Bland Richard D, Xu Liwen, Ertsey Robert, Rabinovitch Marlene, Albertine Kurt H, Wynn Karen A, Kumar Vasanth H, Ryan Rita M, Swartz Daniel D, Csiszar Katalin, Fong Keith S K
Department of Pediatrics, Stanford University School of Medicine, CCSR Bldg., Rm. 1225, 269 Campus Drive, Stanford, CA 94305-5162, USA.
Am J Physiol Lung Cell Mol Physiol. 2007 Jun;292(6):L1370-84. doi: 10.1152/ajplung.00367.2006. Epub 2007 Feb 9.
Failed alveolar formation and excess, disordered elastin are key features of neonatal chronic lung disease (CLD). We previously found fewer alveoli and more elastin in lungs of preterm compared with term lambs that had mechanical ventilation (MV) with O(2)-rich gas for 3 wk (MV-3 wk). We hypothesized that, in preterm more than in term lambs, MV-3 wk would reduce lung expression of growth factors that regulate alveolarization (VEGF, PDGF-A) and increase lung expression of growth factors [transforming growth factor (TGF)-alpha, TGF-beta(1)] and matrix molecules (tropoelastin, fibrillin-1, fibulin-5, lysyl oxidases) that regulate elastin synthesis and assembly. We measured lung expression of these genes in preterm and term lambs after MV for 1 day, 3 days, or 3 wk, and in fetal controls. Lung mRNA for VEGF, PDGF-A, and their receptors (VEGF-R2, PDGF-Ralpha) decreased in preterm and term lambs after MV-3 wk, with reduced lung content of the relevant proteins in preterm lambs with CLD. TGF-alpha and TGF-beta(1) expression increased only in lungs of preterm lambs. Tropoelastin mRNA increased more with MV of preterm than term lambs, and expression levels remained high in lambs with CLD. In contrast, fibrillin-1 and lysyl oxidase-like-1 mRNA increased transiently, and lung abundance of other elastin-assembly genes/proteins was unchanged (fibulin-5) or reduced (lysyl oxidase) in preterm lambs with CLD. Thus MV-3 wk reduces lung expression of growth factors that regulate alveolarization and differentially alters expression of growth factors and matrix proteins that regulate elastin assembly. These changes, coupled with increased lung elastase activity measured in preterm lambs after MV for 1-3 days, likely contribute to CLD.
肺泡形成失败以及弹性蛋白过量、紊乱是新生儿慢性肺病（CLD）的关键特征。我们之前发现，与足月羔羊相比，早产羔羊在接受富含氧气的气体机械通气（MV）3周（MV - 3周）后，肺中的肺泡数量更少，弹性蛋白更多。我们推测，与足月羔羊相比，早产羔羊在MV - 3周后，调节肺泡化的生长因子（血管内皮生长因子、血小板衍生生长因子 - A）的肺表达会降低，而调节弹性蛋白合成和组装的生长因子（转化生长因子 - α、转化生长因子 - β1）以及基质分子（原弹性蛋白、原纤维蛋白 - 1、纤维连接蛋白 - 5、赖氨酰氧化酶）的肺表达会增加。我们测量了早产和足月羔羊在MV 1天、3天或3周后以及胎儿对照组中这些基因的肺表达。MV - 3周后，早产和足月羔羊中血管内皮生长因子、血小板衍生生长因子 - A及其受体（血管内皮生长因子受体 - 2、血小板衍生生长因子受体 - α）的肺mRNA减少，患有CLD的早产羔羊中相关蛋白的肺含量降低。转化生长因子 - α和转化生长因子 - β1的表达仅在早产羔羊的肺中增加。原弹性蛋白mRNA在早产羔羊MV后比足月羔羊增加得更多，并且在患有CLD的羔羊中表达水平仍然很高。相比之下，原纤维蛋白 - 1和类赖氨酰氧化酶 - 1 mRNA短暂增加，患有CLD的早产羔羊中其他弹性蛋白组装基因/蛋白的肺丰度未改变（纤维连接蛋白 - 5）或降低（赖氨酰氧化酶）。因此，MV - 3周会降低调节肺泡化的生长因子的肺表达，并差异改变调节弹性蛋白组装的生长因子和基质蛋白的表达。这些变化，再加上在MV 1 - 3天后早产羔羊中测得的肺弹性蛋白酶活性增加，可能导致CLD。
