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(Chest. 2000;117:248S.)
© 2000 American College of Chest Physicians

Spontaneous Emphysema in Surfactant Protein D Gene-Targeted Mice*

Susan Wert, PhD; Tracy Jones; Thomas Korfhagen, MD; James Fisher, MD, FCCP and Jeffrey Whitsett, MD

* From the Children’s Hospital Medical Center, Cincinnati, OH, and University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Susan Wert, PhD, Division of Pulmonary Biology, Children’s Hospital Medical Center/Research Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229-2029; e-mail: Susan.Wert{at}CHMCC.org


   Introduction
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Abbreviation: SP-D = surfactant protein D

Surfactant protein D (SP-D), a 43-kDa member of the collectin family of innate defense molecules, is expressed primarily in the respiratory epithelium. Targeted deletion of the SP-D gene resulted in pulmonary lipoidosis and accumulation of lipid-laden alveolar macrophages in the lungs of SP-D (-/-) mice by 8 to 12 wk of age.1 Histopathological findings at 6 mo of age consisted of enlarged airspaces with multiple focal areas of macrophage accumulation, and perivascular/peribronchiolar monocytic infiltrates. Mice were maintained in pathogen-free conditions and there was no serologic evidence of viral infection. To characterize the role of SP-D in alveolar formation or enlargement, morphometric analysis of the lungs of SP-D (-/-) mice was performed at 5 days, 14 days, 3 weeks, 6 weeks, and 7 months of age. Three to five SP-D (-/-) mice and SP-D (+/+) controls were sacrificed at each time point; the lungs were inflation-fixed with 4% paraformaldehyde in phosphate-buffered saline, at a pressure of 25 cm H2O. There were no significant differences in body weights, lung volumes, or lung volume to body weight ratios between the SP-D (-/-) mice and age-matched SP-D (+/+) controls. Morphometric measurements were performed on paraffin sections to determine the proportion (percentage of fractional area) of respiratory parenchyma and airspace at each time point. No abnormalities were observed between 5 and 14 days of age, ie, during transition from the saccular to the alveolar stage of lung development. Enlarged airspaces were readily apparent, however, by 3 weeks of age, and they increased in size thereafter. The relative proportion of airspace in the SP-D (-/-) mice increased significantly by 7 months of age, while that of the respiratory parenchyma decreased, compared to SP-D (+/+) controls. At 7 months, the percentage of fractional area for airspace was 68.7% (SP-D -/-) vs 54.0% (SP-D +/+); for the respiratory parenchyma, it was 31.3% (SP-D -/-) vs 45.9% (SP-D +/+) (p = 0.004). Abnormalities in both collagen and elastin staining were also observed. These findings were associated with accumulation of peribronchiolar and subpleural alveolar macrophage infiltrates. SP-D deficiency caused progressive enlargement of pulmonary acini consistent with the development of emphysema. These results demonstrate a previously unknown role for SP-D in the regulation of inflammation and pulmonary remodeling in vivo.


   Footnotes
 
This work was supported by the Cystic Fibrosis Foundation and NIH grants HL56387, HL41320, and HL58795.


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 References
 

  1. Korfhagen, TR, Sheftelyevich, V, Burhans, MS, et al (1998) Surfactant protein-D regulates surfactant phospholipid homeostasis in vivo. J Biol Chem 23,28438-28443



This article has been cited by other articles:


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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. Zhang, M. Ikegami, T. R. Korfhagen, F. X. McCormack, M. Yoshida, R. M. Senior, J. M. Shipley, S. D. Shapiro, and J. A. Whitsett
Neither SP-A nor NH2-terminal domains of SP-A can substitute for SP-D in regulation of alveolar homeostasis
Am J Physiol Lung Cell Mol Physiol, August 1, 2006; 291(2): L181 - L190.
[Abstract] [Full Text] [PDF]

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