TORDAY, J.S.; ROMERO, S.; SANTOS, J.; WANG, Y.; REHAN, V.K.; University of California- Los Angeles; University of California- Los Angeles; University of California- Los Angeles; University of California- Los Angeles; University of California- Los Angeles: Parathyroid Hormone-related Protein (PTHrP) Signaling: Molecular Link from Lung Development to Physiology, Phylogeny and Evolution.

PTHrP and PTHrP receptor are expressed in vertebrate phylogeny from the swim bladder of the fish to the lungs of amphibians, reptiles, mammals and birds. PTHrP expression is needed to form lung alveoli, the key element for the progressive increase in lung surface area. PTHrP signaling up-regulates surfactant production to accommodate increased alveolar surface area, providing selection pressure for PTHrP signaling in ontogeny and phylogeny- we hypothesize that this mechanism underlies the increasing surface area for gas exchange in vertebrate ontogeny and phylogeny. To test this hypothesis we have assayed for the PTHrP stimulation of surfactant in swim bladder, and the lungs of developing frogs, alligators, rats and chicks. PTHrP, PTHrP receptor and pulmonary surfactant are expressed in all of these tissues, PTHrP and surfactant being expressed in endoderm, and the PTHrP in mesoderm; PTHrP/PTHrP receptor signaling is up-regulated in the frog, chick and rat immediately prior to the embryonic onset of surfactant production. Embryonic lung tissue was cultured as explants and incubated with 5 X 10^-7M PTHrP (1-34) for 24h. Tissues were incubated with ³H-choline chloride for the last 4h and subsequently analyzed for³H-saturated phosphatidylcholine (SatPC)content to assay for the rate of surfactant phospholipid synthesis. The embryonic alligator lung showed a 25% increase in de novo SatPC synthesis, whereas the rat lung showed a 200% increase, consistent with the hypothesized amplification of PTHrP signaling through phylogeny. Ongoing experiments empirically test the molecular basis for the ontogeny, phylogeny and evolution of the vertebrate lung.