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1 University of Nebraska Medical Center, Omaha, NE, USA and 2 University of Tokyo, Tokyo, Japan
CORRESPONDENCE: S.I. Rennard, University of Nebraska Medical Center, 985125 Nebraska Medical Center, Omaha, NE, USA. Fax: 1 4025594878. E-mail: srennard@unmc.edu
Keywords: Gel contraction, protease-activated receptor, protein kinase C-
, short interfering RNA, thrombin
Received: January 15, 2004
Accepted August 22, 2004
This work was funded by the Larson Endowment, University of Nebraska Medical Center and NIH grant RO1-HL64088.
The ability of fibroblasts to contract three-dimensional collagen gels has been used as an in vitro model of the tissue contraction which characterises both normal repair and fibrosis. Among its actions, thrombin can activate the protease-activated receptor (PAR)1 and, thereby, stimulate inflammation and repair. The current study evaluated whether thrombin could stimulate fibroblast-mediated collagen gel contraction by activating PAR1 and whether its downstream signalling depends on protein kinase C (PKC)-
Human foetal lung fibroblasts (HFL-1) were cultured in three-dimensional collagen gels and the area of the gels was measured by image analyser.
Both thrombin and TFLLR, a selective PAR1 agonist, stimulated collagen gel contraction mediated by HFL-1. After RNA interference-mediated PAR1 knockdown in HFL-1, both thrombin and the PAR1 agonist-induced gel contraction were partially inhibited (by 22.4±2.2% and 17.6±5.6%, respectively). The gel contraction stimulated by thrombin was also reduced by a nonspecific PKC inhibitor and a calcium-independent PKC-
Thrombin stimulates collagen gel contraction at least partially through activation of protease-activated receptor 1 and protein kinase C-
.
inhibitor. Both thrombin and TFLLR significantly increased PKC-
activity, and this effect was blocked by PAR1 knockdown.
, and may contribute to tissue remodelling in inflammatory airway and lung diseases.
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