| Autor: |
Burgess, Heather A., Daugherty, Louis Eugene, Thatcher, Thomas H., Lakatos, Heather F., Ray, Denise M., Redonnet, Michelle, Phipps, Richard P., Sime, Patricia J. |
| Předmět: |
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| Zdroj: |
American Journal of Physiology: Lung Cellular & Molecular Physiology; Jun2005, Vol. 288, pL1146-L1153, 7p, 18 Color Photographs, 5 Graphs |
| Abstrakt: |
Pulmonary fibrosis is a progressive life-threatening disease for which no effective therapy exists. Myofibroblasts are one of the key effector cells in pulmonary fibrosis and are the primary source of extracellular matrix production. Drugs that inhibit the differentiation of fibroblasts to myofibroblasts have potential as antifibrotic therapies. Peroxisome proliferator-activated receptor (PPARγ is a transcription factor that upon ligation with PPARγ agonists activates target genes containing PPAR response elements. PPARγ agonists have anti-inflammatory activities and may have potential as antifibrotic agents. In this study, we examined the abilities of PPARγ agonists to block two of the most important profibrotic activities of TGF-β on pulmonary fibroblasts: myofibroblast differentiation and production of excess collagen. Both natural (15d-PGJ2) and synthetic (ciglitazone and rosiglitaz one) PPARγ agonists inhibited TGF-β-driven myofibroblast differentiation, as determined by a-smooth muscle actin-specific immunocytochemistry and Western blot analysis. PPARγ agonists also potently attenuated TGF-β-driven type I collagen protein production. A dominant-negative PPARγ partially reversed the inhibition of myofibroblast differentiation by 15d-PGJ2 and rosiglitazone, but the irreversible PPARγ antagonist GW-9662 did not, suggesting that the antifibrotic effects of the PPARγ agonists are mediated through both PPARγ-dependent and independent mechanisms. Thus PPARγ agonists have novel and potent antifibrotic effects in human lung fibroblasts and may have potential for therapy of fibrotic diseases in the lung and other tissues. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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