The molecular genetics of lung morphogenesis and injury repair.

Abstract

Lung development, as well as epithelial injury repair, is tightly coordinated by a fine balance between stimulatory versus inhibitory genes that appear to co-regulate the function of stem/progenitor cells in the lung. Recently, it has been noted that many of the same genes direct development of the respiratory organs (tracheae) in the fruit fly Drosophila as in mice and men. For example, FGF receptor tyrosine kinase signaling is essential for respiratory organogenesis in both fly and mouse and is negatively regulated by the sprouty genes, a family of inducible FGF pathway inhibitors. Additionally, FGF signaling is required for formation of new alveoli, protection of alveolar epithelial cells from injury, as well as migration and proliferation of putative alveolar stem/progenitor cells during lung repair. Conversely, TGFbeta receptor serine-threonine kinase signaling via Smads 2, 3 and 4 inhibits lung morphogenesis and can inhibit postnatal alveolar development, while excessive TGFbeta signaling via Smad3 causes interstitial fibrosis. On the other hand, BMP4 stimulates morphogenesis of intact embryonic lung, while inhibiting proliferation of isolated epithelium. We speculate that evolutionary-developmental, functional conservation of the FGF- FGFR-SPROUTY stimulatory pathway as well as of the TGFbeta/BMP-SMAD modulatory pathways identifies them as potential therapeutic targets for rational therapy. Novel therapy to activate lung stem/progenitor cells, ameliorate lung injury, augment lung repair and/or induce lung regeneration could be highly beneficial in both children and adults with intractable pulmonary insufficiency.

• Authors: David Warburton, Saverio Bellusci
• Journal: Paediatric respiratory reviews (Paediatr Respir Rev) Vol. 5 Suppl A Pg. S283-7 ( 2004) ISSN: 1526-0542 [Print] England
• PMID: 14980285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Growth Substances

Topics

• Animals
• Growth Substances (physiology)
• Humans
• Lung (embryology, growth & development, physiology)
• Lung Diseases
• Morphogenesis