title: A pneumocyte-macrophage paracrine lipid axis drives the lung toward fibrosis.
abstract: Lipid-laden macrophages, or "foam cells," are observed in the lungs of patients with fibrotic lung disease, but their contribution to disease pathogenesis remains unexplored. Here, we demonstrate that fibrosis induced by bleomycin, silica dust, or thoracic radiation promotes early and sustained accumulation of foam cells in the lung. In the bleomycin model, we show that foam cells arise from neighboring alveolar epithelial type II cells, which respond to injury by dumping lipids into the distal airspaces of the lungs. We demonstrate that oxidized phospholipids accumulate within alveolar macrophages (AMs) after bleomycin injury and that murine and human AMs treated with oxidized phosphatidylcholine (oxPc) become polarized along an M2 phenotype and display enhanced production of transforming growth factor-β1. The direct instillation of oxPc into the mouse lung induces foam cell formation and triggers a severe fibrotic reaction. Further, we show that reducing pulmonary lipid clearance by targeted deletion of the lipid efflux transporter ATP-binding cassette subfamily G member 1 increases foam cell formation and worsens lung fibrosis after bleomycin. Conversely, we found that treatment with granulocyte-macrophage colony-stimulating factor attenuates fibrotic responses, at least in part through its ability to decrease AM lipid accumulation. In summary, this work describes a novel mechanism leading to foam cell formation in the mouse lung and suggests that strategies aimed at blocking foam cell formation might be effective for treating fibrotic lung disorders.
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Freddy
authors.initials: F
authors.lastname: Romero
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Dilip
authors.initials: D
authors.lastname: Shah
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Michelle
authors.initials: M
authors.lastname: Duong
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Raymond B
authors.initials: RB
authors.lastname: Penn
authors.affiliation: 2 Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
authors.affiliation: 2 Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Madenspacher
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: William
authors.initials: W
authors.lastname: Stafstrom
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Mani
authors.initials: M
authors.lastname: Kavuru
authors.affiliation: 3 Bodine Cancer Center, and.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
authors.affiliation: 4 Department of Obstetrics and Gynecology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Caleb B
authors.initials: CB
authors.lastname: Kallen
authors.affiliation: 5 Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.affiliation: 1 Center for Translational Medicine and Jane and Leonard Korman Lung Center.
authors.forename: Ross
authors.initials: R
authors.lastname: Summer
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects / Q000494:pharmacology; D001761:Bleomycin / Q000009:adverse effects / Q000494:pharmacology; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000633:toxicity; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D008074:Lipoproteins; D010713:Phosphatidylcholines; D001761:Bleomycin
keywords: alveolar macrophages; foam cells; oxidized phospholipids; pulmonary fibrosis; type II pneumocytes