The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function.
The Lung Elastin Matrix Undergoes Rapid Degradation Upon Adult Loss of Hox5 Function.
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DOI：
10.3389/fcell.2021.767454
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发表时间：
2021
影响因子：
5.5
通讯作者：
Wellik DM
中科院分区：
文献类型：
--
作者：
Li MH;Marty-Santos LM;van Ginkel PR;McDermott AE;Rasky AJ;Lukacs NW;Wellik DM
Hox基因编码的转录因子对胚胎骨骼形成和器官形成至关重要。Hoxa 5、Hoxb 5和Hoxc 5旁系同源物在肺间充质中表达，并且在胚胎肺发育期间冗余地发挥功能。这些基因在出生后阶段的条件性功能丧失导致肺泡发生的严重缺陷，特别是在弹性蛋白网络的产生中，并且动物显示支气管肺发育不良（BPD）或BPD样表型。在这里，我们展示了令人惊讶的结果，即在成人阶段间充质特异性Hox 5功能丧失导致成熟弹性蛋白基质的快速破坏、肺泡扩大和肺气肿样表型。由于肺的弹性蛋白基质被认为是高度稳定的，因此未预测到基质的成人破坏。缺失后仅2周，成年Hox 5突变动物显示肺泡空间显著增加和肺功能变化，包括弹性降低和顺应性增加。检查成人Tbx 4 rtTA; TetOCre; Hox 5afafbcc肺的细胞外基质（ECM）表明弹性蛋白网络的破坏，尽管下层纤连蛋白、间质胶原和基底膜似乎未受影响。在Hox 5缺失后3天，在远端肺中观察到巨噬细胞的流入和增加的基质金属蛋白酶12（MMP 12）。在培养中，来自Hox 5突变肺的成纤维细胞表现出降低的粘附。这些发现建立了一个新的作用，Hox 5转录因子作为关键的调节肺成纤维细胞在成人体内平衡。
Hox genes encode transcription factors that are critical for embryonic skeletal patterning and organogenesis. The Hoxa5, Hoxb5, and Hoxc5 paralogs are expressed in the lung mesenchyme and function redundantly during embryonic lung development. Conditional loss-of-function of these genes during postnatal stages leads to severe defects in alveologenesis, specifically in the generation of the elastin network, and animals display bronchopulmonary dysplasia (BPD) or BPD-like phenotype. Here we show the surprising results that mesenchyme-specific loss of Hox5 function at adult stages leads to rapid disruption of the mature elastin matrix, alveolar enlargement, and an emphysema-like phenotype. As the elastin matrix of the lung is considered highly stable, adult disruption of the matrix was not predicted. Just 2 weeks after deletion, adult Hox5 mutant animals show significant increases in alveolar space and changes in pulmonary function, including reduced elastance and increased compliance. Examination of the extracellular matrix (ECM) of adult Tbx4rtTA; TetOCre; Hox5afafbbcc lungs demonstrates a disruption of the elastin network although the underlying fibronectin, interstitial collagen and basement membrane appear unaffected. An influx of macrophages and increased matrix metalloproteinase 12 (MMP12) are observed in the distal lung 3 days after Hox5 deletion. In culture, fibroblasts from Hox5 mutant lungs exhibit reduced adhesion. These findings establish a novel role for Hox5 transcription factors as critical regulators of lung fibroblasts at adult homeostasis.
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影响因子：
6.9
作者：
Houghton, A. McGarry
通讯作者：
Houghton, A. McGarry
影响因子：
2.7
作者：
Aubin, J;Lemieux, M;Jeannotte, L
通讯作者：
Jeannotte, L
DOI：
10.1165/ajrcmb.20.6.3483
发表时间：
1999-06-01
影响因子：
6.4
作者：
Gibbs, DF;Warner, RL;Varani, J
通讯作者：
Varani, J
动脉生成过程中整合素 α 5β 1 和 α V β 3 以及粘着斑激酶 (FAK) 的激活。
影响因子：
4.3
作者：
Cai, Wei-Jun;Li, Ming Bo;Wu, Xiaoqiong;Wu, Song;Zhu, Wu;Chen, Dan;Luo, Mingying;Eitenmueller, Inka;Kampmann, Andreas;Schaper, Jutta;Schaper, Wolfgang
通讯作者：
Schaper, Wolfgang
影响因子：
2.7
作者：
Chen, F;Capecchi, MR
通讯作者：
Capecchi, MR