Department of Pediatrics, Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095-1752, USA.
Am J Respir Cell Mol Biol. 2011 Jun;44(6):804-12. doi: 10.1165/rcmb.2009-0429OC. Epub 2010 Aug 6.
Alveolar formation is hallmarked by the transition of distal lung saccules into gas exchange units through the emergence of secondary crests and an exponential increase in surface area. Several cell types are involved in this complex process, including families of epithelial cells that differentiate into alveolar type I and II cells. Subsets of cells expressing Clara cell secretory protein (CCSP) have been identified in both lung and bone marrow compartments, and are described as a progenitor/stem cell pool involved in airway regeneration and alveolar homeostasis. Whether these cells also participate in alveolar formation during postnatal development remains unknown. Based on their regenerative capacity, we asked whether these cells participate in alveogenesis. We used a previously described transgenic mouse model (CCSP-tk) in which Ganciclovir exposure selectively depletes all cells with CCSP promoter activity through intracellular generation of a toxic metabolite of thymidine kinase. Our results showed that Ganciclovir treatment in newborn CCtk mice depleted this cell population in lung airways and bone marrow, and was associated with alveolar hypoplasia and respiratory failure. Hypoplastic lungs had fewer alveolar type I and II cells, with impaired secondary crest formation and decreased vascular endothelial growth factor expression in distal airways. These findings are consistent with a model in which a unique population of cells with CCSP promoter activity that expresses vascular endothelial growth factor participates in alveolar development.
肺泡形成的标志是通过次级嵴的出现和表面积的指数级增加，将远端肺小泡转变为气体交换单位。这一复杂过程涉及多种细胞类型，包括分化为肺泡 I 型和 II 型细胞的上皮细胞家族。在肺和骨髓隔室中都鉴定出表达 Clara 细胞分泌蛋白 (CCSP) 的细胞亚群，这些细胞被描述为参与气道再生和肺泡稳态的祖细胞/干细胞池。这些细胞是否也参与出生后发育过程中的肺泡形成仍不清楚。基于它们的再生能力，我们询问这些细胞是否参与肺泡发生。我们使用了先前描述的转基因小鼠模型（CCSP-tk），其中更昔洛韦暴露通过胸苷激酶的细胞内产生有毒代谢物选择性耗尽所有具有 CCSP 启动子活性的细胞。我们的结果表明，新生 CCtk 小鼠中的更昔洛韦处理耗尽了肺气道和骨髓中的这种细胞群，与肺泡发育不全和呼吸衰竭有关。发育不全的肺有较少的肺泡 I 型和 II 型细胞，次级嵴形成受损，远端气道中血管内皮生长因子的表达减少。这些发现与以下模型一致，即具有 CCSP 启动子活性并表达血管内皮生长因子的独特细胞群参与肺泡发育。
