Effect of tyrosine kinase inhibition on surfactant protein A gene expression during human lung development
| Autor: | Troy A. McCarthy, Louis J. Dewild, Jonathan M. Klein |
|---|---|
| Rok vydání: | 1998 |
| Předmět: |
Pulmonary and Respiratory Medicine
Pulmonary Surfactant-Associated Proteins Physiology Proteolipids Gene Expression Protein tyrosine phosphatase Receptor tyrosine kinase Embryonic and Fetal Development chemistry.chemical_compound Epidermal growth factor Physiology (medical) Nitriles Homeostasis Humans RNA Messenger Enzyme Inhibitors Phosphorylation Tyrosine Lung Epidermal Growth Factor Pulmonary Surfactant-Associated Protein A biology Pulmonary Surfactants Tyrosine phosphorylation Cell Biology Protein-Tyrosine Kinases Tyrphostins Genistein Molecular biology ErbB Receptors chemistry Quinazolines biology.protein Tyrosine kinase hormones hormone substitutes and hormone antagonists Platelet-derived growth factor receptor |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 274:L542-L551 |
| ISSN: | 1522-1504 1040-0605 |
| DOI: | 10.1152/ajplung.1998.274.4.l542 |
| Popis: | Epidermal growth factor (EGF) stimulates surfactant protein (SP) A synthesis in human fetal lung explants. Ligand binding to the EGF receptor stimulates an intrinsic receptor tyrosine kinase with subsequent activation of second messengers. We hypothesized that inhibition of EGF-receptor tyrosine kinase activity would block SP-A expression in spontaneously differentiating cultured human fetal lung tissue. Midtrimester fetal lung explants were exposed for 4 days to genistein (a broad-range inhibitor of tyrosine kinases) and tyrphostin AG-1478 (a specific inhibitor of EGF-receptor tyrosine kinase). Genistein significantly decreased SP-A and SP-A mRNA levels without affecting either tissue viability or the morphological differentiation of alveolar type II cells. Tyrphostin AG-1478 also decreased SP-A content and SP-A mRNA levels in cultured fetal lung explants. Treatment with EGF could not overcome the inhibitory effects of either genistein or tyrphostin on SP-A; however, only tyrphostin inhibited EGF-receptor tyrosine phosphorylation. We conclude that specific inhibition of EGF-receptor tyrosine kinase with tyrphostin AG-1478 blocks the expression of SP-A during spontaneous differentiation of cultured human fetal lung tissue. Furthermore, exposure to genistein also decreases SP-A expression and blocks the effects of EGF in human fetal lung tissue without inhibiting EGF-receptor tyrosine phosphorylation. These findings support the importance of tyrosine kinase-dependent signal transduction pathways in the regulation of SP-A during human fetal lung development. |
| Databáze: | OpenAIRE |
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