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Published ahead of print on May 8, 2003, doi:10.1165/rcmb.2002-0243OC

Am. J. Respir. Cell Mol. Biol., Volume 29, Number 5, November 2003, 537-544

A more recent version of this article appeared on November 1, 2003
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Submitted on November 12, 2002
Revised on May 7, 2003

PGE2 Inhibits Fibroblast to Myofibroblast Transition via EP2 Signaling and cAMP Elevation

Jill E Kolodsick1, Marc Peters-Golden1, Jose Larios1, Galen B Toews1, Victor J Thannickal1, and Bethany B Moore1*

1 Internal Medicine, University of Michigan, Ann Arbor, MI, USA

* To whom correspondence should be addressed. E-mail: bmoore{at}umich.edu.

Myofibroblasts, the hallmark of fibrotic disease, contribute to the pathology of fibrosis by secreting large amounts of extracellular matrix and contributing to alveolar contraction. Myofibroblasts are characterized by the expression of {alpha}-smooth muscle actin ({alpha}-SMA), a contractile protein normally associated with smooth muscle cells. Transforming growth factor-{beta}1 (TGF-{beta}1) is a well characterized pro-fibrotic cytokine that induces myofibroblast transformation both in vitro and in vivo. We report here that the lipid mediator prostaglandin E2 (PGE2) inhibits TGF-{beta}1-induced expression of {alpha}-SMA in primary fetal and adult lung fibroblasts. This inhibition of {alpha}-SMA expression is associated with a reduction in the expression of collagen I. Inhibitory actions of PGE2 are mediated via E prostanoid receptor 2 (EP2), but not EP3, signaling and increases in cAMP production. The inhibitory effects of PGE2 on TGF-{beta}1 induced {alpha}-SMA expression are mimicked by an EP2 selective agonist, butaprost, and by forskolin-induced direct activation of adenyl cyclase. An EP2 antagonist blocks the inhibitory effects of PGE2, and an EP3 agonist does not inhibit TGF-{beta}1-mediated increases in {alpha}-SMA expression. Our results demonstrate that PGE2 inhibits transition of fibroblasts to myofibroblasts by an EP2 receptor-activated pathway. Augmenting this pathway may serve as a potent anti-fibrotic therapeutic strategy.




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