Abstract
Developmentally expressed genes are believed to play a central role in tissue repair after injury; however, in lung disease their role has not been established. This study demonstrates that SFRP1, an inhibitor of Wnt signaling normally expressed during lung embryogenesis, is induced in the lungs of emphysema patients and in two murine models of the disease. SFRP1 was found to be essential for alveolar formation as Sfrp1(-/-) mice exhibited aberrant Wnt signaling, mesenchymal proliferation, and impaired alveoli formation. In contrast, SFRP1 activated ERK and up-regulated MMP1 and MMP9 without altering TIMP1 production when expressed in human lung epithelial cells. These findings demonstrate that SFRP1 promotes normal alveolar formation in lung development, although its expression in the adult up-regulates proteins that can cause tissue destruction. Thus, SFRP1 induction during tissue injury is unlikely to contribute to the repair response but rather is a participatory factor in the pathogenesis of emphysema and tissue destruction.
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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Animals
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Cell Line
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Disease Models, Animal
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Emphysema / metabolism*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Lung* / embryology
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Lung* / growth & development
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Lung* / pathology
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Matrix Metalloproteinase 1 / metabolism
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Matrix Metalloproteinase 9 / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Nicotiana / adverse effects
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Organogenesis / physiology*
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Signal Transduction / physiology
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Smoke
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Wnt Proteins / metabolism
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Wnt-5a Protein
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beta Catenin / metabolism
Substances
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CTNNB1 protein, mouse
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Intercellular Signaling Peptides and Proteins
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Membrane Proteins
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SFRP1 protein, human
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Sfrp1 protein, mouse
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Smoke
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Wnt Proteins
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Wnt-5a Protein
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Wnt10b protein, mouse
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Wnt5a protein, mouse
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beta Catenin
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Extracellular Signal-Regulated MAP Kinases
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Matrix Metalloproteinase 9
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Matrix Metalloproteinase 1