The Protective Effects of Protease Inhibitor MG-132 on Sepsis-Induced Acute Lung Rats and Its Possible Mechanisms.

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 alpha (HIF-1alpha). In order to assess the role of HIF-1alpha, YC-1, the inhibitor of HIF-1alpha, 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-1alpha 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-1alpha mediated mTOR/4EBP1/EIF4E pathway.

• Authors: Bingbing Wu, Xiaoli Miao, Jilu Ye, Xuehua Pu
• Journal: Medical science monitor : international medical journal of experimental and clinical research (Med Sci Monit) Vol. 25 Pg. 5690-5699 (Aug 01 2019) ISSN: 1643-3750 [Electronic] United States
• PMID: 31366881 (Publication Type: Journal Article)

Chemical References

• Eif4ebp1 protein, rat
• Eukaryotic Initiation Factor-4E
• Hypoxia-Inducible Factor 1, alpha Subunit
• Intracellular Signaling Peptides and Proteins
• Leupeptins
• Malondialdehyde
• Superoxide Dismutase
• TOR Serine-Threonine Kinases
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• Acute Lung Injury (chemically induced, drug therapy, prevention & control)
• Animals
• Bronchoalveolar Lavage Fluid
• China
• Eukaryotic Initiation Factor-4E (metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Leupeptins (pharmacology)
• Lung (pathology)
• Malondialdehyde (metabolism)
• Pulmonary Edema (metabolism)
• Rats
• Rats, Sprague-Dawley
• Sepsis (complications)
• Superoxide Dismutase (metabolism)
• TOR Serine-Threonine Kinases (metabolism)