Published ahead of print on March 15, 2007, doi:10.1165/rcmb.2007-0009OC Am. J. Respir. Cell Mol. Biol., Volume 37, Number 1, July 2007, 113-120 A more recent version of this article appeared on July 1, 2007
Submitted on January 11, 2007 Prostacyclin Analogues Inhibit Fibroblast Contraction of Collagen Gels Through the cAMP-PKA PathwayKoichiro Kamio1,1 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, NE, USA, 2 Third Department of Internal Medicine, Wakayama Medical Unviersity, Wakayama, Japan, 3 The Third Department of Internal Medicine, Mie University Graduate School of Medicine, Mie, Japan, 4 Department of Rheumatolgoy, The Third Hospital of Peking University, Beijing, China, 5 Department of Pathology, Immunology Program, University of Michigan Medical School, Ann Arbor, MI, USA, 6 Department of Pharmacolgoy, University of Nebraska Medical Center, Omaha, NE, USA * To whom correspondence should be addressed. E-mail: srennard{at}unmc.edu.
Prostacyclin is an arachidonic acid metabolite that modulates vascular tone within the lung. The current study evaluated the hypothesis that prostacyclin can also modulate tissue remodeling by affecting fibroblast-mediated contraction of extracellular matrix. To accomplish this, fibroblasts were cultured in three-dimensional native type I collagen gels in the presence of prostacyclin analogues: carbaprostacyclin, iloprost and beraprost. All three analogues significantly inhibited contraction of the three-dimensional collagen gels mediated by three different fibroblasts. All three analogues significantly inhibited fibronectin release and reduced fibroblast fibronectin mRNA expression. Addition of exogenous fibronectin restored the contractile activity to fibroblasts incubated in the presence of all three analogues. Iloprost and beraprost significantly activated cAMP-dependent protein kinase-A (PKA), and an action through this pathway was confirmed by blockade of the inhibitory effect on contraction and fibronectin release with the PKA inhibitor KT-5720. In contrast, carbaprostacyclin, which is not as selective for the prostacyclin (IP) receptor, did not activate PKA, and its effects on contraction and fibronectin release were not fully blocked by KT-5720. Finally, the cAMP analogues N6-Benzoyl- (6-Bnz-) cAMP and dibutyryl-cAMP inhibited contraction, and this contrasted with the activity of an Epac selective agonist 8-pCPT-2'-O-Me-cAMP, which had no effect. Taken together, these results indicate that prostacyclin, acting through the IP receptor and by activating PKA, can lead to inhibition of fibronectin release and can subsequently inhibit fibroblast-mediated collagen gel contraction. The ability of prostacyclin to modulate fibroblast function suggests that prostacyclin can contribute to tissue remodeling.
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