Fibrotic lung fibroblasts show blunted inhibition by cAMP due to deficient cAMP response element-binding protein phosphorylation
| Autor: | Xiaoqiu Liu, Shu Qiang Sun, Rennolds S. Ostrom |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
medicine.medical_specialty
Pulmonary Fibrosis Blotting Western Electrophoretic Mobility Shift Assay Smad Proteins CREB Dinoprostone Cell Line chemistry.chemical_compound Idiopathic pulmonary fibrosis Transforming Growth Factor beta Internal medicine Pulmonary fibrosis medicine Cyclic AMP Humans Phosphorylation Protein kinase A Cyclic AMP Response Element-Binding Protein Cell Proliferation Pharmacology Forskolin biology Reverse Transcriptase Polymerase Chain Reaction Colforsin DNA Fibroblasts medicine.disease Cyclic AMP-Dependent Protein Kinases Endocrinology chemistry Cell culture biology.protein Molecular Medicine Collagen Signal transduction Transforming growth factor |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 315(2) |
| ISSN: | 0022-3565 |
| Popis: | Pulmonary fibroblasts regulate extracellular matrix production and degradation; thus, they are critical for maintenance of lung structure, function, and repair. In pulmonary fibrosis, fibroblasts produce excess collagen and form fibrotic foci that eventually impair lung function, but the mechanisms responsible for these alterations are not known. Receptors coupled to the stimulation of cAMP production can inhibit activation of fibroblasts and thereby are antifibrotic. To test whether this signaling pathway is altered in pulmonary fibrosis, we compared the ability of normal adult human pulmonary fibroblasts to generate and respond to cAMP with that of cells isolated from lungs with idiopathic pulmonary fibrosis. Serum- and transforming growth factor (TGF)-beta-stimulated cell proliferation was inhibited approximately 50% by forskolin and approximately 100% by prostaglandin (PG) E(2) in the normal cells but substantially less in the diseased cells. Collagen synthesis was also inhibited50% by the same drugs in the normal cells but significantly less so in the diseased cells, despite responding with similar increases in cAMP production. Although expression of protein kinase A (PKA) and cAMP-stimulated PKA activity were similar in both the normal and diseased cell types, forskolin- and PGE(2)-stimulated cAMP response element-binding protein (CREB) phosphorylation was decreased in the diseased cell lines compared with the normal cells. cAMP-mediated activation and TGF-beta-mediated inhibition of CREB DNA binding was also diminished in the diseased cells. Thus, pulmonary fibroblasts derived from patients with pulmonary fibrosis are refractory to the inhibition by cAMP due to altered activity of components distal to the activity of PKA, in particular the phosphorylation of CREB. |
| Databáze: | OpenAIRE |
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