Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers
Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers
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DOI：
10.1165/ajrcmb.23.2.3904
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发表时间：
2000-08-01
影响因子：
6.4
通讯作者：
Snyder, JM
中科院分区：
文献类型：
--
作者：
McGowan, S;Jackson, SK;Snyder, JM
在哺乳动物中，包括大鼠和小鼠，肺泡隔的发育主要限于妊娠晚期和出生后的早期。在此之前，大鼠肺含有相对大量的内源性视黄酯，其与其代谢物视黄酸一起，已显示增加弹性蛋白基因表达和肺泡数量。我们假设，小鼠携带一个或多个编码维甲酸受体（这是DNA结合蛋白，改变维甲酸反应基因的转录）的基因的缺失可能会表现出异常维甲酸介导的肺泡形成。我们的研究表明，视黄酸受体-γ（RAR γ）的缺乏与出生后第12天肺成纤维细胞亚群中弹性蛋白原信使RNA稳态水平的降低相关。RAR γ基因缺失还导致出生后第28天全肺弹性组织和肺泡数量减少，肺泡平均索长（L-m）增加。额外缺失一个维甲酸X受体（RXR）α等位基因导致肺泡表面积和肺泡数量减少，L-m增加。这些数据表明RAR γ是小鼠正常肺泡和肺泡弹性纤维形成所必需的，并且RAR/RXR异二聚体参与肺泡形态发生。
In mammals, including rats and mice, the development of pulmonary alveolar septa is primarily limited to late gestation and the early periods of postnatal life. Before this time, the rat lung contains a relatively large supply of endogenous retinyl ester that, together with its metabolite retinoic acid, has been shown to increase elastin gene expression and the number of alveoli. We have hypothesized that mice bearing a deletion of one or more genes encoding for retinoic acid receptors (which are DNA binding proteins that alter transcription of retinoic acid-responsive genes) may demonstrate abnormalities in retinoid-mediated alveolar formation. Our studies demonstrate that the absence of the retinoic acid receptor-gamma (RAR gamma) is associated with a decrease in the steady-state level of tropoelastin messenger RNA in a subpopulation of lung fibroblasts at Postnatal Day 12. RAR gamma gene deletion also resulted in a decrease in whole lung elastic tissue and alveolar number, and an increase in mean cord length of alveoli (L-m) at Postnatal Day 28, The additional deletion of one retinoid X receptor (RXR)alpha allele resulted in a decrease in alveolar surface area and alveolar number, and an increase in L-m. These data indicate that RAR gamma is required for the formation of normal alveoli and alveolar elastic fibers in the mouse, and that RAR/RXR heterodimers are involved in alveolar morphogenesis.