Abstract
Idiopathic pulmonary fibrosis (IPF) causes progressive fibrosis and worsening pulmonary function. Prognosis is poor and no effective therapies exist. We show that programmed cell death 5 (PDCD5) expression is increased in the lungs of patients with IPF and in mouse models of lung fibrosis. Lung fibrosis is significantly diminished by club cell-specific deletion of Pdcd5 gene. PDCD5 mediates β-catenin/Smad3 complex formation, promoting TGF-β-induced transcriptional activation of matricellular genes. Club cell Pdcd5 knockdown reduces matricellular protein secretion, inhibiting fibroblast proliferation and collagen synthesis. Here, we demonstrate the club cell-specific role of PDCD5 as a mediator of lung fibrosis and potential therapeutic target for IPF.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aged
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Animals
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Apoptosis Regulatory Proteins / deficiency
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Apoptosis Regulatory Proteins / genetics*
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Apoptosis Regulatory Proteins / metabolism
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Bronchioles / metabolism
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Bronchioles / pathology
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Cell Line
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Disease Models, Animal
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Female
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Gene Expression
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Gene Knockdown Techniques
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Humans
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Idiopathic Pulmonary Fibrosis / genetics*
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Idiopathic Pulmonary Fibrosis / pathology*
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Lung / metabolism
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Lung / pathology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Middle Aged
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Respiratory Mucosa / metabolism
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Respiratory Mucosa / pathology
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Signal Transduction
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Smad3 Protein / metabolism
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Transforming Growth Factor beta / metabolism
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Apoptosis Regulatory Proteins
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Neoplasm Proteins
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PDCD5 protein, human
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Pdcd5 protein, mouse
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Smad3 Protein
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Smad3 protein, mouse
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Transforming Growth Factor beta
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p38 Mitogen-Activated Protein Kinases