase contrast X-ray tomographic microscopy images
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.
Imaging samples larger than the field of view: the SLS experience
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.
Lung structure at preterm and term birth
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.
Small angle x-ray scattering with edge-illumination.
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.
The Total Number of Acini Remains Constant throughout Postnatal Rat Lung Development.
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, 00325-2016.
Correlation between alveolar ventilation and electrical properties of lung parenchyma.
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.
Gene expression profile in newborn rat lungs after two days of recovery of mechanical ventilation.
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.
Efficient estimation of the total number of acini in adult rat lung.
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.
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.
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.
Rat lungs show a biphasic formation of new alveoli during postnatal development.
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.
Sprouting and intussusceptive angiogenesis in postpneumonectomy lung growth: mechanisms of alveolar neovascularization.
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.
Strukturelle Entwicklung – von der Anlage zur adulten Lunge
Schittny Johannes C. (2014), Strukturelle Entwicklung – von der Anlage zur adulten Lunge, in von Mutius E. (ed.), Springer, Berlin, 3-16.
Tenascin-C is required for normal Wnt/β-catenin signaling in the whisker follicle stem cell niche.
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.
The long non-coding RNA NEAT1 is increased in IUGR placentas, leading to potential new hypotheses of IUGR origin/development.
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.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Laura van Winkle, University of California in Davis United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. Anthony Wexler, University of California in Davis United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Dr. Max Ackermann, Institut für funktionelle und klinische Anatomie, Universität Mainz Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Dr. Jason Woods, Center for Pulmonary Imaging Research at Cincinnati Children’s Hospital United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. Kent Pinkerton, University of California in Davis United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Dr. Connie C.W. Hsia, UT Southwestern Medical Center, Dallas, TX United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Gordon Reserch Conference Lung Development, Injury & Repair Talk given at a conference Development of the Acinar Airspaces Visualized by High Resolution 3D-Lung 20.08.2017 Colby-Sawyer College in New London, New Hampshire USA, United States of America Stampanoni Marco; Vogiatzis-Oikonomidis Ioannis; Arcadu Filippo; Brenner Carl-Friedrich; Obrist Dominik; Cremona Tiziana; Schittny Johannes C.;
Harvard Public School of Health, Special Seminar Individual talk How 3-dimensiomal Imaging Changes Our Understanding of Lung Development 17.08.2017 Boston, United States of America Brenner Carl-Friedrich; Arcadu Filippo; Stampanoni Marco; Schittny Johannes C.; Vogiatzis-Oikonomidis Ioannis; Obrist Dominik; Cremona Tiziana;
ATS International Conference 2017 Poster Analyzing Acinar Dynamics at the Micrometer Scale 20.05.2017 Washinton, DC, United States of America Cremona Tiziana; Vogiatzis-Oikonomidis Ioannis; Schittny Johannes C.; Stampanoni Marco; Arcadu Filippo;
ATS International Conference 2017 Poster Computational Model of a Breathing Lung Illustrates the Influence of the Acinar Structures on Gas Washout 20.05.2017 Washinton, DC, United States of America Schittny Johannes C.; Obrist Dominik; Brenner Carl-Friedrich;
ATS International Conference 2017 Talk given at a conference In vivo Lung Imaging 20.05.2017 Washinton, United States of America Arcadu Filippo; Vogiatzis-Oikonomidis Ioannis; Stampanoni Marco; Obrist Dominik; Schittny Johannes C.; Cremona Tiziana; Brenner Carl-Friedrich;
ATS International Conference 2017 Poster Surface Charge Effects on Inhaled Engineered Nanomaterial Delivery and Retention in the Respiratory Tract of Mice. 20.05.2017 Washington, DC, United States of America Schittny Johannes C.;
ATS International Conference 2017 Poster Tenascin C Knockout Mice Have an Altered Lung Function at Newborn and Adult Age 20.05.2017 Washington, DC, United States of America Schittny Johannes C.; Cremona Tiziana; Stampanoni Marco;
Lung Science Conference 2017 "Mechanistic overlap between chronic lung injury and cancer" Poster Tenascin C knockout mice have an altered lung function at newborn and adult age 23.03.2017 Estoril, Portugal, Portugal Schittny Johannes C.; Cremona Tiziana;
Lung Science Conference 2017 "Mechanistic overlap between chronic lung injury and cancer" Talk given at a conference Postnatal development of pulmonary acini in rats 23.03.2017 Estoril, Portugal, Portugal Cremona Tiziana; Schittny Johannes C.; Stampanoni Marco;
Annual Meeting of the Swiss Society of Matrix Biology, Bern, 2017 Talk given at a conference The development of integrin alpha 8 deficient lungs shows reduced and altered branching and a correction of the phenotype during alveolarization 15.02.2017 Bern, Switzerland Schittny Johannes C.; Cremona Tiziana;
Annual Meeting of the Swiss Society of Matrix Biology, Bern, 2017 Talk given at a conference Tenascin C knockout mice have an altered lung function at newborn and adult age 15.02.2017 Bern, Switzerland Cremona Tiziana; Schittny Johannes C.;
Children’s Hospital, Los Angeles; The Saban Research Instiute, Sepcial Seminar Individual talk How 3-dimensiomal Imaging Changes Our Understanding of Lung Development 27.07.2016 Los Angeles, CA, United States of America Schittny Johannes C.;
ATS International Conference 2016 Talk given at a conference Postnatal Development of Pulmonary Acini in Rats 13.05.2016 San Francisco, CA, United States of America Cremona Tiziana; Schittny Johannes C.;
CCRBM seminar, University of California in Davis Talk given at a conference How 3-dimensiomal Imaging Changes Our Understanding of Lung Development 12.02.2016 Davis, CA, United States of America Schittny Johannes C.;
Mini-symposium in honor of Prof. Jahar Bhattacharya, Department of Clinical Research, University of Bern Talk given at a conference 3D Lung Structure 16.11.2015 Bern, Switzerland Schittny Johannes C.;
Excellence Cluster Cardio-Pulmonary SystemMini-Symposium, Giessen, BFS Talk given at a conference A 3-Dimensional View of Angiogenesis and Lung Development 26.09.2015 Giessen, Germany Schittny Johannes C.;
Swiss Light Source, Paul-Scherrer-Institut, Seminar Series Individual talk How does the 3-dimensional structure of the pulmonary acinus develop and regenerate and which functional consequences does it have? 24.09.2015 Villigen, PSI, Switzerland Stampanoni Marco; Schittny Johannes C.; Obrist Dominik;
First Symposium of the DCR Research Cluster Lung Development, Regeneration, and Disease Talk given at a conference High Resolution 3D Lung Imaging – How the Third Dimension Extended our View of Lung Development 03.09.2015 Bern, Switzerland Schittny Johannes C.;
ISAM 2015 Poster High Resolution Phase Contrast Imaging of Sub-micron Particles in Unstained 30.05.2015 München, Germany Stampanoni Marco; Schittny Johannes C.;
Children's Hospital, Cincinnati,Special Seminar Individual talk How 3-dimensiomal Imaging Changes Our Understanding of Lung Development 22.05.2015 Cincinnati, OH, United States of America Schittny Johannes C.;
ATS International Conference 2015 Poster Alpha8 Integrin Deficiency Alters Branching Morphogenesis and Alveolarization During Lung Development 15.05.2015 Denver, CO, United States of America Schittny Johannes C.; Cremona Tiziana;
Annual Meeting of the SGP, SGPP, SGPH, and SGT Talk given at a conference Lung Development – from Infancy to Adulthood 17.04.2015 Lugano, Switzerland Schittny Johannes C.;
LS2 Annual Meeting 2015, SSAHE-Symposium, 3-Dimensional Microscopy: From atoms to organisms Talk given at a conference How Imaging Changes Our Understanding of Lung Development 29.01.2015 Zürich, Switzerland Schittny Johannes C.;
Department of Biomedical Engineering, Israel Institute of Technology Haifa, Seminar Series Individual talk How Imaging Changes Our Understanding of Lung Development 19.10.2014 Department of Biomedical Engineering, Israel Institute of Technology Haifa, Israel Schittny Johannes C.;
FECTS/EMB 2014 Talk given at a conference A Neonatal Pulse of Corticosteroids Modifies the Expression of Tenascin-C, Elastin and Smooth Muscle Actin and Induces a Complex Alteration of Rat Lung Development 21.09.2014 Rotterdam, Netherlands Schittny Johannes C.; Stampanoni Marco;
ATS International Conference 2014 Poster Rat Lungs Show A Biphasic Formation Of New Alveoli During Postnatal Development 16.09.2014 San Diego, CA, United States of America Schittny Johannes C.;


