Do lung remodeling, repair, and regeneration recapitulate respiratory ontogeny?
Do lung remodeling, repair, and regeneration recapitulate respiratory ontogeny?
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DOI：
10.1164/ajrccm.164.supplement_2.2106064
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发表时间：
2001-11-15
影响因子：
24.7
通讯作者：
Driscoll, B
中科院分区：
文献类型：
--
作者：
Warburton, D;Tefft, D;Driscoll, B
在此，我们证实，在形态发生，修复和再生过程中，肺的建模是由保守的刺激和抑制信号传导机制，包括特定的转录因子，细胞因子，肽生长因子，蛋白酶和基质元素紧密协调。这种进化-发育（evo-devo）的功能保守性已扩展到果蝇呼吸气管的形态发生。50个或更多基因指导果蝇气管器官发生。其中，hedgehog、patched、smoothened、cubitus interruptus、branchless、breathless、sprougty、decapentaplegic和mad在果蝇、小鼠和人类之间功能保守。例如，成纤维细胞生长因子（FGF）信号传导不仅对于苍蝇气管和小鼠支气管分支形态发生是必需的，而且对于出生后肺泡的建模和修复也是必需的。同样地，发芽家族基因作为FGF信号传导的诱导性负调节因子，其部分地可以决定支气管发育期间的分支间长度。高氧损伤后重塑过程中肺泡上皮的存活、迁移和增殖也需要FGF信号传导。此外，FGF信号似乎调节一小部分（< 5%）推定的表达端粒酶的肺泡干/祖细胞，这些细胞对高氧细胞凋亡具有相对抗性。我们推测，在evo-devo功能保守的信号传导途径，如FGF-FGF受体-Sprouty基因可能提供新的治疗靶点，以增强肺修复和诱导肺再生。
Herein we posit that modeling of the lungs during morphogenesis, repair, and regeneration is tightly coordinated by conserved stimulatory and inhibitory signaling mechanisms, including specific transcriptional factors, cytokines, peptide growth factors, proteases, and matrix elements. This evolutionary-developmental (evo-devo) functional conservation has been extended to morphogenesis of the respiratory tracheae in Drosophila. Fifty or more genes direct fruit fly tracheal organogenesis. Among them, hedgehog, patched, smoothened, cubitus interruptus, branchless, breathless, sprouty, decapentaplegic, and mad are functionally conserved between flies, mice, and humans. For example, fibroblast growth factor (FGF) signaling is essential, not only for fly trachea and mouse bronchial branching morphogenesis, but also for postnatal modeling and repair of alveoli. Likewise, sprouty family genes act as inducible negative regulators of FGF signaling, which in part may determine interbranch length during bronchial development. Alveolar epithelial survival, migration, and proliferation during remodeling after hyperoxic injury also require FGF signaling. In addition, FGF signaling appears to regulate a small (< 5%) population of putative alveolar stem/ progenitor cells that express telomerase and are relatively resistant to hyperoxic apoptosis. We speculate that genes in evo-devo functionally conserved signaling pathways such as FGF-FGF receptor-Sprouty may provide novel therapeutic targets to augment lung repair and induce lung regeneration.