Nabeyrat E, Besnard V, Corroyer S, Cazals V, Clement A
Department of Pediatric Pulmonology, Institut National de la Santé et de la Recherche Médicale U142, Trousseau Hospital, St. Antoine Medical School, University of Paris, 75012 Paris, France.
Am J Physiol. 1998 Jul;275(1):L71-9. doi: 10.1152/ajplung.1998.275.1.L71.
Retinoids, including retinol and retinoic acid (RA) derivatives, are important molecules for lung growth and homeostasis. The presence of RA receptors and of RA-binding proteins in the alveolar epithelium led to suggest a role for RA on alveolar epithelial cell replication. In the present study, we examined the effects of RA on proliferation of the stem cells of the alveolar epithelium, the type 2 cells. We showed that treatment of serum-deprived type 2 cells with RA led to a stimulation of cell proliferation, with an increase in cell number in a dose-dependent manner. To gain some insights into the mechanisms involved, we studied the effects of RA on the expression of several components of the insulin-like growth factor (IGF) system that have been shown to be associated with the growth arrest of type 2 cells, mainly the IGF-binding protein-2 (IGFBP-2), IGF-II, and the type 2 IGF receptor. We documented a marked decrease in the expression of these components upon RA treatment. Using conditioned media from RA-treated cells, we provided evidence that the proliferative response of type 2 cells to RA was mediated through production of growth factor(s) distinct from IGF-I. We also showed that RA was able to reduce the decrease in cell number observed when type 2 cells were treated with transforming growth factor (TGF)-beta1. These results together with the known stimulatory effect of TGF-beta1 on IGFBP-2 expression led to suggest that RA may be associated with type 2 cell proliferation through mechanisms interfering with the TGF-beta1 pathway.
维甲酸，包括视黄醇和维甲酸（RA）衍生物，是肺生长和内环境稳定的重要分子。肺泡上皮中存在RA受体和RA结合蛋白，这表明RA在肺泡上皮细胞复制中发挥作用。在本研究中，我们检测了RA对肺泡上皮干细胞（2型细胞）增殖的影响。我们发现，用RA处理血清饥饿的2型细胞会刺激细胞增殖，细胞数量呈剂量依赖性增加。为了深入了解其中涉及的机制，我们研究了RA对胰岛素样生长因子（IGF）系统几个组分表达的影响，这些组分已被证明与2型细胞的生长停滞有关，主要是IGF结合蛋白-2（IGFBP-2）、IGF-II和2型IGF受体。我们记录到RA处理后这些组分的表达显著降低。利用RA处理细胞的条件培养基，我们证明2型细胞对RA的增殖反应是通过产生不同于IGF-I的生长因子介导的。我们还表明，RA能够减少2型细胞用转化生长因子（TGF）-β1处理时观察到的细胞数量减少。这些结果与TGF-β1对IGFBP-2表达的已知刺激作用一起表明，RA可能通过干扰TGF-β1途径的机制与2型细胞增殖相关。