Self-organised

Title Date Place
Annual Meeting of the Swiss Society of Matrix Biology, Bern, 2017 15.02.2017 Bern, Switzerland

Awards

Title Year
Best Abstract 2nd price of the 34th SSAI Congress 2017, Malmö/Lund (SSAI; Scandinavian Society of Anaesthesiology and Intensive Care) 2017
European Respiratory Society Lung Science Conference 2017 Distinguished Poster Award The European Respiratory Society takes great pleasure in awarding Dr Tiziana Patrizia Cremona for presenting the poster entitled POSTNATAL DEVELOPMENT OF PULMONARY ACINI IN RATS at the 15th ERS Lung Science Conference entitled "Mechanistic Overlap Between Chronic Lung Injury and Cancer", held in Estoril, Portugal,23-26 March 2017. Endowment: The ERS paid the Hotel during the conference 2017

Associated projects

Number Title Start Funding scheme
109874 Lung Development. Are there two phases of alveolarization and which role does the extracellular matrix play? 01.04.2006 Project funding (Div. I-III)
175953 How does the 3-dimensional structure of the pulmonary acinus develop, regenerate, and change during breathing? What are the functional consequences for ventilation and particle deposition? 01.10.2017 Project funding (Div. I-III)
68256 Extracellular matrix during lung development. What are roles of Tenascin-C, alpha8beta1 integrin, Laminin gamma1, and discoidin domain receptor1? 01.10.2002 Project funding (Div. I-III)
125397 How is the 3D-structure of the gas-exchange area altered during lung development and how is this influenced by the extracellular matrix? 01.10.2009 Project funding (Div. I-III)
135550 In-vivo study of lung physiology with sub-second X-ray tomographic microscopy 01.05.2011 Interdisciplinary projects
125397 How is the 3D-structure of the gas-exchange area altered during lung development and how is this influenced by the extracellular matrix? 01.10.2009 Project funding (Div. I-III)
113155 High resolution micro-computer tomograph skyscan 1172 micro-CT system 01.01.2007 R'EQUIP

Abstract

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.
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