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Published ahead of print on July 20, 2006, doi:10.1165/rcmb.2005-0026OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 6, December 2006, 714-721

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Submitted on January 14, 2005
Revised on July 18, 2006

Thrombin and TNF-{alpha}/IL-1{beta} Synergistically Induce Fibroblast Mediated Collagen Gel Degradation

Qiuhong Fang1, Xiangde Liu2, Mona Al-Mugotir2, Tetsu Kobayashi2, Shinji Abe3, Tadashi Kohyama4, and Stephen I Rennard2*

1 Pulmonary and Critical Care Department, First Hospital of Tsinghua University, Beijing, China, 2 Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA, 3 Pulmonary Division, Department of Internal Medicine, Seoul Adventist Hospital, Seoul, Korea, Republic of, 4 Department of Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

* To whom correspondence should be addressed. E-mail: srennard{at}unmc.edu.

Degradation of pre-existing and newly synthesized extracellular matrix (ECM) is thought to play an important role in tissue remodeling. The current study evaluated whether thrombin and TNF{alpha}/IL-1{beta} could collaboratively induce collagen degradation by human fetal lung fibroblasts (HFL-1) and adult bronchial fibroblasts cultured in three-dimensional collagen gels. TNF{alpha}/IL-1{beta} alone induced production of MMPs (MMP-1, MMP-3 and MMP-9), which were released in latent form. With the addition of thrombin, the latent MMPs were converted into active forms and this resulted in collagen gel degradation. Part of the activation of MMPs by thrombin resulted from direct activation of MMP-1, MMP-2, MMP-3 and MMP-9 in the absence of cells. In addition, TIMP-1 production was inhibited by the combination of thrombin and TNF{alpha}/IL-1{beta}. These results suggest that thrombin and TNF{alpha}/IL-1{beta} synergize to induce degradation of three-dimensional collagen gels through increasing the production and activation of MMPs, and that this effect is mediated through both direct activation of MMPs by thrombin and indirectly by thrombin activation of fibroblasts. Through such mechanisms, thrombin could contribute to many chronic lung disorders characterized by tissue remodeling.




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