Autocrine production of matrix metalloproteinase-2 is required for human airway smooth muscle proliferation

1999 ◽  
Vol 277 (6) ◽  
pp. L1109-L1117 ◽  
Author(s):  
Simon Johnson ◽  
Alan Knox
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Airway Smooth Muscle ◽  
Fetal Bovine Serum ◽  
Platelet Derived Growth Factor ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Smooth Muscle Proliferation ◽  
Fetal Bovine

Airway smooth muscle proliferation is important in asthma and is dependent on pro- and antimitogenic factors and cell-matrix interactions. Here we show an antiproliferative effect of protease inhibitors on human airway smooth muscle due to inhibition of autocrine-derived matrix metalloproteinase (MMP)-2. Proliferation in response to fetal bovine serum, thrombin, and platelet-derived growth factor was inhibited by the broad-spectrum protease inhibitor Complete and the MMP inhibitors EDTA and Ro-31-9790 but not by cysteine or serine protease inhibitors. Conditioned medium from airway smooth muscle cells contained 72-kDa gelatinase that was secreted by growth-arrested cells and increased by fetal bovine serum but not by thrombin or platelet-derived growth factor. Immunostaining of cultured human airway smooth muscle cells and normal lung biopsies confirmed this gelatinase to be MMP-2. Our results suggest a novel role for MMP-2 as an important autocrine factor required for airway smooth muscle proliferation. Inhibition of MMPs could provide a target for the prevention of smooth muscle hyperplasia and airway remodeling in asthma.

Tryptase's potent mitogenic effects in human airway smooth muscle cells are via nonproteolytic actions

2002 ◽  
Vol 282 (2) ◽  
pp. L197-L206 ◽  
Author(s):  
James K. Brown ◽  
Cary A. Jones ◽  
Leeann A. Rooney ◽  
George H. Caughey ◽  
Ian P. Hall
Keyword(s):  
Mast Cell ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Dna Synthesis ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway

We reported previously that mast cell tryptase is a growth factor for dog tracheal smooth muscle cells. The goals of our current experiments were to determine if tryptase also is mitogenic in cultured human airway smooth muscle cells, to compare its strength as a growth factor with that of other mitogenic serine proteases, and to determine whether its proteolytic actions are required for mitogenesis. Highly purified preparations of human lung β-tryptase (1–30 nM) caused dose-dependent increases in DNA synthesis in human airway smooth muscle cells. Maximum tryptase-induced increases in DNA synthesis far exceeded those occurring in response to coagulation cascade proteases, such as thrombin, factor Xa, or factor XII, or to other mast cell proteases, such as chymase or mastin. Irreversibly abolishing tryptase's catalytic activity did not alter its effects on increases in DNA synthesis. We conclude that β-tryptase is a potent mitogenic serine protease in cultured human airway smooth muscle cells. However, its growth stimulatory effects in these cells occur predominantly via nonproteolytic actions.

scholarly journals IGFBP-3 mediates TGF-β1-induced cell growth in human airway smooth muscle cells

2000 ◽  
Vol 278 (3) ◽  
pp. L545-L551 ◽  
Author(s):  
Pinchas Cohen ◽  
Roopmathy Rajah ◽  
Joel Rosenbloom ◽  
David J. Herrick
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Cell Growth ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Tgf Β1 ◽  
Igfbp 3

Both insulin-like growth factor binding protein-3 (IGFBP-3) and transforming growth factor-β (TGF-β) have been separately shown to have cell-specific growth-inhibiting or growth-potentiating effects. TGF-β stimulates IGFBP-3 mRNA and peptide expression in several cell types, and TGF-β-induced growth inhibition and apoptosis have been shown to be mediated through the induction of IGFBP-3. However, a link between the growth stimulatory effects of TGF-β and IGFBP-3-induction has not been shown. In this study, we investigated the role of IGFBP-3 in mediating TGF-β1-induced cell growth using human airway smooth muscle (ASM) cells as our model. TGF-β1 (1 ng/ml) treatment induced a 10- to 20-fold increase in the levels of expression of IGFBP-3 mRNA and protein. Addition of either IGFBP-3 or TGF-β1 to the growth medium resulted in an approximately twofold increase in cell proliferation. Coincubation of ASM cells with IGFBP-3 antisense (but not sense) oligomers as well as with an IGFBP-3 neutralizing antibody (but not with control IgG) blocked the growth induced by TGF-β1 ( P < 0.001). Several IGFBP-3-associated proteins were observed in ASM cell lysates, which may have a role in the cellular responses to IGFBP-3. These findings demonstrate that IGFBP-3 is capable of mediating the growth stimulatory effect of TGF-β in ASM cells.

Interleukin-4 inhibits mitogen-induced proliferation of human airway smooth muscle cells in culture

1998 ◽  
Vol 275 (3) ◽  
pp. L469-L477 ◽  
Author(s):  
Kristen M. Hawker ◽  
Peter R. A. Johnson ◽  
J. Margaret Hughes ◽  
Judith L. Black
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Cyclin D1 ◽  
Airway Smooth Muscle ◽  
D1 Protein ◽  
Interleukin 4 ◽  
Airway Smooth Muscle Cells ◽  
Intracellular Camp ◽  
Human Airway Smooth Muscle ◽  
Human Airway

The increase in the amount of airway smooth muscle in the bronchial wall associated with asthma is partly due to hyperplasia. It is therefore important to determine which factors regulate growth and especially proliferation. In this study, we describe the effect of interleukin-4 (IL-4), a mast cell- and T lymphocyte-derived cytokine, on human airway smooth muscle proliferation as determined by [3H]thymidine uptake in the presence of fetal bovine serum (FBS), platelet-derived growth factor, basic fibroblast growth factor, and thrombin. IL-4 (5, 15, 50, and 150 ng/ml) significantly decreased 10% FBS-induced proliferation by 50, 73, 43, and 46%, respectively. The proliferative responses to platelet-derived growth factor (20 and 40 ng/ml), basic fibroblast growth factor (30 ng/ml), and thrombin (1 and 10 U/ml) were significantly reduced by 19, 21, 37, 36, and 57% respectively in the presence of 50 ng/ml of IL-4. We investigated the effect of IL-4 and other known inhibitors of smooth muscle proliferation, namely PGE2, heparin, and forskolin, on intracellular cAMP concentrations. IL-4 (50 ng/ml) and heparin (100 U/ml) did not alter intracellular cAMP levels when cells were treated with 1 or 10% FBS. PGE2 (1 μM) and forskolin (10 μM) significantly increased cAMP concentration above the control value in nonproliferating cells (1% FBS treated) by 7- and 37-fold, respectively. The effect of IL-4 (50 ng/ml), PGE2 (1 μM), and forskolin (10 μM) on cyclin D1 protein expression in 10% FBS-stimulated human airway smooth muscle cells was also examined. PGE2 and forskolin did not significantly inhibit cyclin D1 expression. However, IL-4 decreased cyclin D1 expression by 21%. These results provide evidence that IL-4 decreases human airway smooth muscle cell proliferation via a mechanism that is cAMP independent and mediated, in part, by a decrease in cyclin D1 protein expression.

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