title: The role of inducible nitric oxide synthase for interstitial remodeling of alveolar septa in surfactant protein D-deficient mice.
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.
authors: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, Hannover, Germany; knudsen.lars@mh-hannover.de.
authors: Lars
authors: L
authors: Knudsen
authors: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania;
authors: Elena N
authors: EN
authors: Atochina-Vasserman
authors: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey;
authors: Christopher B
authors: CB
authors: Massa
authors: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
authors: Bastian
authors: B
authors: Birkelbach
authors: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey;
authors: Chang-Jiang
authors: CJ
authors: Guo
authors: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey;
authors: Pamela
authors: P
authors: Scott
authors: Institute of Anatomy, University of Bern, Bern, Switzerland; and.
authors: Beat
authors: B
authors: Haenni
authors: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania;
authors: Michael F
authors: MF
authors: Beers
authors: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany, Biomedical Research in Endstage and Obstructive Lung Disease Hannover, Member of the German Center for Lung Research, Hannover, Germany; REBIRTH Cluster of Excellence, Hannover, Germany.
authors: Matthias
authors: M
authors: Ochs
authors: Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey;
authors: Andrew J
authors: AJ
authors: Gow
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D037663:Pulmonary Surfactant-Associated Protein D / Q000172:deficiency* / Q000378:metabolism; D015656:Respiratory Mechanics
chemical_list: D037663:Pulmonary Surfactant-Associated Protein D; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: inducible nitric oxide synthase; invasive pulmonary function test; modeling; stereology; surfactant protein D