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Updated: Dec 24, 2025
Characterizing Salmonella Typhimurium-induced Septic Peritonitis in Mice
Published on: July 29, 2022
[Effect of inhibiting the activity of double-stranded RNA-dependent protein kinase in sepsis mice]
1Department of Critical Care Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
Abstract:
Objective: To observe the effects of 2-aminopurine (2-AP), a double-stranded RNA-dependent protein kinase (PKR) inhibitor, on organ function, plasma inflammatory factor expression and 7 days mortality in sepsis mice induced by cecal ligation puncture (CLP). Methods: Forty specific specific pathogen free C57BL/6 mice were randomly divided into sham group (n=10), CLP group (n=10), CLP+2-AP group (n=10) and 2-AP group (n=10). CLP was used to establish sepsis mice models.Peripheral blood serum was collected 24 hours after operation, alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum creatinine (Cr), blood urea nitrogen (BUN) and inflammatory factors (IL-1β, IL-10 and TNF-α) were detected; peripheral blood and peritoneal lavage fluid were taken for bacterial clearance detection. Another 60 C57BL/6 mice were selected to observe the 7-day survival rate according to the above groups (n=15). Independent sample t test was used to compare the measurement data between groups. Results: The levels of ALT, AST, Cr and BUN in CLP Group and CLP+2-AP group were significantly higher than those in sham group (all P<0.001). The levels of ALT and AST in CLP+2-AP group were significantly lower than those in CLP Group (t=27.88, 11.33, both P<0.001); the levels of Cr and BUN in CLP+2-AP group were significantly lower than those in CLP Group (t=11.02, 7.15, bothP<0.001). Compared with sham group, the levels of pro-inflammatory (IL-1β and TNF-α) and anti-inflammatory (IL-10) cytokines in CLP group were significantly higher (all P<0.001); the levels of IL-1β and IL-10 in CLP+2-AP group were significantly lower (all P<0.001), but the levels of TNF-α in CLP+2-AP group were not significantly lower (P=0.33). The 7-day survival rate was 100% in sham group, 13.3% in CLP+2-AP group, 86.7% in 2-AP group and 20.0% in CLP+2-AP group. Inhibition of PKR activation slightly improved the trend of 7-days survival rate of CLP model mice (analysis by mantel Cox test, χ(2)=0.0012, P=0.97). Conclusion: In sepsis mice model, inhibition of PKR activity can reduce the expression of inflammatory factors in plasma, decrease bacterial load in blood and abdominal cavity, and protect organ function, which could suggest that inhibition of PKR activity has potential application in sepsis treatment.
Insights
Inhibition of double-stranded RNA-dependent protein kinase (PKR) with 2-aminopurine (2-AP) in sepsis mice models reduced inflammatory factors and protected organ function, though 7-day survival rates showed minimal improvement.
Area of Science:
- Biomedical research
- Sepsis pathophysiology
- Pharmacological intervention
Background:
- Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection.
- Double-stranded RNA-dependent protein kinase (PKR) plays a role in inflammatory responses during sepsis.
- Targeting PKR may offer a therapeutic strategy for sepsis management.
Purpose of the Study:
- To investigate the therapeutic potential of 2-aminopurine (2-AP), a PKR inhibitor, in a murine model of sepsis.
- To evaluate the effects of 2-AP on organ function, inflammatory markers, and survival rates in sepsis.
Main Methods:
- Sepsis was induced in C57BL/6 mice using cecal ligation and puncture (CLP).
- Mice were treated with 2-AP or vehicle, and divided into sham, CLP, CLP+2-AP, and 2-AP groups.
- Organ function (ALT, AST, Cr, BUN), plasma inflammatory factors (IL-1β, IL-10, TNF-α), bacterial load, and 7-day survival rates were assessed.
Main Results:
- 2-AP treatment significantly reduced elevated liver enzymes (ALT, AST) and kidney markers (Cr, BUN) in CLP mice compared to untreated CLP mice.
- While IL-1β and IL-10 levels were decreased by 2-AP, TNF-α levels did not show significant reduction.
- PKR inhibition showed a non-significant trend towards improved 7-day survival rates in sepsis models.
Conclusions:
- Inhibition of PKR activity with 2-AP demonstrates protective effects on organ function and reduces inflammatory markers in a sepsis model.
- These findings suggest that targeting PKR may hold therapeutic promise for sepsis treatment, warranting further investigation.
