Role of HO-1 in sevoflurane-induced improvement in sepsis-associated encephalopathy in mice

Yaxin WANG; Lingling LIU; Keliang XIE; Jun CHEN

ABSTRACT

Objective:

To evaluate the role of heme oxygenase-1 (HO-1) in sevoflurane-induced improvement in sepsis-associated encephalopathy (SAE) in mice.

Methods:

A total of 136 adult male mice, aged 6-8 weeks, weighing 20-25 g, were divided into 4 groups ( n=34 each) using a random number table

method:

sham operation group (group Sham), SAE group, SAE+ sevoflurane group (group SAE+ Sevo) and SAE+ sevoflurane+ HO-1 inhibitor Zn Protoporphyrin Ⅸ (ZnPPⅨ) group (group SAE+ Sevo+ ZnPPⅨ). The model of SAE was established by cecal ligation and puncture (SAE) in anesthetized mice.In SAE+ Sevo and SAE+ Sevo+ ZnPPⅨ groups, 2% sevoflurane-33% oxygen was inhaled for 2 h starting from the time point immediately after establishment of the model, while 33% oxygen was inhaled for 2 h in Sham and SAE groups.ZnPPⅨ 25 mg/kg was intraperitoneally injected at 30 min before the model was established in group SAE+ Sevo+ ZnPPⅨ.Six mice were sacrificed at 6, 12 and 24 h after establishment of the model for determination of levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), high mobility group protein B1 (HMGB1) and HO-1 in cortical tissues (by enzyme-linked immunosorbent assay) and the expression of HO-1 (by Western blot). Another 6 mice were sacrificed for determination of apoptosis in cortical tissue (by TUNEL staining), and apoptotic index (AI) was calcultated.Ten mice in each group were selected, Y maze test was performed at 3, 5, 7 and 14 days after establishment of the model, and the percentage of spontaneous alternation was calculated.

Results:

Compared with Sham group, the levels of TNF-α, IL-1β and HMGB1, AI, HO-1 activity and its expression level in cortex were significantly increased, and the percentage of spontaneous alternation was decreased in SAE, SAE+ Sevo and SAE+ Sevo+ ZnPPⅨ groups ( P<0.05). Compared with group SAE, the levels of TNF-α, IL-1β and HMGB1 and AI were significantly decreased, and HO-1 activity and its expression level and the percentage of spontaneous alternation were increased in group SAE+ Sevo, the levels of TNF-α, IL-1β and HMGB1 in cortex were decreased ( P<0.05), and no significant change was found in the other parameters in group SAE+ Sevo+ ZnPPⅨ ( P>0.05). Compared with group SAE+ Sevo, the levels of TNF-α, IL-1β and HMGB1 and AI were significantly increased, and HO-1 activity and its expression level and the percentage of spontaneous alternation were decreased in group SAE+ Sevo+ ZnPPⅨ ( P<0.05).

Conclusion:

The mechanism by which sevoflurane improves SAE is related to increasing HO-1 activity and reducing inflammatory response in cortical tissues of mice.