Loss of cells expressing fibroblast activation protein has variable effects in models of TGF-β and chronic bleomycin-induced fibrosis
| Autor: | Maria Liousia, Leslie Todd, Toru Kimura, Edmund K. Moon, Ellen Puré, Michael S. Leibowitz, Astero Klampatsa, Patrick Woodruff, Steven M. Albelda, Jing Sun, James Monslow |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pulmonary and Respiratory Medicine congenital hereditary and neonatal diseases and abnormalities Physiology Cell Mice Transgenic Bleomycin Transforming Growth Factor beta1 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation Fibroblast activation protein alpha Transforming Growth Factor beta Fibrosis Physiology (medical) medicine Animals Myofibroblasts Lung neoplasms Serine protease biology Chemistry Cell Differentiation Cell Biology Fibroblasts medicine.disease Idiopathic Pulmonary Fibrosis digestive system diseases Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Collagen Myofibroblast Transforming growth factor |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 317:L271-L282 |
| ISSN: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.00071.2019 |
| Popis: | Fibroblast activation protein (FAP), a cell surface serine protease, is upregulated on a subset of activated fibroblasts (often distinct from α-smooth muscle actin-expressing myofibroblasts) associated with matrix remodeling, including fibroblasts in idiopathic pulmonary fibrosis (Acharya PS, Zukas A, Chandan V, Katzenstein AL, Puré E. Hum Pathol 37: 352–360, 2006.). As FAP+fibroblasts could be pivotal in either breakdown and/or production of collagen and other matrix components, the goal of this study was to define the role of FAP+cells in pulmonary fibrosis in two established, but different, mouse models of chronic lung fibrosis: repetitive doses of intratracheal bleomycin and a single dose of an adenoviral vector encoding constitutively active TGF-β1 (Ad-TGFβ). To determine their role in fibrotic remodeling, FAP-expressing cells were depleted by injection of T cells expressing a chimeric antigen receptor specific for murine FAP in mice with established fibrosis. The contribution of FAP to the function of FAP-expressing cells was assessed in FAP knockout mice. Using histological analyses, quantification of soluble collagen content, and flow cytometry, we found that loss of FAP+cells exacerbated fibrosis in the bleomycin model, a phenotype largely recapitulated by the genetic deletion of FAP, indicating that FAP plays a role in this model. In contrast, depletion of FAP+cells or genetic deletion of FAP had little effect in the Ad-TGFβ model highlighting the potential for distinct mechanisms driving fibrosis depending on the initiating insult. The role of FAP in human lung fibrosis will need to be well understood to guide the use of FAP-targeted therapeutics that are being developed. |
| Databáze: | OpenAIRE |
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