Effect of tyrosine kinase inhibition on surfactant protein A gene expression during human lung development.
Effect of tyrosine kinase inhibition on surfactant protein A gene expression during human lung development.
复制标题
酪氨酸激酶抑制对人肺发育过程中表面活性蛋白 A 基因表达的影响。
DOI：
10.1152/ajplung.1998.274.4.l542
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
McCarthy,TA
中科院分区：
文献类型：
--
作者：
Klein,JM;DeWild,LJ;McCarthy,TA
表皮生长因子 (EGF) 刺激人胎肺外植体中表面活性蛋白 (SP) A 的合成。与 EGF 受体结合的配体刺激内在受体酪氨酸激酶，随后激活第二信使。我们假设抑制 EGF 受体酪氨酸激酶活性会阻断自发分化培养的人胎儿肺组织中 SP-A 的表达。将妊娠中期胎儿肺外植体暴露于金雀异黄酮（一种广泛的酪氨酸激酶抑制剂）和酪氨酸磷酸化抑制剂 AG-1478（一种 EGF 受体酪氨酸激酶的特异性抑制剂）中 4 天。金雀异黄素显着降低 SP-A 和 SP-A mRNA 水平，而不影响组织活力或 II 型肺泡细胞的形态分化。 Tyrphostin AG-1478 还降低培养的胎肺外植体中的 SP-A 含量和 SP-A mRNA 水平。 EGF治疗不能克服金雀异黄酮或酪氨酸磷酸酶对SP-A的抑制作用；然而，只有酪氨酸磷酸化抑制EGF受体酪氨酸磷酸化。我们得出结论，用酪氨酸磷酸酶 AG-1478 特异性抑制 EGF 受体酪氨酸激酶可阻断培养的人胎儿肺组织自发分化过程中 SP-A 的表达。此外，接触金雀异黄素还会降低人胎儿肺组织中 SP-A 的表达并阻断 EGF 的作用，而不抑制 EGF 受体酪氨酸磷酸化。这些发现支持酪氨酸激酶依赖性信号转导途径在人胎肺发育过程中 SP-A 调节中的重要性。
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.