title: Sequential targeted deficiency of SP-A and -D leads to progressive alveolar lipoproteinosis and emphysema.
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.
authors.affiliation: Cardiovascular Research Institute and Department of Pediatrics, University of California San Francisco, San Francisco, California 94118-1944, USA. hawgood@itsa.ucsf.edu
authors.forename: Samuel
authors.initials: S
authors.lastname: Hawgood
authors.forename: Matthias
authors.initials: M
authors.lastname: Ochs
authors.forename: Anja
authors.initials: A
authors.lastname: Jung
authors.forename: Jennifer
authors.initials: J
authors.lastname: Akiyama
authors.forename: Lennell
authors.initials: L
authors.lastname: Allen
authors.forename: Cindy
authors.initials: C
authors.lastname: Brown
authors.forename: Jess
authors.initials: J
authors.lastname: Edmondson
authors.forename: Stacey
authors.initials: S
authors.lastname: Levitt
authors.forename: Elaine
authors.initials: E
authors.lastname: Carlson
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Gillespie
authors.forename: Angela
authors.initials: A
authors.lastname: Villar
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: Francis R
authors.initials: FR
authors.lastname: Poulain
mesh_terms: 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
chemical_list: D010743:Phospholipids; D037662:Pulmonary Surfactant-Associated Protein A; D037663:Pulmonary Surfactant-Associated Protein D; D012333:RNA, Messenger; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12