The role of inducible nitric oxide synthase for interstitial remodeling of alveolar septa in surfactant protein D-deficient mice

Lars Knudsen, Elena N. Atochina-Vasserman, Christopher B. Massa, Bastian Birkelbach, Chang Jiang Guo, Pamela Scott, Beat Haenni, Michael F. Beers, Matthias Ochs, Andrew J. Gow

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Surfactant protein D (SP-D) modulates the lung’s immune system. Its absence leads to NOS2- independent alveolar lipoproteinosis and NOS2-dependent chronic inflammation, which is critical for early emphysematous remodeling. With aging, SP-D knockout mice develop an additional interstitial fibrotic component. We hypothesize that this age-related interstitial septal wall remodeling is mediated by NOS2. Using invasive pulmonary function testing such as the forced oscillation technique and quasistatic pressure-volume perturbation and design-based stereology, we compared 29-wk-old SP-D knockout (Sftpd-/-) mice, SP-D/ NOS2 double-knockout (DiNOS) mice, and wild-type mice (WT). Structural changes, including alveolar epithelial surface area, distribution of septal wall thickness, and volumes of septal wall components (alveolar epithelium, interstitial tissue, and endothelium) were quantified. Twenty-nine-week-old Sftpd-/- mice had preserved lung mechanics at the organ level, whereas elastance was increased in DiNOS. Airspace enlargement and loss of surface area of alveolar epithelium coexist with increased septal wall thickness in Sftpd-/- mice. These changes were reduced in DiNOS, and compared with Sftpd-/- mice a decrease in volumes of interstitial tissue and alveolar epithelium was found. To understand the effects of lung pathology on measured lung mechanics, structural data were used to inform a computational model, simulating lung mechanics as a function of airspace derecruitment, septal wall destruction (loss of surface area), and septal wall thickening. In conclusion, NOS2 mediates remodeling of septal walls, resulting in deposition of interstitial tissue in Sftpd-/-. Forward modeling linking structure and lung mechanics describes the complex mechanical properties by parenchymatous destruction (emphysema), interstitial remodeling (septal wall thickening), and altered recruitability of acinar airspaces.

Original languageEnglish
Pages (from-to)L959-L969
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume309
Issue number9
DOIs
Publication statusPublished - 2015
Externally publishedYes

Keywords

  • Inducible nitric oxide synthase
  • Invasive pulmonary function test
  • Modeling
  • Stereology
  • Surfactant protein D

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

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  • Cite this

    Knudsen, L., Atochina-Vasserman, E. N., Massa, C. B., Birkelbach, B., Guo, C. J., Scott, P., Haenni, B., Beers, M. F., Ochs, M., & Gow, A. J. (2015). The role of inducible nitric oxide synthase for interstitial remodeling of alveolar septa in surfactant protein D-deficient mice. American Journal of Physiology - Lung Cellular and Molecular Physiology, 309(9), L959-L969. https://doi.org/10.1152/ajplung.00017.2015