Platelet-Derived Growth Factor-BB and Thrombin Activate Phosphoinositide 3-Kinase and Protein Kinase B: Role in Mediating Airway Smooth Muscle Proliferation

1998 ◽  
Vol 54 (6) ◽  
pp. 1007-1015 ◽  
Author(s):  
Trevor R. Walker ◽  
Sarah M. Moore ◽  
Mark F. Lawson ◽  
Reynold A. Panettieri ◽  
Edwin R. Chilvers
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Protein Kinase ◽  
Airway Smooth Muscle ◽  
Protein Kinase B ◽  
Platelet Derived Growth Factor ◽  
Smooth Muscle Proliferation ◽  
Phosphoinositide 3 Kinase

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.

scholarly journals Platelet-derived-growth-factor stimulation of the p42/p44 mitogen-activated protein kinase pathway in airway smooth muscle: role of pertussis-toxin-sensitive G-proteins, c-Src tyrosine kinases and phosphoinositide 3-kinase

1999 ◽  
Vol 337 (2) ◽  
pp. 171-177 ◽  
Author(s):  
Ann-Marie CONWAY ◽  
Soma RAKHIT ◽  
Susan PYNE ◽  
Nigel J. PYNE
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Protein Kinase ◽  
G Protein ◽  
Pertussis Toxin ◽  
Mitogen Activated Protein Kinase ◽  
Platelet Derived Growth Factor ◽  
Mapk Activation ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase

The mechanism used by the platelet-derived growth factor receptor (PDGFR) to activate the mitogen-activated- protein-kinase (p42/p44 MAPK) pathway was investigated in cultured airway smooth muscle (ASM) cells. We have found that pertussis toxin (PTX, which was used to inactivate the heterotrimeric G-protein Gi) induced an approx. 40–50% decrease in the activation of c-Src and p42/p44 MAPK by PDGF. An essential role for c-Src was confirmed using the c-Src inhibitor, PP1, which abolished p42/p44 MAPK activation (PP1 and PTX were without effect on PDGFR tyrosine phosphorylation). Furthermore, the PTX-dependent decrease in c-Src and p42/p44 MAPK activation appeared correlated. These findings suggest that the PDGFR can utilize the PTX-sensitive G-protein, Gi, to regulate c-Src and subsequent p42/p44 MAPK activation. Phosphoinositide 3-kinase (PI3K) has been shown by others to be involved in p42/p44 MAPK activation. This is confirmed here by experiments which showed that PI3K inhibitors (wortmannin and LY294002) reduced the activation of p42/p44 MAPK by PDGF. PI3K activity was increased in Grb-2 immunoprecipitates from PDGF-stimulated cells and was decreased by pretreating these cells with PTX. These findings show that Gi might also promote Grb-2–PI3K complex formation and that Grb-2 may be a site at which PI3K is integrated into the p42/p44 MAPK cascade. In conclusion, our results demonstrate that Gi enables the PDGFR to signal more efficiently to p42/p44 MAPK, and this appears to be achieved through the regulation of c-Src and Grb-2/PI3K, which are intermediates in the p42/p44 MAPK cascade.

In VivoRole of Platelet-Derived Growth Factor–BB in Airway Smooth Muscle Proliferation in Mouse Lung

2011 ◽  
Vol 45 (3) ◽  
pp. 566-572 ◽  
Author(s):  
Jeremy A. Hirota ◽  
Kjetil Ask ◽  
Laszlo Farkas ◽  
Jane Ann Smith ◽  
Russ Ellis ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Airway Smooth Muscle ◽  
Platelet Derived Growth Factor ◽  
Mouse Lung ◽  
Smooth Muscle Proliferation
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