PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels

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

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

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 E 2 (PGE 2 ) inhibited both chemotaxis and gel contraction, and the PDE4 inhibitors shifted the PGE 2 concentration-dependence curve to the left in both systems. The inhibition of endogenous PGE 2 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.

Original languageEnglish (US)
Pages (from-to)694-701
Number of pages8
JournalAmerican journal of respiratory cell and molecular biology
Volume26
Issue number6
DOIs
StatePublished - Jan 1 2002

Fingerprint

Phosphodiesterase 4 Inhibitors
Chemotaxis
Fibroblasts
Rolipram
Collagen
Gels
Prostaglandins E
Cyclic AMP
Phosphodiesterase 3 Inhibitors
Amrinone
Phosphodiesterase 5 Inhibitors
Pulmonary diseases
Phosphodiesterase Inhibitors
Fibronectins
Indomethacin
Lung Diseases
Assays
Fibrosis
Control systems
Lung

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels. / Kohyama, Tadashi; Liu, Xiang-de; Wen, Fu Qiang; Yun, Kui Zhu; Wang, Hangjun; Hui, Jung Kim; Takizawa, Hajime; Cieslinski, Lenora B.; Barnette, Mary S.; Rennard, Stephen I.

In: American journal of respiratory cell and molecular biology, Vol. 26, No. 6, 01.01.2002, p. 694-701.

Research output: Contribution to journalArticle

Kohyama, T, Liu, X, Wen, FQ, Yun, KZ, Wang, H, Hui, JK, Takizawa, H, Cieslinski, LB, Barnette, MS & Rennard, SI 2002, 'PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels', American journal of respiratory cell and molecular biology, vol. 26, no. 6, pp. 694-701. https://doi.org/10.1165/ajrcmb.26.6.4743
Kohyama, Tadashi ; Liu, Xiang-de ; Wen, Fu Qiang ; Yun, Kui Zhu ; Wang, Hangjun ; Hui, Jung Kim ; Takizawa, Hajime ; Cieslinski, Lenora B. ; Barnette, Mary S. ; Rennard, Stephen I. / PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels. In: American journal of respiratory cell and molecular biology. 2002 ; Vol. 26, No. 6. pp. 694-701.
@article{a542c477e54b48819d629198801104a6,
title = "PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels",
abstract = "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 E 2 (PGE 2 ) inhibited both chemotaxis and gel contraction, and the PDE4 inhibitors shifted the PGE 2 concentration-dependence curve to the left in both systems. The inhibition of endogenous PGE 2 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.",
author = "Tadashi Kohyama and Xiang-de Liu and Wen, {Fu Qiang} and Yun, {Kui Zhu} and Hangjun Wang and Hui, {Jung Kim} and Hajime Takizawa and Cieslinski, {Lenora B.} and Barnette, {Mary S.} and Rennard, {Stephen I.}",
year = "2002",
month = "1",
day = "1",
doi = "10.1165/ajrcmb.26.6.4743",
language = "English (US)",
volume = "26",
pages = "694--701",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "6",

}

TY - JOUR

T1 - PDE4 inhibitors attenuate fibroblast chemotaxis and contraction of native collagen gels

AU - Kohyama, Tadashi

AU - Liu, Xiang-de

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.

PY - 2002/1/1

Y1 - 2002/1/1

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 E 2 (PGE 2 ) inhibited both chemotaxis and gel contraction, and the PDE4 inhibitors shifted the PGE 2 concentration-dependence curve to the left in both systems. The inhibition of endogenous PGE 2 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 E 2 (PGE 2 ) inhibited both chemotaxis and gel contraction, and the PDE4 inhibitors shifted the PGE 2 concentration-dependence curve to the left in both systems. The inhibition of endogenous PGE 2 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.

UR - http://www.scopus.com/inward/record.url?scp=0036014828&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036014828&partnerID=8YFLogxK

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 -