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1 Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA
2 Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA
* To whom correspondence should be addressed. E-mail: rostrom{at}utmem.edu.
Pulmonary fibroblasts are recruited to sites of lung injury where they are activated to produce extracellular matrix proteins and to facilitate repair. However, these cells become dysregulated in pulmonary fibrosis, producing excess collagen at sites of injury and forming fibrotic loci that impair lung function. In this study, we used WI-38 human lung fibroblasts and evaluated the ability of G protein-coupled receptor agonists to increase cAMP production and regulate cell proliferation and collagen synthesis. WI-38 cells increase cAMP in response to the 
-adrenergic agonist isoproterenol (Iso), prostaglandin E2 (PGE2), certain prostanoid receptor-selective agonists (beraprost, butaprost), an adenosine receptor agonist and the direct adenylyl cyclase (AC) activator, forskolin. Responses to Iso, PGE2, and forskolin were studied in more detail. Each induced a dose-dependent inhibition of serum-stimulated cell proliferation (as measured by [3H]thymidine incorporation) and collagen synthesis (as measured by [3H]proline incorporation, collagenase-sensitive [3H]proline incorporation or levels of procollagen type 1 C-peptide). Quantitative RT-PCR analyses indicated that elevation in cellular cAMP levels decrease expression of collagen types 1
(II) and 5(I) and increase expression and activity of matrix metalloproteinase 2 (MMP2). Over-expression of adenylyl cyclase type 6 or inhibition of cyclic nucleotide phosphodiesterases also increased cellular cAMP levels and decreased cell proliferation and collagen synthesis. Thus, multiple approaches that increase cAMP signaling reduce proliferation and differentiated function in human pulmonary fibroblasts. These results suggest that therapies that raise cAMP levels may prove useful in the treatment of pulmonary fibrosis.
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