title: Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.
abstract: Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally after lung injury and are preferentially produced by fibrogenic (e.g., bleomycin-induced) rather than nonfibrogenic (e.g., LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including platelet-derived growth factor receptor-β, lysophosphatidic acid 1, epidermal growth factor receptor, and fibroblast growth factor receptor 2, mitigated the non-cell-autonomous fibroblast invasion induced by bronchoalveolar lavage from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Neil
authors.identifier: 0000-0001-6262-401X
authors.initials: N
authors.lastname: Ahluwalia
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Paula E
authors.initials: PE
authors.lastname: Grasberger
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Mugo
authors.affiliation: 2 Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.affiliation: 3 Universidad Nacional Autónoma de México, Mexico City, Mexico; and.
authors.forename: Annie
authors.initials: A
authors.lastname: Pardo
authors.affiliation: 4 Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico.
authors.forename: Moisés
authors.initials: M
authors.lastname: Selman
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Lagares
authors.affiliation: 1 Division of Pulmonary and Critical Care Medicine and the Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew M
authors.identifier: 0000-0002-5826-918X
authors.initials: AM
authors.lastname: Tager
mesh_terms: D000818:Animals; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid; D002465:Cell Movement / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology*; D055785:Gene Knockdown Techniques; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000150:complications* / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000150:complications* / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D001761:Bleomycin
keywords: fibroblast; idiopathic pulmonary fibrosis; invasion; migration; pathogenesis