Department of Respiratory Medicine, Traditional Chinese Medical Hospital of Jiangbei District, Chongqing, China.
Department of Respiratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Respir Physiol Neurobiol. 2020 Aug;279:103470. doi: 10.1016/j.resp.2020.103470. Epub 2020 May 28.
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.
在一些研究和最近的荟萃分析中，肥胖患者的急性肺损伤（ALI）的死亡率较低，这被称为肥胖悖论。高胰岛素血症是肥胖的主要表现，外源性胰岛素可减轻 LPS 诱导的肺水肿。需要阐明高胰岛素血症对肺水肿和肺泡填充的影响的详细机制。SD 大鼠喂食高脂肪饮食（HFD）共 14 周。SD 大鼠麻醉并腹膜内注射 10mg/kg 脂多糖（LPS），而对照大鼠仅接受生理盐水载体。胰岛素受体拮抗剂 S961（20nmol/kg）经尾静脉和血清给予，糖皮质激素诱导的蛋白激酶-1（SGK-1）抑制剂 EMD638683（20mg/kg）在 LPS 暴露前经胃给药。分离肺以测量肺泡液清除率。通过 Western blot 检测上皮钠通道（ENaC）的蛋白表达。与正常饮食大鼠相比，HFD 大鼠的血清胰岛素水平在存在或不存在 LPS 预处理的情况下均显着升高。高脂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，这些作用在 S961 作用下逆转。EMD638683 可防止 HFD 大鼠 ALI 中肺泡液清除率和 ENaC 蛋白表达的模拟。这些发现表明，肥胖引起的高胰岛素血症通过上调 ENaC 的丰度刺激临床急性肺损伤中的肺泡液清除率，而这些作用被 SGK-1 抑制剂所阻止。
