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Pulmonary, Critical Care, and Sleep Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., University of Nebraska Medical Center, 985885 Nebraska Medical Center, Omaha, NE 68198-5885. E-mail: srennard{at}unmc.edu
Transforming growth factor (TGF)-ß1 regulates mesenchymal cell profibrotic responses. It also stimulates synthesis of prostaglandin E2 (PGE2), which may function to limit its actions by autocrine/paracrine feedback mechanisms. PGE inhibits fibroblasts through stimulation of cAMP. Phosphodiesterase 4 (PDE4) is present in fibroblasts and mediates degradation of cAMP to AMP. Therefore, we hypothesized that PDE4 inhibitors would modulate fibroblast response to TGF-ß1. The effects of the PDE4 inhibitors roflumilast and rolipram on human fetal lung fibroblast (HFL-1) chemotaxis in the presence and absence of TGF-ß1 and indomethacin were evaluated by Boyden's blind-well chamber technique. Similarly, the effect of PDE4 inhibitors on TGF-ß1–induced gel contraction was determined on HFL-1 cells cultured in three-dimensional type I collagen gels in serum-free medium by an image analysis system. In addition, the release of TGF-ß1, fibronectin, and PGE2 into fibroblast culture medium was quantified by ELISA. In the presence of TGF-ß1, PDE4 inhibitors decreased fibroblast migration (TGF-ß1, 119 ± 4%, vs. TGF-ß1 + roflumilast, 64 ± 3% [p < 0.001], vs. TGF-ß1 + rolipram, 63% ± 9 [p < 0.05]) and inhibited collagen gel contraction (TGF-ß1, 39.7 ± 2.2%, vs. TGF-ß1 + roflumilast, 46.2 ± 3.0 [p < 0.03], vs. TGF-ß1 + rolipram, 47.3 ± 3.7 [p < 0.04]). The relative effect of roflumilast (10–6 M) and rolipram (10–5 M) was almost the same. The magnitude of the effect of the PDE inhibitors was greater in the presence of TGF-ß1 and was blocked by indomethacin. PDE4 inhibitors also increased PGE2 release and decreased fibronectin release in the presence of TGF-ß1. In contrast, PDE4 inhibitors did not affect TGF-ß1 release. PDE4 inhibition attenuates TGF-ß1 stimulation of fibroblast chemotaxis and collagen gel contraction. Two related mechanisms appear to be involved: (1) potentiation of PGE2 release and (2) augmentation of cAMP feedback regulation of fibroblast activity.
FOOTNOTES
Conflict of Interest Statement: S.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. X.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.F.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.J.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.I.R. has participated as a speaker in scientific meetings and courses under the sponsorship of AstraZeneca and GlaxoSmithKline (GSK). He serves on advisory boards for Altana, AstraZeneca, Dey, GSK, and Inspire. He has conducted clinical trials for AstraZeneca, Centocor, GSK, Pfizer, Roche, and Sanofi. He has served as a consultant for AstraZeneca, GSK, Novartis, Pfizer, and Roche. A patent is pending on the use of PDE4 inhibitors in repair; he is a coinventor of the patent owned by the University of Nebraska Medical Center.
(Received in original form March 17, 2006; accepted in final form March 28, 2006)
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