Transfer of the active form of transforming growth factor-β1 gene to newborn rat lung induces changes consistent with bronchopulmonary dysplasia
Transfer of the active form of transforming growth factor-β1 gene to newborn rat lung induces changes consistent with bronchopulmonary dysplasia
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DOI：
10.1016/s0002-9440(10)63612-7
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发表时间：
2003-12-01
影响因子：
6
通讯作者：
Warburton, D
中科院分区：
文献类型：
--
作者：
Gauldie, J;Galt, T;Warburton, D
支气管肺发育不良是一种人类早产儿的慢性肺部疾病，其表现出包括与扭曲的大肺泡空间相关的不同大小的间质纤维化区域的病理特征。我们先前已经证明，通过腺病毒载体将活性转化生长因子（TGF）-β 1（AdTGF β 1（223/225））基因转移到胚胎肺导致分支形态发生和原始外周肺发育的抑制，而转移到成人肺导致进行性间质纤维化。在此，我们表明，转移TGF-β 1到新生大鼠幼崽的结果在整个28天的时间内转移后发展的间质纤维化的斑片状区域。这些纤维化区域出现在与出生时所见的前肺泡相似的肺泡腔扩大区域旁边，表明出生后肺发育和肺泡化受到抑制。在用AdTGF β 1处理的大鼠中（223/225），到第21天肺泡腔明显扩大，到第28天，平均肺泡索长度几乎是对照载体或未处理大鼠的两倍。羟脯氨酸测量证实存在纤维化。这些数据表明，过度表达TGF-β 1在出生后大鼠肺泡形成的关键时期引起的病理，生化和形态学的变化与人类支气管肺发育不良，从而推断TGF-β在这种疾病的致病作用。
Bronchopulmonary dysplasia is a chronic lung disease of premature human infancy that shows pathological features comprising varying sized areas of interstitial fibrosis in association with distorted large alveolar spaces. We have previously shown that transfer of active transforming growth factor (TGF)-beta1 (AdTGFbeta1(223/225)) genes by adenovirus vector to embryonic lungs results in inhibition of branching morphogenesis and primitive peripheral lung development, whereas transfer to adult lungs results in progressive interstitial fibrosis. Herein we show that transfer of TGF-beta1 to newborn rat pups results in patchy areas of interstitial fibrosis developing throughout a period of 28 days after transfer. These areas of fibrosis appear alongside areas of enlarged alveolar spaces similar to the prealveoli seen at birth, suggesting that postnatal lung development and alveolarization has been inhibited. In rats treated with AdTGFbeta1(223/225), enlarged alveolar spaces were evident by day 21, and by 28 days, the mean alveolar cord length was nearly twice that in control vector or untreated rats. Hydroxyproline measurements confirmed the presence of fibrosis. These data suggest that overexpression of TGF-beta1 during the critical period of postnatal rat lung alveolarization gives rise to pathological, biochemical, and morphological changes consistent with those seen in human bronchopulmonary dysplasia, thus inferring a pathogenic role for TGF-beta in this disorder.