Deficiency in type 1 insulin-like growth factor receptor in mice protects against oxygen-induced lung injury.
BACKGROUND
Cellular responses to aging and oxidative stress are regulated by type 1 insulin-like growth factor receptor (IGF-1R). Oxidant injury, which is implicated in the pathophysiology of a number of respiratory diseases, acutely upregulates IGF-1R expression in the lung. This led us to suspect that reduction of IGF-1R levels in lung tissue could prevent deleterious effects of oxygen exposure.


METHODS
Since IGF-1R null mutant mice die at birth from respiratory failure, we generated compound heterozygous mice harboring a hypomorphic (Igf-1rneo) and a knockout (Igf-1r-) receptor allele. These IGF-1Rneo/- mice, strongly deficient in IGF-1R, were subjected to hyperoxia and analyzed for survival time, ventilatory control, pulmonary histopathology, morphometry, lung edema and vascular permeability.


RESULTS
Strikingly, after 72 h of exposure to 90% O2, IGF-1Rneo/- mice had a significantly better survival rate during recovery than IGF-1R+/+ mice (77% versus 53%, P < 0.05). The pulmonary injury was consistently, and significantly, milder in IGF-1Rneo/- mice which developed conspicuously less edema and vascular extravasation than controls. Also, hyperoxia-induced abnormal pattern of breathing which precipitated respiratory failure was elicited less frequently in the IGF-1Rneo/- mice.


CONCLUSIONS
Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury.
Ahamed
Karmene
K
INSERM U719, Hospital Saint-Antoine, 75012 Paris, France. ahamed@st-antoine.inserm.fr
Epaud
Ralph
R
Holzenberger
Martin
M
Bonora
Monique
M
Flejou
Jean-François
JF
Puard
Julien
J
Clement
Annick
A
Henrion-Caude
Alexandra
A
D000818:Animals; D019610:Cytoprotection; D005260:Female; D018496:Hyperoxia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D010100:Oxygen; D011654:Pulmonary Edema / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D012123:Pulmonary Ventilation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000172:deficiency*
D017526:Receptor, IGF Type 1; D010100:Oxygen