Surfactantdysfunktion, alveoläre Kollapsneigung und deren Rollen für die Entwicklung der Lungenfibrose in zwei Tiermodellen der Ratte

• Antragsteller: Heinz-Gerd Hoymann, Ph.D.; Professor Dr. Lars Knudsen; Clemens Ruppert, Ph.D.
• Fachliche Zuordnung: Pneumologie,Thoraxchirurgie
• Förderung: Förderung von 2014 bis 2020
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 242799095

• Erstellungsjahr: 2018

Zusammenfassung der Projektergebnisse

The volume and shape of alveoli changes periodically during respiration which is called alveolar dynamics. The alveolar surfactant system in concert with a very small amount of collagen and elastin fibers is responsible for homogenous ventilation of the lung and stabilization of surface area for gas exchange even at low lung volumes at the end of exspiration. Within this project we analyzed disturbances of alveolar dynamics during the development of pulmonary fibrosis. Employing animal models, which are frequently used in the context of pulmonary fibrosis research, i.e. the bleomycin and TGF-β1 model, we could document that surfactant dysfunction with increased surface tension occurs during the very early period of disease development. This is linked with alveolar instability such as alveolar collapse and the formation of microatelectases predating the development of pulmonary fibrosis. In the bleomycin model, we could already detect alveolar instability at a time point at which there were no signs of lung injury or disease. We simulated alveolar dynamics based on our structural and lung mechanical data and predicted that there is hardly any cyclic opening and closing of alveoli during the respiratory cycle. Instead, there is permanent alveolar collapse/ derecruitment throughout the respiratory cycle which results in dynamic strain of those alveoli which remain open during inspiration. Using surfactant replacement therapy we could reduce dynamic strain of alveolar walls during respiration and this was linked with a reduction of markers of lung injury and fibrosis at later time points. These observations could be reproduced in a second animal model, the TGF-β1 animal model of lung fibrosis. These findings suggest that mechanical stress due to heterogeneous ventilation triggered by alveolar collapse represents one factor during the progression towards lung fibrosis. Hence, stabilization of alveoli might represent a therapeutic approach to reduce fibrotic remodeling since the occurrence of microatelectases have recently been found in patients suffering from idiopathic pulmonary fibrosis in areas of the lung which were not yet effected from fibrosis. We also studied the distribution of fibrotic lesions in the lung. While in human lung fibrosis these lesions form a network this appeared not to be the case in the animal models we studied with this regard.

Projektbezogene Publikationen (Auswahl)

• Alveolar derecruitment and collapse induration as crucial mechanisms in lung injury and fibrosis. Am J Respir Cell Mol Biol 2015; 52(2):232-43
  Lutz D, Gazdhar A, Lopez-Rodriguez E, Ruppert C, Mahavadi P, Günther A, Klepetko W, Bates JH, Smith B, Geiser T, Ochs M, and Knudsen L
  
• Linking progression of fibrotic lung remodeling and ultrastructural alterations of alveolar epithelial type II cells in the amiodarone mouse model. Am J Physiol Lung Cell Mol Physiol 2015; 309(1):L63-75
  Birkelbach B, Lutz D, Ruppert C, Henneke I, Lopez-Rodriguez E, Günther A, Ochs M, Mahavadi P, and Knudsen L
  
• A combined method for correlative 3D imaging of biological samples from macro to nano scale. Scientific Reports; 2016; 6:35606
  Kellner M, Heidrich M, Lorbeer R-A, Antonopoulos G, Knudsen L, Wrede C, Izykowski N, Grothausmann R, Jonigk D, Ochs M, Ripken T, Kühnel M, and Meyer H
  
• Pressure dependent alveolar derecruitment is linked with surfactant dysfunction in bleomycin-induced acute lung injury. Am J Respir Crit Care Med; 2016. p. A4813
  Knudsen L, Lopez-Rodriguez E, Berndt L, Boden C, Bates J, Smith B
  
• Surfactant dysfunction during overexpression of TGF-β1 precedes profibrotic lung remodeling in vivo. Am J Physiol Lung Cell Mol Physiol. 2016; 310(11):L1260-71
  Lopez-Rodriguez E, Boden C, Echaide M, Perez-Gil J, Kolb M, Gauldie J, Maus UA, Ochs M, and Knudsen L
  
• Using electron microscopes to look into the lung. Histochem Cell Biol. 2016; 146: 695-707
  Ochs M, Knudsen L, Hegermann J, Wrede C, Grothausmann R, and Mühlfeld C
  
• Using pulmonary surfactant as Pirfenidone vehicle to target lung epithelium in bleoycin-induced lung fibrosis. Am J Respir Crit Care Med; 2016. p. A2378
  Lopez-Rodriguez E, Laucamp C, Hidalgo A, Cruz A, Perez-Gil J, Ochs M, Knudsen L
  
• Surfactant replacement therapy reduces acute lung injury and collapse induration related lung remodeling in the bleomycin model. Am J Physiol Lung cell Mol Physiol 2017; 313(2):L313-L327
  Steffen L, Ruppert C, Hoymann HG, Funke M, Ebener S, Kloth C, Mühlfeld C, Ochs M, Knudsen L, and Lopez-Rodriguez E
  
• Tissue remodeling in pulmonary fibrosis. Cell Tissue Res. 2017; 367: 607-626
  Knudsen L, Ruppert C, and Ochs M