Sequential targeted deficiency of SP-A and -D leads to progressive alveolar lipoproteinosis and emphysema

Samuel Hawgood, Matthias Ochs, Anja Jung, Jennifer Akiyama, Lennell Allen, Cindy Brown, Jess Edmondson, Stacey Levitt, Elaine Carlson, Anne Marie Gillespie, Angela Villar, Charles J. Epstein, Francis R Poulain

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

Surfactant proteins-A and -D (SP-A and SP-D) are members of the collectin protein family. Mice singly deficient in SP-A and SP-D have distinct phenotypes. Both have altered inflammatory responses to microbial challenges. To further investigate the functions of SP-A and SP-D in vivo, we developed mice deficient in both proteins by sequentially targeting the closely linked genes in embryonic stem cells using graded resistance to G-418. There is a progressive increase in bronchoalveolar lavage phospholipid, protein, and macrophage content through 24 wk of age. The macrophages from doubly deficient mice express high levels of the matrix metalloproteinase MMP-12 and develop intense but patchy lung inflammation. Stereological analysis demonstrates significant air space enlargement and reduction in alveolar septal tissue per unit volume, consistent with emphysema. These changes qualitatively resemble the lung pathology seen in SP-D-deficient mice. These doubly deficient mice will be useful in dissecting the potential overlap in function between SP-A and SP-D in host defense.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume283
Issue number5 27-5
StatePublished - Nov 1 2002
Externally publishedYes

Keywords

  • Alveolar macrophages
  • Collectins
  • Sequential gene targeting
  • Surfactant proteins

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

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    Hawgood, S., Ochs, M., Jung, A., Akiyama, J., Allen, L., Brown, C., Edmondson, J., Levitt, S., Carlson, E., Gillespie, A. M., Villar, A., Epstein, C. J., & Poulain, F. R. (2002). Sequential targeted deficiency of SP-A and -D leads to progressive alveolar lipoproteinosis and emphysema. American Journal of Physiology - Lung Cellular and Molecular Physiology, 283(5 27-5).