Protective effect of Olaparib against acute lung injury induced by endotoxin in mice
Objective To evaluate the protective effect of Olaparib against endotoxic-induced acute lung injury in mice.Methods Twenty-four SPF male C57BL/6 mice,aged 8-10 weeks,weighing 20-30 g,were divided into four groups(n=6):control group,lipopolysaccharide(LPS)group,5 mg/kg Olaparib group and 10 mg/kg Olaparib group.The ALI model was constructed by nebulisation of 1 mg/mL LPS for 30 min per day for 3 d in LPS group,5 mg/kg Olaparib group,and 10 mg/kg Olaparib group.The mice in 5 mg/kg Olaparib group and 10 mg/kg Olaparib group were respectively injected intraperitoneally with 5,10 mg/kg Olaparib immediately after the nebulisation on the 3rd day.The mice in control group were injected intraperitoneally with an equal amount of saline.The beha-vioural changes and other general conditions of mice were observed after drug administration,and the mice were executed at 24 h after the administration.The wet/dry weight ratio of lung was calculated.The total protein content in serum and alveolar lavage fluid was determined using BCA method,and the lung permeability index(LPI)was calculated.The concentrations of IL-6,TNF-α,and IL-1 βin lung tissues and serum were measured using ELISA.Additionally,enzyme colorimetry was used to measure the contents of malondial-dehyde(MDA)and total antioxidant capacity(T-AOC),and the activities of superoxide dismutase(SOD)and myeloperoxidase(MPO)in lung tissues.The degree of lung tissue injury was determined using HE staining,and the level of Caspase-1 expression in lung tissues was assessed using immunohistochemistry.Results After intraperitoneal injection of Olaparib,all the mice survived,no obvious irritability or malaise were found,and no symptoms such as nausea,vomiting,diarrhea and loss of appetite were observed.Compared with control group,lung wet/dry ratio and LPI were significantly increased in LPS group,5 mg/kg Olaparib group and 10 mg/kg Olaparib group(P＜0.05),the levels of IL-6,TNF-α and IL-1β were significantly increased in lung tissue and serum(P＜0.05),the content of MDA and the activity of MPO in lung tissues were significantly increased(P＜0.05),the content of T-AOC and the activity of SOD were significantly decreased(P＜0.05),the expression level of Caspase-1 in lung tissue was significantly increased(P＜0.05),and the pathological injury score of lung tissue was significantly increased(P＜0.05).Compared with LPS group,lung wet/dry ratio and LPI were significantly decreased in 5 mg/kg Olaparib group and 10 mg/kg Olaparib group(P＜0.05),the levels of IL-6,TNF-αand IL-1β were significantly decreased in lung tissues and serum(P＜0.05),the content of MDA and the activity of MPO in lung tissue were significantly decreased(P＜0.05),the content of T-AOC and the activity of SOD were significantly increased(P＜0.05),the expression level of Caspase-1 in lung tissue was significantly decreased(P＜0.05),and the pathological injury score of lung tissue was significantly decreased(P＜0.05).Compared with 5 mg/kg Olaparib group,lung wet/dry ratio and LPI were significantly decreased in 10 mg/kg group(P＜0.05),IL-6,TNF-α and IL-1β levels in lung tissue and serum were significantly decreased(P＜0.05),the content of MDA and the activity of MPO in lung tissue were significantly decreased(P＜0.05),the content of T-AOC and the activity of SOD were significantly increased(P＜0.05),the expression level of Caspase-1 in lung tissue was significantly decreased(P＜0.05),and the pathological injury score of lung tissue was significantly decreased(P＜0.05).Conclusion Intraperitoneal injection of Olaparib can attenuate pulmonary and systemic inflammatory reactions,pulmonary edema and lung tissue injury,reduce the level of oxidative stress in lung tissues,and attenuate the cellular pyroptosis by inhibiting the Caspase-1/IL-1 β signaling pathway in mice with endotoxin-induced ALI,and the efficacy is better at a dose of 10 mg/kg,without any significant adverse effects.
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