Deregulation of the lysyl hydroxylase matrix cross-linking system in experimental and clinical bronchopulmonary dysplasia.
Deregulation of the lysyl hydroxylase matrix cross-linking system in experimental and clinical bronchopulmonary dysplasia.
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DOI：
10.1152/ajplung.00109.2013
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发表时间：
2014-02
期刊：
影响因子：
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通讯作者：
T. Witsch;P. Turowski;E. Sakkas;Gero Niess;S. Becker;S. Herold;K. Mayer;I. Vadász;Jesse D. Roberts-Jess
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文献类型：
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作者：
T. Witsch;P. Turowski;E. Sakkas;Gero Niess;S. Becker;S. Herold;K. Mayer;I. Vadász;Jesse D. Roberts-Jess
支气管肺发育不良（BPD）是早产常见的严重并发症，其特征是肺泡发育明显停滞。尽管细胞外基质（ECM）的成熟和重塑的扰动正在成为候选疾病病理机制，但对潜在的病理生理机制知之甚少。在这项研究中，表达和调节的三个成员的赖氨酰羟化酶家族ECM重塑酶（Plod 1，Plod 2，Plod 3）在临床BPD，以及在实验动物模型的BPD，得到解决。所有这三种酶都定位于发育中的小鼠肺的间隔壁，Plod 1也在发育中的肺的血管壁中表达，Plod 3在发育中的隔膜的基部独特地表达。在暴露于85%O2的BPD实验动物模型小鼠幼仔的肺中，plod 1、plod 2和plod 3的表达上调。转化生长因子（TGF）-β在体外增加肺上皮细胞和肺成纤维细胞中plod 2 mRNA水平并激活plod 2启动子。在BPD实验动物模型中使用TGF-β信号传导的体内中和，TGF-β被鉴定为异常plod 2表达的调节剂。与出生时胎龄或死亡时实际年龄相匹配的新生儿相比，死于BPD或有BPD风险的人类新生儿PLOD 2 mRNA表达也升高。这些数据表明赖氨酰羟化酶在正常肺发育以及与BPD相关的扰动晚期肺发育中的潜在作用。
Bronchopulmonary dysplasia (BPD) is a common and serious complication of premature birth, characterized by a pronounced arrest of alveolar development. The underlying pathophysiological mechanisms are poorly understood although perturbations to the maturation and remodeling of the extracellular matrix (ECM) are emerging as candidate disease pathomechanisms. In this study, the expression and regulation of three members of the lysyl hydroxylase family of ECM remodeling enzymes (Plod1, Plod2, and Plod3) in clinical BPD, as well as in an experimental animal model of BPD, were addressed. All three enzymes were localized to the septal walls in developing mouse lungs, with Plod1 also expressed in the vessel walls of the developing lung and Plod3 expressed uniquely at the base of developing septa. The expression of plod1, plod2, and plod3 was upregulated in the lungs of mouse pups exposed to 85% O2, an experimental animal model of BPD. Transforming growth factor (TGF)-β increased plod2 mRNA levels and activated the plod2 promoter in vitro in lung epithelial cells and in lung fibroblasts. Using in vivo neutralization of TGF-β signaling in the experimental animal model of BPD, TGF-β was identified as the regulator of aberrant plod2 expression. PLOD2 mRNA expression was also elevated in human neonates who died with BPD or at risk for BPD, compared with neonates matched for gestational age at birth or chronological age at death. These data point to potential roles for lysyl hydroxylases in normal lung development, as well as in perturbed late lung development associated with BPD.