TY - JOUR
T1 - PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels
AU - Kohyama, Tadashi
AU - Liu, Xiangde
AU - Wen, Fu Qiang
AU - Yun, Kui Zhu
AU - Wang, Hangjun
AU - Hui, Jung Kim
AU - Takizawa, Hajime
AU - Cieslinski, Lenora B.
AU - Barnette, Mary S.
AU - Rennard, Stephen I.
N1 - Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2002
Y1 - 2002
N2 - 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 blind-well 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.
AB - 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 blind-well 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.
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U2 - 10.1165/ajrcmb.26.6.4743
DO - 10.1165/ajrcmb.26.6.4743
M3 - Article
C2 - 12034568
AN - SCOPUS:0036014828
VL - 26
SP - 694
EP - 701
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 6
ER -