Abstract

BACKGROUND: The aim of the present study was to investigate the protective effects of protease inhibitor MG-132 on sepsis-induced acute lung injury rats.

MATERIAL AND METHODS: Sprague Dawley rats were employed to induce sepsis by cecal ligation and puncture (CLP) method. Rats were divided into 4 groups: control, sham, model (CLP), and MG-132. Histopathology observation was detected by hematoxylin and eosin staining. The ratio of wet lung to dry lung (W/D) was calculated. In addition, the levels of inflammatory factors in bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). Also, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were evaluated. Western blotting was performed to measure the expression of hypoxia-inducible factor-1 α (HIF-1α). In order to assess the role of HIF-1α, YC-1, the inhibitor of HIF-1α, was used to treat the rats. The expression of phosphor-mTOR (p-mTOR), p-4EBP1, and p-EIF4E were evaluated by western blotting.

RESULTS: Obvious pathological injury and increasing ratio of W/D in the model group were observed. Both pathological injury and W/D were improved in the MG-132 group, and the greatest improvement could be seen in the YC-1+MG-132 group. Furthermore, the MDA levels in the MG-132 group was decreased, accompanied by an increase in SOD levels. The level of HIF-1α was increased in the model group while a decreased was detected in the MG-132 group. The levels of inflammatory factors were high in the model group, whereas the opposite result was found in the MG-132 group, and the lowest in were in the YC-1+MG-132 group. Furthermore, the expression levels of p-mTOR, p-4EBP1, and p-EIF4E proteins were downregulated in the MG-132 group compared to the model group, and the lowest was in the YC-1+MG-132 group.

CONCLUSIONS: Our study suggested that MG-132 was able to protect against acute lung injury via inhibition of HIF-1α mediated mTOR/4EBP1/EIF4E pathway.

Keywords: acute lung injury, Hypoxia-Inducible Factor 1, Sepsis, Bronchoalveolar Lavage Fluid, Eukaryotic Initiation Factor-4E, Hypoxia-Inducible Factor 1, alpha Subunit, Intracellular Signaling Peptides and Proteins, Leupeptins, Lung, Malondialdehyde, Pulmonary Edema, TOR Serine-Threonine Kinases