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Am J Physiol Lung Cell Mol Physiol 292 (3): 608-611

Copyright © 2007 by the American Physiological Society.


The evolutionary continuum from lung development to homeostasis and repair

J. S. Torday1,2, and V. K. Rehan1

Departments of 1Pediatrics and 2Obstetrics and Gynecology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California

ABSTRACT Back to Top

Abstract: A functional, developmental, and comparative biological approach is probably the most effective way for arranging gene regulatory networks (GRNs) in their biological contexts. Evolutionary developmental biology allows comparison of GRNs during development across phyla. For lung evolution, the parathyroid hormone-related protein (PTHrP) GRN exemplifies a continuum from ontogeny to phylogeny, homeostasis, and repair. PTHrP signaling between the lung endoderm and mesoderm stimulates lipofibroblast differentiation by downregulating the myofibroblast Wnt signaling pathway and upregulating the protein kinase A-dependent cAMP signaling pathway, inducing the lipofibroblast phenotype. Leptin secreted by the lipofibroblast, in turn, binds to its receptor on the alveolar type II cell, stimulating surfactant synthesis to ensure alveolar homeostasis. Failure of the PTHrP/PTHrP receptor signaling mechanism causes transdifferentiation of lipofibroblasts to myofibroblasts, which are the hallmark for lung fibrosis. We have shown that by targeting peroxisome proliferator-activated receptor {gamma}, the downstream target for lipofibroblast PTHrP signaling, we can prevent lung fibrosis. We speculate that the recapitulation of the myofibroblast phenotype during transdifferentiation is consistent with lung injury as lung evolution in reverse. Repair recapitulates ontogeny because it is programmed to express the cross talk between epithelium and mesoderm through evolution. This model demonstrates how epithelial-mesenchymal cross talk, when seen as a recapitulation of ontogeny and phylogeny (in both a forward and reverse direction), predicts novel, effective diagnostic and therapeutic targets.

Key Words: Evo-Devo • alveoli • parathyroid hormone-related protein • peroxisome proliferator-activated receptor {gamma} • Wnt

Address for reprint requests and other correspondence: J. S. Torday, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson St., Torrance, CA 90502-2006 (e-mail: jtorday{at}

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J. S. Torday (2013)
Am J Physiol Cell Physiol 305, C682-C689
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A Cell-Molecular Approach Predicts Vertebrate Evolution.
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Antenatally administered PPAR-{gamma} agonist rosiglitazone prevents hyperoxia-induced neonatal rat lung injury.
V. K. Rehan, R. Sakurai, J. Corral, M. Krebs, B. Ibe, K. Ihida-Stansbury, and J. S. Torday (2010)
Am J Physiol Lung Cell Mol Physiol 299, L672-L680
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Cell-cell signaling drives the evolution of complex traits: introduction--lung evo-devo.
J. S. Torday and V. K. Rehan (2009)
Integr. Comp. Biol. 49, 142-154
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Lung evolution as a cipher for physiology.
J. S. Torday and V. K. Rehan (2009)
Physiol Genomics 38, 1-6
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Hyperoxia-induced neonatal rat lung injury involves activation of TGF-{beta} and Wnt signaling and is protected by rosiglitazone.
C. Dasgupta, R. Sakurai, Y. Wang, P. Guo, N. Ambalavanan, J. S. Torday, and V. K. Rehan (2009)
Am J Physiol Lung Cell Mol Physiol 296, L1031-L1041
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Gene expression profiling in lung fibroblasts reveals new players in alveolarization.
O. Boucherat, M.-L. Franco-Montoya, C. Thibault, R. Incitti, B. Chailley-Heu, C. Delacourt, and J. R. Bourbon (2007)
Physiol Genomics 32, 128-141
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Comment on "Evo-Devo and the lungfish: the last gasp of intelligent design".
J. S. Torday and V. K. Rehan (2007)
FASEB J 21, 2640-2641
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