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Am J Physiol Lung Cell Mol Physiol 280: L999-L1008, 2001;
1040-0605/01 $5.00
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Vol. 280, Issue 5, L999-L1008, May 2001

Release of biologically active TGF-beta from airway smooth muscle cells induces autocrine synthesis of collagen

Amanda Coutts1,*, Gang Chen2,*, Newman Stephens3, Stuart Hirst4, Deborah Douglas1,2, Thomas Eichholtz5, and Nasreen Khalil1,2

1 Department of Medicine and Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba R3E 0V9; 2 Vancouver Hospital, University of British Columbia, Vancouver, British Columbia V6H 3Z6; 3 Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada R3A 1R9; 4 The Guy's King's College and St. Thomas' School of Medicine, King's College London, London SE1 9RT; and 5 Glaxo Wellcome, Stevenage SG1 2NY, United Kingdom

In severe or chronic asthma, there is an increase in airway smooth muscle cell (ASMC) mass as well as an increase in connective tissue proteins in the smooth muscle layer of airways. Transforming growth factor-beta (TGF-beta ) exists in three isoforms in mammals and is a potent regulator of connective tissue protein synthesis. Using immunohistochemistry, we had previously demonstrated that ASMCs contain large quantities of TGF-beta 1-3. In this study, we demonstrate that bovine ASMC-derived TGF-beta associates with the TGF-beta latency binding protein-1 (LTBP-1) expressed by the same cells. The TGF-beta associated with LTBP-1 localizes TGF-beta extracellularly. Furthermore, plasmin, a serine protease, regulates the secretion of a biologically active form of TGF-beta by ASMCs as well as the release of extracellular TGF-beta . The biologically active TGF-beta released by plasmin induces ASMCs to synthesize collagen I in an autocrine manner. The autocrine induction of collagen expression by ASMCs may contribute to the irreversible fibrosis and remodeling seen in the airways of some asthmatics.

plasmin; bovine; transforming growth factor-beta latency binding protein-1; fibrosis; remodeling

* Amanda Coutts and Gang Chen contributed equally to this work.
  Address for reprint requests and other correspondence: N. Khalil, Division of Respiratory Medicine, Univ. of British Columbia, 655 West 12th Ave., Vancouver, BC, Canada V5Z 4R4 (E-mail: nasreen.khalil{at}bccdc.hnet.bc.ca).




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