Ahamed Karmene, Epaud Ralph, Holzenberger Martin, Bonora Monique, Flejou Jean-François, Puard Julien, Clement Annick, Henrion-Caude Alexandra
INSERM U719, Hospital Saint-Antoine, 75012 Paris, France.
Respir Res. 2005 Apr 8;6(1):31. doi: 10.1186/1465-9921-6-31.
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.
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.
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.
Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury.
细胞对衰老和氧化应激的反应受1型胰岛素样生长因子受体（IGF-1R）调控。氧化损伤与多种呼吸系统疾病的病理生理学有关，可急性上调肺组织中IGF-1R的表达。这使我们推测降低肺组织中IGF-1R水平可预防氧暴露的有害影响。
由于IGF-1R基因敲除突变小鼠出生时死于呼吸衰竭，我们构建了携带低表达（Igf-1rneo）和敲除（Igf-1r-）受体等位基因的复合杂合小鼠。这些严重缺乏IGF-1R的IGF-1Rneo/-小鼠接受高氧处理，并分析其存活时间、通气控制、肺组织病理学、形态学、肺水肿和血管通透性。
令人惊讶的是，在暴露于90%氧气72小时后，IGF-1Rneo/-小鼠在恢复过程中的存活率显著高于IGF-1R+/+小鼠（77%对53%，P<0.05）。IGF-1Rneo/-小鼠的肺损伤始终明显较轻，其水肿和血管渗出明显少于对照组。此外，高氧诱导的导致呼吸衰竭的异常呼吸模式在IGF-1Rneo/-小鼠中出现的频率较低。
总之，这些数据表明小鼠中IGF-1R信号的降低可预防氧化诱导的肺损伤。
