Title: NOS2 is critical to the development of emphysema in Sftpd deficient mice but does not affect surfactant homeostasis.
Authors: Knudsen, Lars; Atochina-Vasserman, Elena N; Guo, Chang-Jiang; Scott, Pamela A; Haenni, Beat; Beers, Michael F; Ochs, Matthias; Gow, Andrew J
Published In PLoS One, (2014)
Abstract: Surfactant protein D (SP-D) has important immuno-modulatory properties. The absence of SP-D results in an inducible NO synthase (iNOS, coded by NOS2 gene) related chronic inflammation, development of emphysema-like pathophysiology and alterations of surfactant homeostasis.In order to test the hypothesis that SP-D deficiency related abnormalities in pulmonary structure and function are a consequence of iNOS induced inflammation, we generated SP-D and iNOS double knockout mice (DiNOS).Structural data obtained by design-based stereology to quantify the emphysema-like phenotype and disturbances of the intracellular surfactant were correlated to invasive pulmonary function tests and inflammatory markers including activation markers of alveolar macrophages and compared to SP-D (Sftpd(-/-)) and iNOS single knockout mice (NOS2(-/-)) as well as wild type (WT) littermates.DiNOS mice had reduced inflammatory cells in BAL and BAL-derived alveolar macrophages showed an increased expression of markers of an alternative activation as well as reduced inflammation. As evidenced by increased alveolar numbers and surface area, emphysematous changes were attenuated in DiNOS while disturbances of the surfactant system remained virtually unchanged. Sftpd(-/-) demonstrated alterations of intrinsic mechanical properties of lung parenchyma as shown by reduced stiffness and resistance at its static limits, which could be corrected by additional ablation of NOS2 gene in DiNOS.iNOS related inflammation in the absence of SP-D is involved in the emphysematous remodeling leading to a loss of alveoli and associated alterations of elastic properties of lung parenchyma while disturbances of surfactant homeostasis are mediated by different mechanisms.
PubMed ID: 24465666
MeSH Terms: Animals; Bronchoalveolar Lavage Fluid/chemistry; Bronchoalveolar Lavage Fluid/cytology; Gene Expression; Homeostasis*; Inflammation/enzymology; Inflammation/genetics; Inflammation/pathology; Macrophage Activation; Macrophages, Alveolar/enzymology; Macrophages, Alveolar/pathology; Mice; Mice, Knockout; Nitric Oxide Synthase Type II/deficiency*; Nitric Oxide Synthase Type II/genetics; Pulmonary Alveoli/enzymology; Pulmonary Alveoli/pathology*; Pulmonary Emphysema/enzymology; Pulmonary Emphysema/genetics; Pulmonary Emphysema/pathology*; Pulmonary Surfactant-Associated Protein D/deficiency*; Pulmonary Surfactant-Associated Protein D/genetics; Pulmonary Surfactants/metabolism; Respiratory Function Tests