Souza P, Tanswell A K, Post M
Department of Pediatrics, Hospital for Sick Children Research Institute, University of Toronto, Ontario, Canada.
Am J Respir Cell Mol Biol. 1996 Oct;15(4):551-62. doi: 10.1165/ajrcmb.15.4.8879189.
Platelet-derived growth factor (PDGF) is implicated in the process of normal lung development. We have previously shown the presence of PDGF-AA and BB homodimers in embryonic rat lung. Also, we reported that PDGF-AA is involved in embryonic lung branching, whereas PDGF-BB influences embryonic lung growth. PDGF isoforms bind with different affinities to two related receptors, denoted the PDGF alpha- and beta-receptors, respectively. The alpha-receptor binds both PDGF isoforms, whereas the beta-receptor binds only PDGF-BB. In the present study, we investigated the role of both receptors in early embryonic rat lung development. Reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that both PDGF alpha- and beta-receptor mRNAs are mainly expressed in the mesenchyme. Phosphorothioate antisense receptor oligonucleotides decreased PDGF receptor mRNA expression in early lung explants. PDGF-induced receptor tyrosine phosphorylation was also reduced by the antisense oligonucleotides. Incubation of embryonic lung explants with antisense beta-receptor oligonucleotides inhibited lung growth but not early lung branching. Neither growth nor branching were affected by sense beta-receptor oligonucleotides. The inhibitory effect of antisense beta-receptor oligonucleotides on embryonic lung growth was reversed by the addition of PDGF-BB or PDGF-AA, suggesting that the alpha-receptor can transduce similar mitogenic signals as the beta-receptor in early lung development. Antisense alpha-receptor oligonucleotides reduced both embryonic lung growth and branching. Sense alpha-receptor treatment had no effect on lung growth and branching. PDGF-BB but not PDGF-AA partially attenuated the inhibitory effect of antisense alpha-receptor oligonucleotides on lung growth. In contrast, PDGF-BB did not overcome the inhibitory effect on early lung branching, indicating that the beta-receptor cannot replace this biologic role of the alpha-receptor in early lung development. These data suggest that PDGF-BB stimulation of both receptors leads to lung growth, whereas PDGF-AA stimulation of the alpha-receptor induces transduction pathways that lead lung branching.
血小板衍生生长因子（PDGF）与正常肺发育过程有关。我们之前已证明胚胎大鼠肺中存在PDGF-AA和BB同型二聚体。此外，我们报道PDGF-AA参与胚胎肺分支，而PDGF-BB影响胚胎肺生长。PDGF亚型分别以不同亲和力与两种相关受体结合，即PDGFα受体和β受体。α受体结合两种PDGF亚型，而β受体仅结合PDGF-BB。在本研究中，我们调查了这两种受体在大鼠胚胎肺早期发育中的作用。逆转录聚合酶链反应（RT-PCR）分析显示，PDGFα受体和β受体的mRNA主要在间充质中表达。硫代磷酸酯反义受体寡核苷酸降低了早期肺外植体中PDGF受体mRNA的表达。反义寡核苷酸也降低了PDGF诱导的受体酪氨酸磷酸化。用反义β受体寡核苷酸孵育胚胎肺外植体可抑制肺生长，但不影响早期肺分支。正义β受体寡核苷酸对生长和分支均无影响。添加PDGF-BB或PDGF-AA可逆转反义β受体寡核苷酸对胚胎肺生长的抑制作用，这表明在早期肺发育中，α受体可转导与β受体相似的促有丝分裂信号。反义α受体寡核苷酸可同时降低胚胎肺生长和分支。正义α受体处理对肺生长和分支无影响。PDGF-BB可部分减弱反义α受体寡核苷酸对肺生长的抑制作用，但PDGF-AA无此作用。相反，PDGF-BB不能克服对早期肺分支的抑制作用，这表明在早期肺发育中，β受体不能替代α受体的这一生物学作用。这些数据表明，PDGF-BB对两种受体的刺激均导致肺生长，而PDGF-AA对α受体的刺激诱导导致肺分支的转导途径。
