Nobuhara K K, DiFiore J W, Ibla J C, Siddiqui A M, Ferretti M L, Fauza D O, Schnitzer J J, Wilson J M
Department of Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
J Pediatr Surg. 1998 Jul;33(7):1057-60; discussion 1061. doi: 10.1016/s0022-3468(98)90531-0.
BACKGROUND/PURPOSE: We have learned previously that in utero tracheal ligation reverses the structural and physiological effects of surgically created congenital diaphragmatic hernia. In addition, we have discovered that postnatal lung growth similarly can be accelerated using liquid-based airway distension with perfluorocarbon. Another model of accelerated lung growth is that of compensatory growth seen after neonatal pneumonectomy. In all of these models, growth has occurred because of an increase in alveolar number rather than enlargement of preexisting alveoli. However, the molecular mechanisms underlying these processes remain unknown. The purpose of this study was to determine if gene expression could be altered by changes in physical forces in the prenatal and postnatal lung.
The three models of accelerated lung growth studied were the following: (1) The prenatal group, consisted of fetal lambs (n = 12) that underwent the surgical creation of a left diaphragmatic hernia at 90 days' gestation. Six of these animals also underwent simultaneous tracheal ligation. (2) The PFC group consisted of five neonatal animals that underwent isolation of the superior segment of the right upper lobe, with intrabronchial distension with perfluorocarbon to 7 to 10 mm Hg pressure for a 3-week period. (3) The postpneumonectomy group consisted of four neonatal animals that underwent left pneumonectomy. In the fetal study, lungs were retrieved at term (130 days), and in the postnatal study, lungs were retrieved 3 weeks after initial intervention. In all cases, RNA was extracted from snap-frozen lung samples and Northern blot analysis performed.
Insulinlike growth factor-I, insulinlike growth factor-II, and vascular endothelial growth factor gene expression were analyzed by densitometry. Insulinlike growth factor-I gene expression was found to be decreased in association with experimental diaphragmatic hernia (P = .005), but restored to normal with tracheal ligation. Insulinlike growth factor-I gene expression was significantly increased in both postnatal models of accelerated lung growth (P = .022, P = .016). No significant differences were found in insulinlike growth factor-II or vascular endothelial growth factor gene expression.
The authors conclude from these preliminary data that (1) insulin like growth factor-I gene expression is reduced in experimental fetal diaphragmatic hernia and restored to normal by tracheal ligation, and (2) insulinlike growth factor-I gene expression is increased in both the liquid-based airway distension and postpneumonectomy models of accelerated postnatal lung growth. The authors speculate that all of these manipulations exploit a natural pathway essential for normal lung growth.
背景/目的：我们之前了解到，子宫内气管结扎可逆转手术造成的先天性膈疝的结构和生理影响。此外，我们还发现，使用基于液体的气道扩张和全氟化碳可同样加速出生后肺的生长。加速肺生长的另一种模型是新生儿肺切除术后的代偿性生长。在所有这些模型中，肺生长是由于肺泡数量增加而非已有肺泡的扩大。然而，这些过程背后的分子机制仍然未知。本研究的目的是确定产前和产后肺中的物理力变化是否会改变基因表达。
所研究的三种加速肺生长模型如下：（1）产前组，由妊娠90天时接受左侧膈疝手术创建的胎羊（n = 12）组成。其中6只动物还同时接受了气管结扎。（2）全氟化碳组由5只新生动物组成，这些动物接受了右上叶上段的分离，并通过全氟化碳在支气管内扩张至7至10 mmHg压力，持续3周。（3）肺切除术后组由4只接受左肺切除术的新生动物组成。在胎儿研究中，足月时（130天）取出肺，在产后研究中，在初次干预3周后取出肺。在所有情况下，从速冻的肺样本中提取RNA并进行Northern印迹分析。
通过光密度测定法分析胰岛素样生长因子-I、胰岛素样生长因子-II和血管内皮生长因子的基因表达。发现胰岛素样生长因子-I基因表达与实验性膈疝相关降低（P = .005），但气管结扎后恢复正常。在两种出生后加速肺生长模型中，胰岛素样生长因子-I基因表达均显著增加（P = .022，P = .016）。胰岛素样生长因子-II或血管内皮生长因子基因表达未发现显著差异。
作者从这些初步数据得出结论：（1）实验性胎儿膈疝中胰岛素样生长因子-I基因表达降低，气管结扎后恢复正常；（2）在基于液体的气道扩张和肺切除术后加速出生后肺生长模型中，胰岛素样生长因子-I基因表达均增加。作者推测，所有这些操作都利用了正常肺生长所必需的自然途径。
