Synergistic Stimulation of Airway Smooth Muscle Cell Mitogenesis1
Abstract
Previous studies showed that human airway smooth muscle (HASM) cells treated with lysophosphatidic acid (LPA), a pertussis toxin (PTX)-sensitive G protein-coupled (GPC) mitogen, simultaneously with epidermal growth factor (EGF), a receptor tyrosine kinase (RTK) mitogen, exhibit markedly synergistic stimulation of mitogenesis. We now show that the RTK mitogens basic fibroblast growth factor, insulin-like growth factor-1, insulin, platelet-derived growth factor-AA, and platelet-derived growth factor-BB, as well as transforming growth factor-β, all induced synergistic stimulation of mitogenesis in the presence of LPA. The PTX-sensitive GPC mitogens carbachol and endothelin-1 and the PTX-insensitive GPC mitogens sphingosine-1-phosphate and thrombin exhibited synergistic stimulation together with EGF. Several RTK-RTK growth factor pairs and GPC-GPC mitogen pairs were also synergistic. HASM cells showed synergistic responses to serum plus EGF but not to serum plus LPA. Testing various other cell types showed that synergism between LPA and EGF occurred in other smooth muscle cells because both vascular smooth muscle cells and mesangial cells exhibited synergism. Additionally, human fetal lung fibroblasts also showed striking synergism. These results indicate that HASM cells can respond synergistically to a wide variety of mitogen combinations and that this synergism is a feature shared with other contractile cell types.
Footnotes
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Send reprint requests to: Myron L. Toews, Ph.D. Department of Pharmacology, 986260 Nebraska Medical Center, Omaha, NE 68198-6260. E-mail: mtoews{at}unmc.edu
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↵1 This work was supported in part by research seed grants from the University of Nebraska Medical Center (to M.L.T.) and a University of Nebraska Medical Center McDonald Fellowship (to T.L.E).
- Abbreviations:
- LPA
- lysophosphatidic acid
- GPC
- G protein-coupled
- EGF
- epidermal growth factor
- RTK
- receptor tyrosine kinase
- HASM
- human airway smooth muscle
- FGF
- fibroblast growth factor
- PDGF
- platelet-derived growth factor
- DMEM
- Dulbecco's modified Eagle's medium
- FBS
- fetal bovine serum
- bFGF
- basic fibroblast growth factor
- TGF-β
- transforming growth factor-β
- PTX
- pertussis toxin
- IGF-1
- insulin-like growth factor-1
- HFL-1
- human fetal lung fibroblasts
- HFF
- human foreskin fibroblasts
- VSM
- vascular smooth muscle
- HMC
- human mesangial cell
- S1P
- sphingosine-1-phosphate
- CCh
- carbachol
- ET-1
- endothelin-1
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- Received January 6, 2000.
- Accepted May 9, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
