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Am J Physiol Lung Cell Mol Physiol 277: L174-L182, 1999;
1040-0605/99 $5.00
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Vol. 277, Issue 1, L174-L182, July 1999

Regulation of gelatinases in human airway smooth muscle cells: mechanism of progelatinase A activation

Hussein D. Foda1,2, Suni George1, Ellen Rollo1, Michelle Drews1, Cathleen Conner1, Jian Cao2, Reynold A. Panettieri Jr.3, and Stanley Zucker1,2

1 Department of Medicine and Research, Veterans Affairs Medical Center, Northport 11768; 2 Department of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794-8172; and 3 Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283

Matrix metalloproteinases (MMPs) play an important role in tumor metastasis and invasion, inflammatory tissue destruction and remodeling, wound healing, and angiogenesis. The 72-kDa gelatinase A is the most widely distributed of all the MMPs, and along with the 92-kDa gelatinase B, both play an important role in the turnover of basement membrane. The role of MMPs in chronic airway inflammation and remodeling has received scant attention. In this study, we sought to examine the release and activation of gelatinases from human airway smooth muscle (ASM) cells and the effect of tumor necrosis factor-alpha and phorbol 12-myristate 13-acetate (PMA) on this release and activation. The role of membrane type 1 MMP (MT1-MMP) and tissue inhibitor of MMP (TIMP)-2 in activating progelatinase A has been explored. We have demonstrated, using human airway smooth muscle cells in culture, that 1) ASM releases gelatinase A constitutively and when stimulated with PMA and tumor necrosis factor-alpha releases gelatinase B, and the release of gelatinase B is protein kinase C dependent because it is blocked by H-7 and staurosporin; 2) treatment of ASM cells with PMA or concanavalin A failed to activate progelatinase A despite these agents increasing cell expression of MT1-MMP; and 3) the inability of ASM cell membranes to activate progelatinase A is most likely secondary to the high levels of TIMP-2 on the cell membrane. In conclusion, our results demonstrate that human ASM cells constitutively secrete progelatinase A and when stimulated with proinflammatory mediators secrete gelatinase B. The released gelatinases A and B may be important factors in the airway remodeling that occurs in asthma.

human; matrix metalloproteinase; membrane-type matrix metalloproteinase; tissue inhibitor of matrix metalloproteinase


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