A lower mortality rate is observed in obese patients with acute lung injury (ALI), which is referred to as the obesity paradox, in several studies and recent meta-analyses. Hyperinsulinemia is characterized as the primary effect of obesity, and exogenous insulin attenuates LPS-induced pulmonary edema. The detailed mechanism responsible for the effect of hyperinsulinemia on pulmonary edema and alveolar filling needs to be elucidated. SD rats were fed with a high-fat diet (HFD) for a total of 14 weeks. SD rats were anesthetized and intraperitoneally injected with 10 mg/kg lipopolysaccharide (LPS), while control rats received only saline vehicle. Insulin receptor antagonist S961 (20 nmol/kg) was given by the tail vein and serum, and glucocorticoid-induced protein kinase-1 (SGK-1) inhibitor EMD638683 (20 mg/kg) was administrated intragastrically prior to LPS exposure. The lungs were isolated for the measurement of alveolar fluid clearance. The protein expression of epithelial sodium channel (ENaC) was detected by Western blot. Insulin level in serum was significantly higher in HFD rats compared with normal diet rats in the presence or absence of LPS pretreatment. Hyperinsulinemia induced by high fat feeding increased alveolar fluid clearance and the abundance of α-ENaC, β-ENaC, and γ-ENaC in both normal rats and ALI rats. Moreover, these effects were reversed in response to S961. EMD638683 prevented the simulation of alveolar fluid clearance and protein expression of ENaC in HFD rats with ALI. These findings suggest that hyperinsulinemia induced by obesity results in the stimulation of alveolar fluid clearance via the upregulation of the abundance of ENaC in clinical acute lung injury, whereas theses effects are prevented by an SGK-1 inhibitor.

在几项研究和最近的荟萃分析中，观察到患有急性肺损伤 (ALI) 的肥胖患者的死亡率较低，这被称为肥胖悖论。高胰岛素血症的特征是肥胖的主要影响，外源性胰岛素减轻 LPS 诱导的肺水肿。需要阐明高胰岛素血症对肺水肿和肺泡充盈的影响的详细机制。SD大鼠用高脂肪饮食（HFD）喂养总共14周。SD 大鼠被麻醉并腹腔注射 10 mg/kg 脂多糖 (LPS)，而对照大鼠仅接受盐水载体。胰岛素受体拮抗剂 S961 (20 nmol/kg) 通过尾静脉和血清给予，和糖皮质激素诱导的蛋白激酶-1 (SGK-1) 抑制剂 EMD638683 (20 mg/kg) 在 LPS 暴露前灌胃给药。分离肺用于测量肺泡液清除率。Western blot检测上皮钠通道（ENaC）蛋白表达。在存在或不存在 LPS 预处理的情况下，HFD 大鼠的血清胰岛素水平显着高于正常饮食大鼠。高脂肪喂养引起的高胰岛素血症增加了正常大鼠和 ALI 大鼠的肺泡液清除率和 α-ENaC、β-ENaC 和 γ-ENaC 的丰度。此外，这些影响在响应 S961 时被逆转。EMD638683 阻止了 ALI 的 HFD 大鼠肺泡液清除率和 ENaC 蛋白表达的模拟。