title: Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice.
abstract: Idiopathic pulmonary fibrosis is a disease characterized by progressive, unrelenting lung scarring, with death from respiratory failure within 2-4 years unless lung transplantation is performed. New effective therapies are clearly needed. Fibroblast activation protein (FAP) is a cell surface-associated serine protease up-regulated in the lungs of patients with idiopathic pulmonary fibrosis as well as in wound healing and cancer. We postulate that FAP is not only a marker of disease but influences the development of pulmonary fibrosis after lung injury. In two different models of pulmonary fibrosis, intratracheal bleomycin instillation and thoracic irradiation, we find increased mortality and increased lung fibrosis in FAP-deficient mice compared with wild-type mice. Lung extracellular matrix analysis reveals accumulation of intermediate-sized collagen fragments in FAP-deficient mouse lungs, consistent within vitrostudies showing that FAP mediates ordered proteolytic processing of matrix metalloproteinase (MMP)-derived collagen cleavage products. FAP-mediated collagen processing leads to increased collagen internalization without altering expression of the endocytic collagen receptor, Endo180. Pharmacologic FAP inhibition decreases collagen internalization as expected. Conversely, restoration of FAP expression in the lungs of FAP-deficient mice decreases lung hydroxyproline content after intratracheal bleomycin to levels comparable with that of wild-type controls. Our findings indicate that FAP participates directly, in concert with MMPs, in collagen catabolism and clearance and is an important factor in resolving scar after injury and restoring lung homeostasis. Our study identifies FAP as a novel endogenous regulator of fibrosis and is the first to show FAP's protective effects in the lung.
authors.affiliation: From the Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, fanm@upmc.edu.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Fan
authors.affiliation: the Molecular and Cellular Pathology Graduate Program, University of North Carolina at Chapel Hill Chapel Hill, North Carolina 27599.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: From the Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Li
authors.affiliation: the Department of Hematology and Oncology and.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Ra
authors.affiliation: the Wistar Institute, Philadelphia, Pennsylvania 19104.
authors.forename: Sonali
authors.initials: S
authors.lastname: Majumdar
authors.affiliation: From the Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Dexter L
authors.initials: DL
authors.lastname: Gulick
authors.affiliation: From the Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Jerome
authors.affiliation: the Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, NIDCR, Center for Cancer Immune Therapy, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Madsen
authors.affiliation: the Department of Hematology and Oncology and.
authors.forename: Melpo
authors.initials: M
authors.lastname: Christofidou-Solomidou
authors.affiliation: the Wistar Institute, Philadelphia, Pennsylvania 19104.
authors.forename: David W
authors.initials: DW
authors.lastname: Speicher
authors.affiliation: the Sackler School of Biomedical Graduate Sciences, Tufts University, Boston, Massachusetts 02111, and.
authors.forename: William W
authors.initials: WW
authors.lastname: Bachovchin
authors.affiliation: the Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Carol
authors.initials: C
authors.lastname: Feghali-Bostwick
authors.affiliation: the Departments of Biomedical Sciences and Medicine, Pulmonary Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D010450:Endopeptidases; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D059748:Proteolysis; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D003094:Collagen; D010450:Endopeptidases; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D008565:Membrane Proteins; D012333:RNA, Messenger; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
keywords: collagen; extracellular matrix; fibroblast; gelatinase; interstitial lung disease; pulmonary fibrosis; serine protease