Overexpression of transforming growth factor-beta1 in fetal monkey lung results in prenatal pulmonary fibrosis.
Overexpression of transforming growth factor-beta1 in fetal monkey lung results in prenatal pulmonary fibrosis.
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DOI：
10.1183/09031936.00011810
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Shi W
中科院分区：
文献类型：
--
作者：
Tarantal AF;Chen H;Shi TT;Lu CH;Fang AB;Buckley S;Kolb M;Gauldie J;Warburton D;Shi W
改变的转化生长因子（TGF）-β表达水平与多种人类呼吸系统疾病相关，包括支气管肺发育不良和肺纤维化。然而，尚未在灵长类动物中确定异常TGF-β在新生儿肺部疾病中的致病作用。通过在妊娠中晚期经腹部超声引导的胎猴肺内注射表达TGF-β1的腺病毒载体，在胎猴肺中实现外源性和瞬时性TGF-β 1过表达。然后在近期收获肺，并固定用于组织学和免疫组织化学。在妊娠中期TGF-β1过度表达的地方观察到肺发育不全。最明显的表型包括严重的肺和胸膜纤维化，这与TGF-β1过表达的妊娠时间点无关。在纤维化病灶内检测到细胞增殖增加，特别是α-平滑肌肌动蛋白阳性肌成纤维细胞。但未检测到上皮向间充质的转分化。大量胶原纤维沉积在胸膜的内侧和外侧，中间是完整的弹性蛋白层。即使在腺病毒介导的TGF-β1过表达不再明显后，这种诱导的纤维化病理仍持续存在。因此，在发育中的胎猴肺中TGF-β1的过度表达除了肺发育不良之外还导致肺实质和胸膜中的严重和进行性纤维化。
Altered transforming growth factor (TGF)-β expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-β in neonatal lung diseases has not been defined in primates. Exogenous and transient TGF-β1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-β1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry. Lung hypoplasia was observed where TGF-β1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-β1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-β1 overexpression was no longer evident. Therefore, overexpression of TGF-β1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia.
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