Sunday M E, Hua J, Dai H B, Nusrat A, Torday J S
Department of Pathology, Harvard Medical School, Boston, MA 02115.
Am J Respir Cell Mol Biol. 1990 Sep;3(3):199-205. doi: 10.1165/ajrcmb/3.3.199.
Pulmonary neuroendocrine cells (PNECs) in fetuses synthesize gastrin-releasing peptide (GRP, or mammalian bombesin) at high levels, but the role of this hormone in lung development has been obscure. The present study demonstrates that bombesin administered for 2 to 4 d toward the end of gestation in utero led to increased DNA (days 17 and 18) and saturated phosphatidylcholine (SPC) synthesis (day 18) in a dose-dependent fashion in fetal lung. These kinetics coincide with the timing of endogenous GRP gene activation in untreated fetal mouse lung, where GRP mRNA is detectable on day 16 and peaks at day 18. Electron microscopy on in vivo bombesin-treated fetal lung showed an increase in the number of cells containing lamellar bodies on both days 17 and 18, consistent with increased growth and/or maturation of type II cells. In mouse fetal lung organ cultures, the addition of bombesin led to accelerated uptake of [3H]thymidine into DNA, [3H]leucine into protein, and [3H]choline into SPC, indicating that increased growth and maturation may be direct effects. Extending these observations to another species, bombesin was found to induce growth and maturation of human fetal lung in organ culture. A monoclonal antibody to bombesin (2A11) prevented bombesin-induced increases in choline and thymidine incorporation in lung organ cultures and also blocked baseline automaturation of control lung organ cultures in serum-free medium. These data suggest that bombesin, and thus PNECs, play a role in normal lung development.
胎儿肺部的神经内分泌细胞（PNECs）会大量合成胃泌素释放肽（GRP，即哺乳动物铃蟾肽），但这种激素在肺部发育中的作用一直不明确。本研究表明，在子宫内妊娠末期给予铃蟾肽2至4天，会使胎儿肺中的DNA（第17天和第18天）和饱和磷脂酰胆碱（SPC，第18天）合成呈剂量依赖性增加。这些动力学变化与未处理的胎儿小鼠肺中内源性GRP基因激活的时间一致，在未处理的胎儿小鼠肺中，GRP mRNA在第16天可检测到，并在第18天达到峰值。对体内给予铃蟾肽处理的胎儿肺进行电子显微镜检查显示，在第17天和第18天，含有板层小体的细胞数量均增加，这与II型细胞生长和/或成熟增加一致。在小鼠胎儿肺器官培养物中，添加铃蟾肽会导致[3H]胸苷加速掺入DNA、[3H]亮氨酸加速掺入蛋白质以及[3H]胆碱加速掺入SPC，表明生长和成熟增加可能是直接作用。将这些观察结果扩展到另一个物种，发现铃蟾肽可在器官培养中诱导人胎儿肺的生长和成熟。一种针对铃蟾肽的单克隆抗体（2A11）可阻止铃蟾肽诱导的肺器官培养物中胆碱和胸苷掺入增加，并且还可阻断无血清培养基中对照肺器官培养物的基线自动成熟。这些数据表明，铃蟾肽以及PNECs在正常肺发育中发挥作用。
