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Am. J. Respir. Cell Mol. Biol., Volume 26, Number 6, June, 2002 694-701

PDE4 Inhibitors Attenuate Fibroblast Chemotaxis and Contraction of Native Collagen Gels

Tadashi Kohyama, Xiangde Liu, Fu-Qiang Wen, Yun Kui Zhu, Hangjun Wang, Hui Jung Kim, Hajime Takizawa, Lenora B. Cieslinski, Mary S. Barnette, and Stephen I. Rennard

University of Nebraska Medical Center, Omaha, Nebraska; Jincheng Hospital, Lanzhou, China; Mount Sinai Hospital, Toronto, Ontario, Canada; Tokyo University School of Medicine, Tokyo, Japan; and GlaxoSmithKline, King of Prussia, Pennsylvania

Therapies that mitigate the fibrotic process may be able to slow progressive loss of function in many lung diseases. Because cyclic adenosine monophosphate is known to regulate fibroblasts, the current study was designed to evaluate the activity of selective phosphodiesterase (PDE) inhibitors on two in vitro fibroblast responses: chemotaxis and contraction of three-dimensional collagen gels. Selective PDE4 inhibitors, rolipram and cilomilast, each inhibited the chemotaxis of human fetal lung fibroblasts (HFL-1) toward fibronectin in the blindwell assay system (control: 100% versus cilomilast [10 µM]: 40.5 ± 7.3% versus rolipram: [10 µM] 32.1 ± 2.7% cells/5 high-power fields; P < 0.05, both comparisons). These PDE4 inhibitors also inhibited contraction of three-dimensional collagen gels (control: 100% versus cilomilast: 167.7 ± 6.9% versus rolipram: 129.9 ± 1.9% of initial size; P < 0.05, both comparisons). Amrinone, a PDE3 inhibitor, and zaprinast, a PDE5 inhibitor, had no effect in either system. Prostaglandin E2 (PGE2) inhibited both chemotaxis and gel contraction, and the PDE4 inhibitors shifted the PGE2 concentration-dependence curve to the left in both systems. The inhibition of endogenous PGE2 production by indomethacin diminished the effects of the PDE4 inhibitors in both chemotaxis and gel contraction, consistent with the concept that the PDE4 inhibitory effects on fibroblasts are related to the presence of cyclic adenosine monophosphate in the cells. In summary, these in vitro results suggest that PDE4 inhibitors may be able to suppress fibroblast activity and, thus, have the potential to block the development of progressive fibrosis.

Abbreviations: one-way analysis of variance, ANOVA; cyclic adenosine monophosphate, cAMP; chronic obstructive pulmonary disease, COPD; Dulbecco's modified Eagle's medium, DMEM; fetal calf serum, FCS; human fetal lung fibroblasts, HFL-1; phosphodiesterase, PDE; prostaglandin E2, PGE2; reverse transcriptase-polymerase chain reaction, RT-PCR; rat tail tendon collagen, RTTC; standard error of the mean, SEM.




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