NOS2 is critical to the development of emphysema in Sftpd deficient mice but does not affect surfactant homeostasis.
BACKGROUND
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.


OBJECTIVE
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Institute of Anatomy, University of Bern, Bern, Switzerland ; 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), Hannover, Germany.
Lars
L
Knudsen
Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Elena N
EN
Atochina-Vasserman
Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey, United States of America.
Chang-Jiang
CJ
Guo
Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey, United States of America.
Pamela A
PA
Scott
Institute of Anatomy, University of Bern, Bern, Switzerland.
Beat
B
Haenni
Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Michael F
MF
Beers
Institute of Anatomy, University of Bern, Bern, Switzerland ; 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), Hannover, Germany ; REBIRTH Cluster of Excellence, Hannover, Germany.
Matthias
M
Ochs
Department of Pharmacology & Toxicology, Rutgers University, Piscataway, New Jersey, United States of America.
Andrew J
AJ
Gow
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D015870:Gene Expression; D006706:Homeostasis; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000235:genetics; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology*; D011656:Pulmonary Emphysema / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D037663:Pulmonary Surfactant-Associated Protein D / Q000172:deficiency* / Q000235:genetics; D011663:Pulmonary Surfactants / Q000378:metabolism; D012129:Respiratory Function Tests
D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse