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Phosphodiesterase Inhibitor Attenuation of Fibroblast Chemotaxis Depends on Endogenous Prostaglandin Production* FREE TO VIEW

Tadashi Kohyama, MD; Xiangder Liu, MD; Yunkui Zhu, MD; Fu-Qiang Wen, MD, PhD; Hangjun Wang, MD; Stephen I. Rennard, MD, FCCP
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*From the University of Nebraska Medical Center, Omaha, NE.

Correspondence to: Tadashi Kohyama, MD, Pulmonary and Critical Care Medicine Section, Department of Internal Medicine, University of Nebraska Medical Center, 600 South 42nd St, Omaha, NE 68198-5300

Chest. 2001;120(1_suppl):S14-S15. doi:10.1378/chest.120.1_suppl.S14
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Fibroblasts are the major source of extracellular connective tissue matrix, and the recruitment and activation of these cells are thought to play an important role in wound healing and in the development of fibrosis. Agents that could block fibroblast accumulation could play a therapeutic role in modulating fibrosis. Previous studies have demonstrated that the phosphodiesterase 4 (PDE4) inhibitor SB207499 (Ariflo; Smith Kline Beecham; King of Prussia, PA) can attenuate fibroblast chemotaxis toward the chemoattractant fibronectin. Since the activity of a PDE4 inhibitor should be dependent on endogenous cyclic adenosine monophosphate levels, the current study was designed to determine if endogenous prostaglandin production rendered cells susceptible to the effects of Ariflo. To accomplish this, human fetal lung fibroblasts were cultured and, after achieving confluence, were incubated for 60 min with and without indomethacin (2 × 10−6 mol/L) to inhibit cyclooxygenase. Fibroblasts were then trypsinized and placed in the upper portion of a Boyden blindwell chemotaxis chamber. Fibronectin, 20 μg/mL, was placed in the lower portion of the chamber as the chemoattractant. Indomethacin (2 × 10−6 mol/L) was added to the upper side of the chemotaxis chamber. Indomethacin alone resulted in a slight but variable stimulation of chemotaxis (159 ± 33% compared to control p < 0.05). Ariflo added to control fibroblasts inhibited chemotaxis in a concentration-dependent manner. In three separate experiments, the concentration of Ariflo required to inhibit chemotaxis by 50% was 4.9 ± 2.5 μg/mL. In the presence of indomethacin, Ariflo inhibited chemotaxis only at the highest concentration tested, 10 μg/mL, reducing the response to 58.7 ± 21.0% of control (p < 0.005) compared to indomethacin. The current study, therefore, demonstrates that the PDE4 inhibitor Ariflo is dependent, at least in part, on endogenous cyclooxygenase activity and, presumably, prostaglandin production in order to exert its inhibitory effect on fibroblast chemotaxis. That Ariflo is active even in the presence of indomethacin suggests alternate mechanisms for stimulating cyclic adenosine monophosphate may also play a role. Since cyclooxygenase activity and prostaglandin production can be modulated by a variety of mediators present in an inflammatory milieu, fibroblasts in such a setting may be particularly sensitive to the inhibitory effects of Ariflo. Such an effect may have therapeutic potential in fibrotic disorders.

Abbreviation: PDE4 = phosphodiesterase 4




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