Maden Malcolm
MRC Centre for Developmental Neurobiology, 4th floor, New Hunt's House, King's College London, Guy's Campus, London Bridge, London SE1 1UL, United Kingdom.
Am J Respir Cell Mol Biol. 2006 Aug;35(2):260-7. doi: 10.1165/rcmb.2006-0029OC. Epub 2006 Mar 30.
We have investigated the relative efficacy of a range of natural and synthetic retinoids on the induction of alveolar regeneration in a dexamethasone-treated mouse model. The aim was to explore the roles of the different retinoic acid receptors using receptor-selective agonists and to determine whether other natural retinoids in addition to all-trans-retinoic acid (tRA) were effective. Dexamethasone treatment of newborn pups led to a reduced lung surface area and increased mean chord length. Subsequently, tRA induced alveolar repair, improved mean chord length, and improved the lung surface area to volume ratio. We found that 4-oxo-RA and a retinoic acid receptor (RAR) alpha-selective compound were as effective as tRA at inducing alveolar regeneration, with neither showing a significantly better efficacy. An RARbeta-selective compound was also effective, whereas a RARgamma-selective compound was not. Other retinoids, such as 9-cis-RA, 13-cis-RA, retinol, and a pan retinoid X receptor (RXR) agonist, do not induce significant responses. Neither did granulocyte colony-stimulating factor. We also showed that an RARbeta-null mutant mouse line responded to dexamethasone by failing to develop alveoli appropriately and that tRA induced alveolar regeneration, suggesting that RARbeta was not required for the regenerative response.
我们研究了一系列天然和合成类视黄醇在经地塞米松处理的小鼠模型中诱导肺泡再生的相对功效。目的是使用受体选择性激动剂探索不同视黄酸受体的作用,并确定除全反式视黄酸(tRA)外的其他天然类视黄醇是否有效。对新生幼崽进行地塞米松处理会导致肺表面积减小和平均弦长增加。随后,tRA诱导肺泡修复,改善平均弦长,并提高肺表面积与体积比。我们发现4-氧代视黄酸和一种视黄酸受体(RAR)α选择性化合物在诱导肺泡再生方面与tRA一样有效,两者均未显示出明显更好的功效。一种RARβ选择性化合物也有效,而一种RARγ选择性化合物则无效。其他类视黄醇,如9-顺式视黄酸、13-顺式视黄酸、视黄醇和一种泛视黄酸X受体(RXR)激动剂,不会诱导显著反应。粒细胞集落刺激因子也不会。我们还表明,一种RARβ基因敲除突变小鼠品系对地塞米松的反应是未能适当地发育肺泡,而tRA诱导肺泡再生,这表明RARβ对于再生反应不是必需的。