Fibroblast growth factor-2 and receptor-1alpha(IIIc) regulate postnatal rat lung cell apoptosis.
BACKGROUND
Fibroblast growth factor receptor-1alpha(IIIc) [FGF-R1alpha(IIIc)] regulates recovery of neonatal rat lung growth, after 95% oxygen-mediated growth arrest. Its role in normal postnatal alveologenesis is unknown.


OBJECTIVE
To determine if FGF-R1alpha(IIIc) regulates normal postnatal alveologenesis.


METHODS
Truncated soluble FGF-R1alpha(IIIc) or neutralizing antibodies to FGF-1 or FGF-2 were injected intraperitoneally into 3-d-old rats. The pups were killed at Day 7 for studies of alveolar development.


RESULTS
Injected, truncated soluble FGF-R1alpha(IIIc) inhibited phosphorylation of the endogenous FGF-R1, and downstream pathway, and paradoxically increased lung DNA content and tissue fraction while inhibiting lung cell DNA synthesis. The increase in tissue thickness was due to reduced apoptosis, as indicated by reductions in cleaved effector caspases 3 and 7. Inhibition of the intrinsic apoptosis pathway was suggested by decreases in the proapoptotic protein Bax and mitochondrial cytochrome c release, and an increase in the antiapoptotic protein Bcl-x(L). Injected antibodies to FGF-1 and FGF-2 had no effect on DNA synthesis, but both increased Bcl-x(L) content and decreased cytochrome c release and cleaved caspase-7 protein expression. However, only injection of the antibody to FGF-2 replicated the increased tissue fraction and inhibited apoptosis observed with the injection of truncated soluble FGF-R1alpha(IIIc).


CONCLUSIONS
Inhibition of ligand binding, most likely of FGF-2, to the FGF-R1alpha(IIIc) inhibits normal postnatal lung cell apoptosis.
Yi
Man
M
Canadian Institute of Health Research Group in Lung Development, Lung Biology Programme, Hospital for Sick Children Research Institute, Toronto, ON, Canada.
Belcastro
Rosetta
R
Shek
Samuel
S
Luo
Daochun
D
Post
Martin
M
Tanswell
A Keith
AK
D000818:Animals; D000831:Animals, Newborn; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D019014:fas Receptor; D016222:Fibroblast Growth Factor 2; D045304:Cytochromes c; D004247:DNA; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D051496:Receptor, Fibroblast Growth Factor, Type 1