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Updated: Aug 6, 2025
Evaluation of a Reliable Biomarker in a Cecal Ligation and Puncture-Induced Mouse Model of Sepsis
Published on: December 9, 2022
Protective effect of HDACIs in improves survival and organ injury after CLP-induced sepsis
Kunwei Niu1, Shibin Qu1, Long Yang1
1Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, 127 Changle Road, Xi'an, Shaanxi 710032, China.
Insights
Histone deacetylase inhibitors (HDACIs) targeting classes I and IIb, along with non-selective HDACIs, significantly improved survival in sepsis models. These treatments also reduced organ injury and inflammation by modulating immune cell populations and NF-κB acetylation.
Area of Science:
- Sepsis research
- Pharmacology
- Molecular biology
Background:
- Histone deacetylase inhibitors (HDACIs) are known to impact sepsis outcomes.
- However, the specific HDAC classes most effective in sepsis treatment remain underexplored.
- This study investigates the differential effects of various HDACIs on sepsis survival and organ damage.
Purpose of the Study:
- To determine which classes of HDACIs are most effective in improving survival during sepsis.
- To evaluate the protective effects of different HDACIs against sepsis-induced organ injury.
- To elucidate the molecular mechanisms underlying HDACI efficacy in sepsis.
Main Methods:
- Sepsis was induced in Sprague-Dawley rats via cecal ligation and puncture.
- Animals were treated with various isoform-specific and non-selective HDACIs.
- Survival rates, serum biomarker levels (cytokines, liver/cardiac enzymes), tissue histology, protein acetylation (NF-κB, histones), and immune cell populations were analyzed.
Main Results:
- HDACI classes I and IIb, along with non-selective HDACIs (MS-275, TubA, TSA), significantly prolonged survival.
- These treatments reduced histopathological scores and levels of key inflammatory markers (IL-6, IL-1β, TNF-α) and tissue damage indicators (AST, ALT, CK, LDH).
- HDACIs increased NF-κB acetylation and altered immune cell proportions, indicating modulation of inflammatory pathways.
Conclusions:
- Class I and IIb HDACIs, as well as non-selective HDACIs, are effective in prolonging survival in a sepsis model.
- Both non-selective and specific HDACIs (class I, IIa/IIb) demonstrate potential in attenuating sepsis-induced inflammation and organ injury.
- These findings highlight specific HDAC inhibitor classes as promising therapeutic candidates for sepsis management.
Introduction:
The effects of isoform-specific histone deacetylase inhibitors (HDACIs) and the non-selective HDACI on sepsis have been profoundly reported. However, the best HDAC classes have not been fully evaluated. Therefore, this study aimed to determine which HDACIs are responsible for survival and beneficial for organ injury.
Methods:
Experiment I, SD rats were subjected to cecal ligation and puncture and randomly assigned to the no treatment, dimethyl sulfoxide (DMSO) only, MS-275, LMK-235, tubastatinA (TubA), trichostatin-A (TSA), and sirtinol groups (n = 5). Survival was monitored for 48 h. Experiment II, the animals were monitored for 12 h, then, blood and tissues sample were collected. Interleukin (IL)-6, IL-1β, tumour necrosis factor (TNF)-α, alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatine kinase (CK) and lactate dehydrogenase (LDH) expressions were evaluated using ELISA. Liver, heart and lung tissues were analysed via hematoxylin and eosin staining. Liver and heart tissue lysates were analysed for acetylated histones H3, H4, a-tubulin and nuclear factor kappa B (NF-κB), IL-6, IL-1β, and TNF-α using western blotting. Splenocytes were examined via flow cytometry to analyse the immune cell population.
Results:
MS-275, TubA and TSA treatments significantly prolonged survival. MS-275, LMK-235, TubA and TSA significantly reduced the histopathological scores and AST, ALT, CK, LDH, IL-6, IL-1β and TNF-α levels, significantly increased acetylated of NF-κB and changed the immune cell proportion.
Conclusion:
Our results indicated that HDACI classes I and IIb and non-selective HDACI can significantly prolong survival. Moreover, non-selective and isoform-specific class I and IIa/IIb HDACIs can attenuate inflammation and organ injury.
