RESUMO
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. CONCLUSION: Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury.
Assuntos
Hiperóxia/patologia , Hiperóxia/fisiopatologia , Pulmão/patologia , Pulmão/fisiopatologia , Edema Pulmonar/patologia , Edema Pulmonar/fisiopatologia , Receptor IGF Tipo 1/deficiência , Animais , Citoproteção , Feminino , Hiperóxia/induzido quimicamente , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Oxigênio , Edema Pulmonar/induzido quimicamente , Ventilação Pulmonar/efeitos dos fármacosRESUMO
SUT1 constitutive expression in aerobiosis suppressed the ts phenotype of the sec14-1 mutation, restored growth of the sec14-null mutant and corrected the translocation defect of the vacuolar carboxypeptidase Y. Therefore SUT1 was shown to be a novel potent sec14-1 suppressor. Further, the hypoxic gene CSR1 (YLR380W), a Sec14 homolog, was upregulated upon SUT1 constitutive expression. In addition, SUT1 effects on both sec14-1 suppression and on free sterol composition were abolished in a csr1-null background, showing that this gene acts downstream of SUT1.