〔Abstract〕 Objective To investigate the protective effect and possible mechanism of inhibiting miR-128-3 p expression on oleic acid-induced lung injury in rats. Methods One hundred SD rats were randomly divided into five groups: sham operation group(sham), Model group(Model), antagomir NC group(NC), miR-128-3 p antagomir group(antagomir) and miR-128-3 p antagomir+ML385 group(antagomir+ML385), with 20 rats in each group. ARDS rat model was established by injecting oleic acid(0.15 ml/kg) into tail vein. miR-128-3 p antagomir or ML385 were given for intervention 1 h before surgery. After 24 h of successful modeling, arterial blood oxygen partial pressure(PaO2), oxygenation index(OI) and lung tissue wet/dry weight ratio(W/D) were measured. Lung histopathological changes were observed and scored by hematoxylin-eosin(HE) staining. The contents of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β) and interleukin-6(IL-6) in bronchoalveolar lavage fluid(BALF) were determined by enzyme linked immunosorbent assay(ELISA). Superoxide dismutase(SOD), malondialdehyde(MDA) and reactive oxide species(ROS) levels in lung tissue were determined by colorimetric method. The expression levels of miR-128-3 p and mRNA levels of Nrf2 and HO-1 in lung tissues were detected by RT-PCR, and the protein expression levels of E2 related factor 2(Nrf2) and heme oxygenase-1(HO-1) in lung tissues were detected by Western blot. Luciferase reporting experiments verified the targeting relationship between miR-128-3 p and Nrf2. Results Compared with the sham group, the lung tissues of the Model group were seriously damaged, and the lung pathological scores, W/D values, TNF-α, IL-1β and IL-6 contents in BALF, ROS and MDA levels and miR-128-3 p expression levels in the lung tissues increased(P<0.01), However, the values of PaO2, OI, SOD activity, mRNA and protein expression levels of Nrf2 and HO-1 reduced(P<0.01). Compared with the Model group, the degree of lung tissue injury in antagomir group improved, the lung pathological scores, W/D values, TNF-α, IL-1β and IL-6 contents in BALF, ROS and MDA levels and miR-128-3 p expression levels in the lung tissues decreased(P<0.01), However, the values of PaO2, OI, SOD activity, mRNA and protein expression levels of Nrf2 and HO-1 were induced(P<0.01), there was no significant difference in antagomir NC group(P>0.05). Compared with the antagomir group, the variation trend of antagomir+ML385 group was reversed(P<0.01). Luciferase reporting experiments confirmed that miR-128-3 p could target and regulate Nrf2 expression. Conclusion Inhibition of miR-128-3 p expression can reduce lung injury in rats, and its mechanism may be related to the inhibition of inflammation in lung tissues through targeted regulation of Nrf2 expression.