基于Nrf2/HO-1信号通路4-辛基衣康酸对脂多糖诱导小鼠急性肺损伤的作用

Effects of 4-octyl itaconate on lipopolysaccharide-induced acute lung injury in mice based on Nrf2/HO-1 signaling pathways

目的 探究4-辛基衣康酸(4-octyl itaconate, 4-OI)对急性肺损伤小鼠的保护作用及其可能机制。方法 腹腔注射LPS(10 mg/kg)建立小鼠急性肺损伤模型,将小鼠随机分成对照组、LPS组和4-OI+LPS组,造模6 h后检测小鼠肺湿/干重(W/D)比值、肺组织髓过氧化物(myeloperoxidase, MPO)、超氧化物歧化酶(superoxide dismutase, SOD)活性和丙二醛(malon dialdehyde, MDA)含量;ELISA法检测肺组织白细胞介素1β(IL-1β)含量;采用蛋白质印迹法检测肺组织核因子NF-E2相关因子(nuclear factor erythroid 2-related factor 2,Nrf2)和血红素氧合酶-1(heme oxygenase-1,HO-1)蛋白表达。结果 与对照组相比,LPS组小鼠W/D、MPO活性和IL-1β含量显著性升高(P<0.01或P<0.05),肺组织中MDA含量升高,SOD活性下降(P<0.01),Nrf2和HO-1蛋白表达降低(P<0.01)。与LPS组相比,4-OI+LPS组降低了肺W/D、MPO活性、IL-1β和MDA含量,使肺SOD活性升高,同时也提高了肺组织中Nrf2和HO-1蛋白表达(均P<0.05)。结论 4-OI可通过改善氧化应激和炎症反应减轻LPS诱导的急性肺损伤,这可能与激活Nrf2/HO-1通路有关。

Objective To investigated the effects of 4-octyl itaconate on lipopolysaccharide(LPS)-induced acute lung injury and its possible mechanisms in mice. Methods Acute lung injury model was established by intraperitoneal injection of LPS(10 mg/kg). Mice were randomly divided into a control group, a LPS group and a 4-OI+LPS group. After 6 h, the lung W/D weight ratio of the mice in each group was calculated, and myeloperoxidase(MPO) activities, dismutase(SOD) activities, malondialdehyde(MDA) in lung tissues were measured. The level of IL-1β in lung tissue was measured by ELISA. The expression of Nrf2 and HO-1 in lung tissue were analyzed by Western blotting. Results Compared with the control group, the wet/dry weight ratio(W/D) of the lung, MPO activity, and the level of IL-1β in lung tissue of the LPS group obviously increased(P<0.01 or P<0.05). In addition, the levels of SOD decreased significantly(P<0.01), while MDA increased in the LPS group(P<0.01). Compared with the LPS group, the levels of IL-1β and MDA in lung tissues of 4-OI +LPS group significantly decreased, while the contents of SOD increased, and lung W/D and the activity of MPO reduced(all P<0.05). LPS inhibited the expression of Nrf2 and HO-1(P<0.01), and 4-OI up-regulated the expression of Nrf2 and HO-1(P<0.05). Conclusions 4-OI shows protective effect on mice with acute lung injury by inhibiting inflammation and oxidative stress route through activating Nrf2/HO-1 pathway.