Leptin resistance protects mice from hyperoxia-induced acute lung injury
Leptin resistance protects mice from hyperoxia-induced acute lung injury
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DOI：
10.1164/rccm.200603-312oc
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发表时间：
2007-03-15
影响因子：
24.7
通讯作者：
Mutlu, Gokhan M.
中科院分区：
文献类型：
--
作者：
Bellmeyer, Amy;Martino, Janice M.;Mutlu, Gokhan M.
依据：人体数据表明，II型糖尿病患者的急性肺损伤发生率降低。然而，糖尿病赋予保护肺injury的机制是unknown. Objective. To确定是否瘦素抵抗，这是在人类糖尿病，保护小鼠高氧肺injury.Methods：野生型（瘦素反应）和db/db（瘦素抵抗）小鼠被用于这些研究。将小鼠暴露于高氧（100%O-2）84小时以诱导肺损伤，并长达168小时用于存活研究。在体内测量肺泡液体清除率。测量和主要结果：高氧后，野生型和瘦素受体缺陷型db/db小鼠的肺瘦素水平均升高。与野生型小鼠相比，db/db中高氧诱导的肺损伤减少。高氧增加了野生型小鼠的肺通透性，但在db/db小鼠中没有。与野生型对照动物相比，db/db小鼠对高氧诱导的死亡率具有抗性（50%小鼠的致死剂量，152 vs. 108 h）。气管内滴注瘦素（其剂量与高氧期间支气管肺泡灌洗液中观察到的剂量相同）会导致野生型小鼠肺损伤，但不会导致db/db小鼠肺损伤。腹腔内给予瘦素受体抑制剂可减轻瘦素诱导的肺水肿。db/db小鼠中高氧诱导的促炎细胞因子释放减弱。尽管抗肺损伤，db/db小鼠减少了肺泡液体清除率和减少Na，K-ATP酶功能相比，野生型mice.Conclusions：这些结果表明，瘦素可以诱导和抵抗瘦素减弱高氧诱导的肺损伤和高氧诱导的炎症细胞因子在肺。
Rationale: Human data suggest that the incidence of acute lung injury is reduced in patients with type II diabetes mellitus. However, the mechanisms by which diabetes confers protection from lung injury are unknown.Objectives: To determine whether leptin resistance, which is seen in humans with diabetes, protects mice from hyperoxic lung injury.Methods: Wild-type (leptin responsive) and db/db (leptin resistant) mice were used in these studies. Mice were exposed to hyperoxia (100% O-2) for 84 hours to induce lung injury and up to 168 hours for survival studies. Alveolar fluid clearance was measured in vivo. Measurements and Main Results: Lung leptin levels were increased both in wild-type and leptin receptor-defective db/db mice after hyperoxia. Hyperoxia-induced lung injury was decreased in db/db compared with wild-type mice. Hyperoxia increased lung permeability in wild-type mice but not in db/db mice. Compared with wild-type control animals, db/db mice were resistant to hyperoxia-induced mortality (lethal dose for 50% of mice, 152 vs. 108 h). Intratracheal instillation of leptin at a dose that was observed in the bronchoalveolar lavage fluid during hyperoxia caused lung injury in wild-type but not in db/db mice. Intratracheal pretreatment with a leptin receptor inhibitor attenuated leptin-induced lung edema. The hyperoxia-induced release of proinflammatory cytokines was attenuated in db/db mice. Despite resistance to lung injury, db/db mice had diminished alveolar fluid clearance and reduced Na, K-ATPase function compared with wild-type mice.Conclusions: These results indicate that leptin can induce and that resistance to leptin attenuates hyperoxia-induced lung injury and hyperoxia-induced inflammatory cytokines in the lung.