Sequential targeted deficiency of SP-A and -D leads to progressive alveolar lipoproteinosis and emphysema.
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.
Hawgood
Samuel
S
Cardiovascular Research Institute and Department of Pediatrics, University of California San Francisco, San Francisco, California 94118-1944, USA. hawgood@itsa.ucsf.edu
Ochs
Matthias
M
Jung
Anja
A
Akiyama
Jennifer
J
Allen
Lennell
L
Brown
Cindy
C
Edmondson
Jess
J
Levitt
Stacey
S
Carlson
Elaine
E
Gillespie
Anne Marie
AM
Villar
Angela
A
Epstein
Charles J
CJ
Poulain
Francis R
FR
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002874:Chromosome Mapping; D018450:Disease Progression; D004646:Emphysema / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D008065:Lipoid Proteinosis of Urbach and Wiethe / Q000235:genetics* / Q000473:pathology; D016676:Macrophages, Alveolar / Q000473:pathology; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000032:analysis; D037662:Pulmonary Surfactant-Associated Protein A / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D037663:Pulmonary Surfactant-Associated Protein D / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
D010743:Phospholipids; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D012333:RNA, Messenger; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12