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Updated: Apr 26, 2026
Evaluation of a Reliable Biomarker in a Cecal Ligation and Puncture-Induced Mouse Model of Sepsis
Published on: December 9, 2022
Histone deacetylase III as a potential therapeutic target for the treatment of lethal sepsis
Ting Zhao1, Yongqing Li, Baoling Liu
1From the Department of Surgery (T.Z.), Division of Trauma, Emergency Surgery & Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts; Department of Surgery (Y.L., B.L., I.H., H.B.A.), University of Michigan Hospital, Ann Arbor, Michigan; and Department of Microbiology and Immunobiology (R.T.B.), Harvard Medical School, Boston, Massachusetts.
Insights
Inhibiting Sirtuin 1 (SIRT1) with EX-527 significantly improved survival in a sepsis model by reducing inflammation and coagulopathy. This study highlights SIRT1 as a therapeutic target for severe sepsis.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Histone deacetylase (HDAC) inhibition improves survival in a mouse model of lethal cecal ligation and puncture (CLP) sepsis.
- The role of HDAC Class III inhibition, specifically Sirtuin 1 (SIRT1), in sepsis survival remains unexplored.
- This study investigates the therapeutic potential of a selective SIRT1 inhibitor, EX-527, in a lethal CLP-sepsis model.
Purpose of the Study:
- To determine the effect of EX-527 on survival in a lethal CLP-sepsis mouse model.
- To assess the impact of EX-527 on inflammatory cytokine production, coagulopathy, and bone marrow atrophy.
- To evaluate the in vitro effect of EX-527 on lipopolysaccharide-stimulated splenocyte cytokine production.
Main Methods:
- Mice underwent CLP and were treated with either EX-527 or vehicle (DMSO).
- Survival was monitored, and blood/peritoneal fluid were analyzed for cytokines and coagulation status (thrombelastography).
- Bone marrow morphology was assessed, and splenocytes were cultured to measure cytokine responses to EX-527.
Main Results:
- EX-527 treatment significantly improved survival (50% vs. 0%) and reduced levels of tumor necrosis factor α and interleukin 6.
- SIRT1 inhibition improved fibrin cross-linkage, platelet function, and clot rigidity, while decreasing bone marrow atrophy.
- In vitro, EX-527 reduced cytokine production by splenocytes stimulated with lipopolysaccharide.
Conclusions:
- Selective inhibition of SIRT1 using EX-527 significantly enhances survival in a lethal mouse model of sepsis.
- EX-527 treatment attenuates sepsis-induced cytokine storm, coagulopathy, and bone marrow atrophy.
- Targeting SIRT1 represents a promising therapeutic strategy for managing severe sepsis.
Background:
We have recently demonstrated that inhibition of histone deacetylase (HDAC) Class I, II, and IV with nonspecific HDAC inhibitors improves survival in a mouse model of lethal cecal ligation and puncture (CLP). However, the consequence of HDAC Class III inhibition is unknown in this model. The aims of the present study were to explore the effect of EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, on survival in the lethal model of CLP-sepsis and to assess the impact of the treatment on inflammatory cytokine production, coagulopathy, and bone marrow atrophy during severe sepsis.
Methods:
For Experiment I, C57BL/6J mice were subjected to CLP and, 1 hour later, intraperitoneally injected with either EX-527 dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Survival was monitored for 10 days. For Experiment II, 1 hour after CLP animals were randomly treated with (1) DMSO vehicle and (2) EX-527. Peritoneal fluid and blood samples were collected for measurement of cytokines, and blood was also used to evaluate coagulation status using thrombelastography. In addition, long bones (femurs and tibias) were examined to determine morphologic changes in the marrow by hematoxylin and eosin staining. For Experiment III, normal primary splenocytes were cultured and treated with lipopolysaccharide in the presence or absence of EX-527 to assess cytokine production.
Results:
EX-527 significantly improved survival (50% vs. 0% survival as compared to vehicle, p = 0.0007) and attenuated levels of cytokines tumor necrosis factor α and interleukin 6 in the blood and the peritoneal fluid compared with the vehicle control. It also decreased tumor necrosis factor α and interleukin 6 production by splenocytes in vitro. Selective inhibition of SIRT1 was associated with significant improvements in fibrin cross-linkage, platelet function, and clot rigidity but had no significant impact on the clot initiation parameters. Moreover, inhibition of SIRT1 was associated with a significant decrease in bone marrow atrophy.
Conclusion:
Selective inhibition of Class III HDAC SIRT1 significantly improves survival, attenuates cytokine levels and sepsis-associated coagulopathy, and decreases bone marrow atrophy in a lethal mouse septic model.
