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-1 r(neo)) and a knockout (Igf-1r(-)) receptor allele. These IGF-1R(neo/-) 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% O-2, IGF-1R(neo/-) 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-1R(neo/-) 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-1R(neo/-) mice. Conclusion: Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury.
