Saquinavir (SQV) is the first FDA approved HIV protease inhibitor.Previous studies showed that SQV can limit Toll-like receptor-4 (TLR4)-mediated inflammatory pathway and nuclear factor-κB (NF-κB) activation,thereby playing a protective role in many kinds of diseases.High-mobility group box 1 (HMGB1) has been identified as an inflammatory mediator and it might express its toxicity in a short period of time in ventilator-induced lung injury (VILI).In this study,C57BL/6 mice were randomly divided into four groups (n =10):control group and control with SQV group (Con + SQV) were spontaneous breath.HTV group (HTV) received high tidal volume ventilation (HTV) for 4 h.HTV with SQV group (HTV + SQV) were pretreated with 5 mg/kg of SQV for 7 days before HTV.Mice were sacrificed after 4 h of HTV.Lung wet/dry weight (W/D) ratio,alveolar-capillary permeability to Evans blue albumin (EBA),cell counts,total proteins in bronchoalveolar lavage fluid (BALF),tumor necrosis factor-α(TNF-α),interleukin-6 (IL-6) level in BALF and lung tissue,and lung histopathology were examined.Our results showed that HTV caused significant lung injury and NF-κB activation,which was correlated with the increase of TNF-α and IL-6 levels in BALF and plasma.SQV pretreatment significantly attenuated pulmonary inflammatory injury,as well as NF-κB activation.These findings indicate that the protective effect of SQV may be associated with the inhibition of NF-κB activation and HMGB1 expression in mice.