Fibroblast growth factor receptors control epithelial-mesenchymal interactions necessary for alveolar elastogenesis.
BACKGROUND
The mechanisms contributing to alveolar formation are poorly understood. A better understanding of these processes will improve efforts to ameliorate lung disease of the newborn and promote alveolar repair in the adult. Previous studies have identified impaired alveogenesis in mice bearing compound mutations of fibroblast growth factor (FGF) receptors (FGFRs) 3 and 4, indicating that these receptors cooperatively promote postnatal alveolar formation.


OBJECTIVE
To determine the molecular and cellular mechanisms of FGF-mediated alveolar formation.


METHODS
Compound FGFR3/FGFR4-deficient mice were assessed for temporal changes in lung growth, airspace morphometry, and genome-wide expression. Observed gene expression changes were validated using quantitative real-time RT-PCR, tissue biochemistry, histochemistry, and ELISA. Autocrine and paracrine regulatory mechanisms were investigated using isolated lung mesenchymal cells and type II pneumocytes.


RESULTS
Quantitative analysis of airspace ontogeny confirmed a failure of secondary crest elongation in compound mutant mice. Genome-wide expression profiling identified molecular alterations in these mice involving aberrant expression of numerous extracellular matrix molecules. Biochemical and histochemical analysis confirmed changes in elastic fiber gene expression resulted in temporal increases in elastin deposition with the loss of typical spatial restriction. No abnormalities in elastic fiber gene expression were observed in isolated mesenchymal cells, indicating that abnormal elastogenesis in compound mutant mice is not cell autonomous. Increased expression of paracrine factors, including insulin-like growth factor-1, in freshly-isolated type II pneumocytes indicated that these cells contribute to the observed pathology.


CONCLUSIONS
Epithelial/mesenchymal signaling mechanisms appear to contribute to FGFR-dependent alveolar elastogenesis and proper airspace formation.
Srisuma
Sorachai
S
Division of Neonatology and Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, New York 14642, USA.
Bhattacharya
Soumyaroop
S
Simon
Dawn M
DM
Solleti
Siva K
SK
Tyagi
Shivraj
S
Starcher
Barry
B
Mariani
Thomas J
TJ
D000704:Analysis of Variance; D000818:Animals; D004549:Elastin / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004847:Epithelial Cells / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000378:metabolism; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000648:ultrastructure; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D017468:Receptors, Fibroblast Growth Factor; D004549:Elastin