title: Aberrant lung remodeling in a mouse model of surfactant dysregulation induced by modulation of the Abca3 gene.
abstract: The lipid transporter, ATP binding cassette class A3 (ABCA3), plays a critical role in the biogenesis of alveolar type 2 (AT2) cell lamellar bodies (LBs). A relatively large number of mutations in the ABCA3 gene have been identified in association with diffuse parenchymal lung disease (DPLD), the most common of which is a missense mutation (valine substitution for lysine at residue 292 (ABCA3E292V)) that leads to functional impairment of the transporter in vitro. The consequences of ABCA3E292Vgene expression in vivo are unknown. To address this question, we developed mouse models expressing ABCA3E292Vknocked-in to the endogenous mouse locus. The parental (F1) mouse line (mAbca3E292V) that retained an intronic pgk-Neo selection cassette (inserted in reverse orientation) (mAbca3E292V-rNeo) demonstrated an allele dependent extracellular surfactant phospholipid (PL) deficiency. We hypothesize that this PL deficiency leads to aberrant parenchymal remodeling contributing to the pathophysiology of the DPLD phenotype. Compared to wild type littermates, baseline studies of mice homozygous for the pgk-Neo insert (mAbca3E292V-rNeo+/+) revealed nearly 50% reduction in bronchoalveolar lavage (BAL) PL content that was accompanied by quantitative reduction in AT2 LB size with a compensatory increase in LB number. The phenotypic alteration in surfactant lipid homeostasis resulted in an early macrophage predominant alveolitis which peaked at 8 weeks of age. This was followed by age-dependent development of histological DPLD characterized initially by peribronchial inflammatory cell infiltration and culminating in both an emphysema-like phenotype (which included stereologically quantifiable reductions in both alveolar septal surface area and volume of septal wall tissue) plus foci of trichrome-positive collagen deposition together with substantial proliferation of hyperplastic AT2 cells. In addition to spontaneous lung remodeling, mABCA3E292V-rNeo mice were rendered more vulnerable to exogenous injury. Three weeks following intratracheal bleomycin challenge, mAbca3-rNeo mice demonstrated allele-dependent susceptibility to bleomycin including enhanced weight loss, augmented airspace destruction, and increased fibrosis. Removal of the rNeo cassette from mAbca3 alleles resulted in restoration of BAL PL content to wild-type levels and an absence of changes in lung histology up to 32 weeks of age. These results support the importance of surfactant PL homeostasis as a susceptibility factor for both intrinsic and exogenously induced lung injury/remodeling.
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Beers
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Knudsen
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Tomer
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Maronn
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany; Biomedical Research in End-stage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany; REBIRTH Cluster of Excellence, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ochs
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States. Electronic address: mulugeta@mail.med.upenn.edu1.
authors.forename: Surafel
authors.initials: S
authors.lastname: Mulugeta
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006706:Homeostasis; D008168:Lung / Q000473:pathology*; D008171:Lung Diseases / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010743:Phospholipids / Q000172:deficiency; D011663:Pulmonary Surfactants / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; C512026:Abca3 protein, mouse; D000900:Anti-Bacterial Agents; D010743:Phospholipids; D011663:Pulmonary Surfactants; D001761:Bleomycin
keywords: ABCA3; Lamellar bodies; Lung disease; Pathogenesis; Phospholipids; Pulmonary; Surfactant