Submitted on November 7, 2005
Accepted on May 22, 2006
Fibroblast Growth Factor-2 and Receptor-1
(IIIc) Regulate Postnatal Rat Lung Cell Apoptosis
Man Yi1, Rosetta Belcastro2, Samuel Shek2, Daochun Luo2, Martin Post3, and A. Keith Tanswell3*
1 Canadian Institutes of Health Research (CIHR) Group in Lung Development, Lung Biology Programme, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada,
2 Canadian Institutes of Health Research (CIHR) Group in Lung Development, Lung Biology Programme, Hospital for Sick Children Research Institute, Toronto, ON, Canada,
3 Canadian Institutes of Health Research (CIHR) Group in Lung Development, Lung Biology Programme, Hospital for Sick Children Research Institute, Toronto, ON, Canada; Department of Paediatrics, University of Toronto, Toronto, ON, Canada; Department of Physiology, University of Toronto, Toronto, ON, Canada
* To whom correspondence should be addressed. E-mail: keith.tanswell{at}sickkids.ca.
Rationale: Fibroblast growth factor receptor-1
(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 fibroblast growth factor receptor-1(IIIc) regulates normal postnatal
alveologenesis.
Methods: Truncated soluble fibroblast growth factor receptor-1(IIIc), or neutralizing antibodies to fibroblast growth factors-1 or -2, were injected intraperitoneally into 3-day-old rats. The pups were sacrificed at day 7 for studies of alveolar development.
Measurements and Main Results: Injected truncated soluble fibroblast growth factor receptor-1(IIIc) inhibited phosphorylation of the endogenous fibroblast growth factor receptor-1, and down-stream 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 pro-apoptotic protein Bax and mitochondrial cytochrome c release, and an increase in the anti-apoptotic protein Bcl-xL. Injected antibodies to fibroblast growth factors-1 and -2 had no effect on DNA synthesis, but both increased Bcl-xL content and decreased cytochrome c release and cleaved caspase-7 protein expression. However, only injection of the antibody to fibroblast growth factor-2 replicated the 2 increased tissue fraction and inhibited apoptosis observed with the injection of truncated soluble fibroblast growth factor receptor-1(IIIc).
Conclusions: Inhibition of ligand binding, most likely of fibroblast growth factor-2, to the fibroblast growth factor receptor-1(IIIc) inhibits normal postnatal lung cell apoptosis.
Key words: lung growth, lung development, fibroblast growth factors, truncated soluble receptors
