Regulation of cell proliferation by insulin-like growth factor 1 in hyperoxia-exposed neonatal rat lung.
Hyperoxic exposure of the developing lung leads to characteristic peribronchial and mesenchymal fibroproliferative changes. We hypothesize that O2-induced changes in the neonatal lung are mediated by Insulin-like growth factor 1 (IGF-1) and IGF-1 receptor (IGF-1R). Lung explant cultures were prepared from 3-day-old neonatal rat pups and exposed to room air or 95% O2 for 72 h. Western blots and immunohistochemistry were used to determine if hyperoxia stimulated IGF-1 and IGF-1R, and to identify the cell types involved. Retinoic acid was used to learn if this would inhibit oxygen-induced cell proliferation. Hyperoxia induced a significant increase in thymidine incorporation (control, 54 +/- 9; hyperoxia, 254 +/- 24 dpm/nM DNA; mean +/- SEM; N = 3; P < 0.05). This was inhibited by 5 x 10(-5) M RA (149 +/- 18 dpm/nM DNA; P < 0.05) and by anti-IGF-1 antibody (115 +/- 25 dpm/nM DNA; P < 0.05; N = 3). BrdU labeling in the mesenchymal cells was significantly increased in mesenchymal cells after exposure to oxygen (91% higher than the room air control) but not in epithelial cells. This increase was inhibited in the presence of retinoic acid. Western blots showed IGF-1 protein was increased after 72 h of O2 exposure compared to room air exposure (57 +/- 7 compared to 32 +/- 5 densitometric units; P < 0.05; N = 3). The increase was inhibited when the cultures were exposed to 95% O2 in the presence of anti-IGF-1 antibody (28 +/- 4; P < 0.05; N = 3). IGF-1 protein decreased in the presence of retinoic acid after oxygen exposure but not in room air. Immunostaining of O2-exposed lung showed IGF-1 was most abundant in airway and alveolar epithelial cells. We conclude that hyperoxia increases cell proliferation by stimulating IGF-1 in the neonatal rat lung. Interaction of IGF-1 and IGF-1R is an important cell-cell communication mechanism in the developmental and repair processes of hyperoxic neonatal lung injury.
Chetty
Anne
A
Department of Pediatrics, New England Medical Center, Boston, Massachusetts 02111, USA.
Nielsen
Heber C
HC
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D046508:Culture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D018496:Hyperoxia / Q000503:physiopathology; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010100:Oxygen / Q000494:pharmacology*; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D014316:Tritium
D014316:Tritium; D014212:Tretinoin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D010100:Oxygen; D013936:Thymidine