Pneumologie 2018; 72(03): 229-230
DOI: 10.1055/s-0037-1615326
Lungenfibrose
Georg Thieme Verlag KG Stuttgart · New York

Stereological characterization of progressive fibrotic lung remodeling in conditional Nedd4 – 2 deficient mice

T Engelmann
1   Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL)
,
D Leitz
2   Department of Translational Pulmonology, Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
,
J Dürr
2   Department of Translational Pulmonology, Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
,
M Mall
2   Department of Translational Pulmonology, Translational Lung Research Center (TLRC), Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany
,
L Knudsen
1   Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL)
,
M Ochs
1   Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL)
› Author Affiliations
Further Information

Publication History

Publication Date:
07 March 2018 (online)

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The ubiquitin-ligase Nedd4 – 2 is involved in post-translational processing of a diversity of proteins which are important for cellular homeostasis in the pulmonary epithelium, such as pro-surfactant protein C (proSP-C). Conditional Nedd4 – 2 knockout in pulmonary epithelial cells in adult mice leads to mistrafficking of proSP-C and subsequent fibrotic remodeling in the lung resulting in end-stage lung disease after 3 to 4 months. However, the time course of disease progression at structural level and above all the initial structural alterations have not yet been investigated in detail. The purpose of this study was to monitor the progress of structural changes after induction of the knockout. To that end wildtype and Nedd4 – 2 knockout lungs were instillation fixed after 2 weeks, 2 months and 3 months of induction and samples were investigated quantitatively by design-based stereology at light and electron microscopic level.

After 2 weeks there were no differences between the knockout and control group in total volume of septal wall tissue per lung, mean septal wall thickness, and volume density of septal wall tissue. After 2 months the values of these parameters increased significantly while the surface area of the alveolar epithelium as well as the total volume of alveolar airspaces remained roughly stable. After 3 months the volume of septal wall tissue and septal wall thickness further increased and nearly doubled compared to the control group.

In conclusion Nedd4 – 2 knockout and proSP-C mistrafficking lead to progressive remodeling in lung tissue within a period of 3 months. The stable surface area of alveolar epithelium and volume of alveolar airspaces in concert with progressive thickening of septal wall tissue suggests a predominantly interstitial remodeling process and at best minor intraalveolar fibrosis or collaps induration.