Do lung remodeling, repair, and regeneration recapitulate respiratory ontogeny?
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.
Warburton
D
D
Developmental Biology Program, Childrens Hospital Los Angeles Research Institute, Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA. dwarburton@chla.usc.edu
Tefft
D
D
Mailleux
A
A
Bellusci
S
S
Thiery
J P
JP
Zhao
J
J
Buckley
S
S
Shi
W
W
Driscoll
B
B
D000328:Adult; D000818:Animals; D001980:Bronchi / Q000196:embryology; D001997:Bronchopulmonary Dysplasia / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D004175:Diptera / Q000196:embryology / Q000235:genetics; D004330:Drosophila / Q000196:embryology / Q000235:genetics; D000939:Epitopes; D019143:Evolution, Molecular; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D005865:Gestational Age; D006801:Humans; D017403:In Situ Hybridization; D007231:Infant, Newborn; D008168:Lung / Q000196:embryology / Q000502:physiology*; D051379:Mice; D009024:Morphogenesis; D009154:Mutation; D010641:Phenotype; D011650:Pulmonary Alveoli / Q000166:cytology; D051381:Rats; D012038:Regeneration; D012137:Respiratory System / Q000196:embryology*; D013234:Stem Cells / Q000502:physiology; D014132:Trachea / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology
D000939:Epitopes; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D005346:Fibroblast Growth Factors