Abstract: Objective To observe the protective effect and mechanism of ulinastatin on acute lung injury in septic rats. Methods Eighty rats were randomly divided into sham operation group, model group, ulinastatin group, inhibitor group, ulinastatin + inhibitor group, 16 rats in each group. Ulinastatin + inhibitor group was intraperitoneally injected with ulinastatin 20 000 U/kg and solasodine 50 mg/kg. Ulinastatin group was intraperitoneally injected with ulinastatin 20 000 U/kg and 5% DMSO saline. In the inhibitor group, solasodine 50 mg/kg and the same amount of normal saline were injected intraperitoneally. The model group and sham operation group were intraperitoneally injected with the same amount of normal saline and normal saline containing 5% DMSO. The ratio of wet weight to dry weight （W/D） of lung tissue was detected, and tumor necrosis factor-α （TNF-α）, interleukin-6 （IL-6） and IL-10 were detected by ELISA. HE staining was used to observe lung histopathology and evaluate lung injury score. TUNEL staining was used to observe the apoptosis of lung tissue. Western blot was used to detect the relative expression of phosphatidylinositol 3-kinase （PI3K）, protein kinase B （Akt）, p-Akt, rapamycin target protein （mTOR） and p-mTOR. Results Compared with the sham operation group, W/D value, TNF-α, IL-6, apoptosis rate of model group, ulinastatin group, inhibitor group and ulinastatin + inhibitor group were increased, while IL-10 was decreased, and W/D value, TNF-α, IL-6, apoptosis rate, inhibitor group > model group > ulinastatin + inhibitor group > ulinastatin group, IL-10, inhibitor group < model group < ulinastatin + inhibitor group < ulinastatin group （P<0.05）. HE staining showed that compared with model group and inhibitor group, ulinastatin + inhibitor group and ulinastatin group had mild disorder of lung tissue structure, less abnormal changes such as bleeding, edema, alveolar wall thickening and inflammatory cell infiltration, especially in ulinastatin group. Pathological score of lung tissue: inhibitor group>model group > ulinastatin + inhibitor group > ulinastatin group > sham operation group （P<0.05）. Compared with the sham operation group, the relative expression of PI3K, p-Akt, p-mTOR protein in model group, ulinastatin group, inhibitor group and ulinastatin + inhibitor group decreased, ulinastatin group > ulinastatin + inhibitor group > model group > inhibitor group （P<0.05）. Conclusions Ulinastatin had protective effect on acute lung injury in sepsis rats, and the mechanism may be related to activation of Akt signaling pathway.