title: Retinoic acid decreases fetal lung mesenchymal cell proliferation in vivo and in vitro.
abstract: Retinoic acid (RA) is an important coordinator of mammalian organogenesis. RA is implicated in critical lung developmental events. Cell proliferation is precisely regulated during development. We investigated the effect of RA on proliferating mesenchymal cells in both whole organ lung cultures and cell cultures. The potential pathways required for the response were studied in cultures of lung mesenchymal cells from embryonic day (e) 12. We observed an RA-dependent reduction in proliferation of mesenchymal cells in both whole organ and in cell culture. In mesenchymal cell cultures, RA decreased proliferation in lung mesenchymal cells by 72%. This was associated with a decrease of erk-1/2 activity by 68%. Mesenchymal cell proliferation is erk-1/2 dependent. Erk-1/2 can be activated by G-protein coupled receptors (GPCR) or tyrosine kinase receptors (RTK). RA treatment altered both the RTK and the GPCR pathways in primary lung mesenchymal cells. The Epidermal Growth Factor (EGF) dependent erk-1/2 activation was increased by 35% whereas the G(i)-protein cascade was inhibited by 44% in cells treated with RA. Our results suggest that RA decreases proliferation of lung mesenchyme via a G(i)-protein and the erk-1/2 signaling cascade.
authors.affiliation: Pediatric Pulmonary Unit, Department of Pediatrics, Massachusetts General Hospital for Children, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Sussie
authors.initials: S
authors.lastname: Dalvin
authors.forename: Katsumi
authors.initials: K
authors.lastname: Komatsuzaki
authors.forename: Mark A
authors.initials: MA
authors.lastname: Anselmo
authors.forename: David E
authors.initials: DE
authors.lastname: Kling
authors.forename: Jay J
authors.initials: JJ
authors.lastname: Schnitzer
authors.forename: T Bernard
authors.initials: TB
authors.lastname: Kinane
mesh_terms: D000818:Animals; D002455:Cell Division / Q000502:physiology*; D002478:Cells, Cultured; D046508:Culture Techniques; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000502:physiology; D008168:Lung / Q000166:cytology / Q000196:embryology*; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D014212:Tretinoin / Q000502:physiology*
chemical_list: D014212:Tretinoin; D004815:Epidermal Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases