Torday John S, Rehan Virender K
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA, Torrance, California 90502, USA.
Pediatr Res. 2006 Oct;60(4):382-8. doi: 10.1203/01.pdr.0000238326.42590.03. Epub 2006 Aug 28.
Lung development depends on endodermal Sonic Hedgehog (Shh) signaling to mesodermal Wingless/int/beta catenin (Wnt/betacatenin), followed by parathyroid hormone-related protein (PTHrP) signaling from endoderm to mesoderm. Fluid distension of fetal rat lung explants up-regulates PTHrP signaling and down-regulates Shh/Wnt/betacatenin signaling, marked by decreases in Patched, Gli, Frizzled, and Dishevelled, inducing fibroblast triglyceride uptake, type II cell saturated phosphatidylcholine, and surfactant protein-B expression. Bumetanide, which inhibits fluid distension, blocked down-regulation of the Shh/Wnt/betacatenin pathway and up-regulation of the PTHrP pathway, whereas PTHrP (1-34, 5 x 10(-7) M) treatment overcame bumetanide inhibition, and the PTHrP receptor antagonist PTHrP (7-34) amide (5 x 10(-6) M) mimicked bumetanide, indicating that PTHrP signaling mediates fluid distension-induced alveolar differentiation. Fetal rat lung explant automaturation was characterized by decreased Wnt/betacatenin signaling and increased PTHrP/PTHrP receptor signaling, up-regulating fibroblast-specific adipocyte differentiation related protein (ADRP) and peroxisome proliferator-activated receptor gamma. Wnt/betacatenin agonists (LiCl or SB415268) maintained Shh/Wnt/betacatenin signaling, blocking spontaneous up-regulation of the PTHrP pathway, whereas PTHrP or cAMP down-regulated Shh/Wnt/betacatenin signaling and stimulated PTHrP signaling for fibroblast and type II cell differentiation. This is the first evidence that alveolar fluid distension is an organizing principle for PTHrP signaling down-regulation of the Shh/Wnt/betacatenin pathway.
肺的发育依赖于内胚层的音猬因子（Shh）信号传导至中胚层的无翅型/整合蛋白/β-连环蛋白（Wnt/β-catenin）信号，随后是甲状旁腺激素相关蛋白（PTHrP）从内胚层到中胚层的信号传导。胎鼠肺组织块的液体扩张上调PTHrP信号并下调Shh/Wnt/β-catenin信号，表现为patched、Gli、卷曲蛋白和散乱蛋白减少，诱导成纤维细胞甘油三酯摄取、II型细胞饱和磷脂酰胆碱和表面活性蛋白B表达。抑制液体扩张的布美他尼阻断了Shh/Wnt/β-catenin途径的下调和PTHrP途径的上调，而PTHrP（1-34，5×10^(-7)M）处理克服了布美他尼的抑制作用，并且PTHrP受体拮抗剂PTHrP（7-34）酰胺（5×10^(-6)M）模拟了布美他尼的作用，表明PTHrP信号介导液体扩张诱导的肺泡分化。胎鼠肺组织块的自动成熟表现为Wnt/β-catenin信号减少和PTHrP/PTHrP受体信号增加，上调成纤维细胞特异性脂肪细胞分化相关蛋白（ADRP）和过氧化物酶体增殖物激活受体γ。Wnt/β-catenin激动剂（氯化锂或SB415268）维持Shh/Wnt/β-catenin信号，阻断PTHrP途径的自发上调，而PTHrP或cAMP下调Shh/Wnt/β-catenin信号并刺激成纤维细胞和II型细胞分化的PTHrP信号。这是肺泡液体扩张是Shh/Wnt/β-catenin途径PTHrP信号下调的组织原则的首个证据。
