Histone deacetylase III as a potential therapeutic target for the treatment of lethal sepsis

Abstract

Background We have recently demonstrated that inhibition of histone deacetylase (HDAC) class I, II and IV with non-specific 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 present study were to explore the effect of EX-527, a selective 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 Experiment I: C57BL/6J mice were subjected to CLP, and 1 h later intraperitoneally injected with either EX-527 dissolved in dimethyl sulfoxide (DMSO), or DMSO only. Survival was monitored for 10 days. Experiment II: One hour after CLP animals were randomly treated with: (i) DMSO vehicle, and (ii) 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 harvested from animals to determine morphological changes of bone marrow by H&E staining. 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, and attenuated levels of cytokines in blood and peritoneal fluid compared to the vehicle control. It also decreased TNF-α and IL-6 production by splenocytes in vitro. Selective inhibition of SIRT1 was associated with dramatic improvements in fibrin cross-linkage, platelet function and clot rigidity, but without a significant impact on the clot initiation parameters. Moreover, inhibition of SIRT1 decreased bone marrow atrophy significantly. Conclusions Selective inhibition of Class III histone deacetylase SIRT1 significantly improves survival, attenuates “cytokine storm” and sepsis-associated coagulopathy, and decreases bone marrow atrophy in a lethal mouse septic model.

Protective effect of Cl-amidine against CLP-induced lethal septic shock in mice

“…Excessive cytokine production is detrimental to cells, tissue, and organs during sepsis19, and the attenuation of cytokine storm protects against inflammatory damage20212223. We unveiled that Cl-amidine attenuated production of cytokines (IL-β, IL-6, and TNF-α) in the plasma of CLP-subjected animals and expression of cytokine (TNF-α) in cell culture supernatant of LPS-insulted splenocytes.…”

Inhibition of histone deacetylase 6 improves long-term survival in a lethal septic model

“…Mouse primary splenocytes were prepared as previously described 14 . Phagocytosis was then assessed using a pHrodo ™ E. coli BioParticles ® Phagocytosis Kit (Invitrogen, Grand Island, NY) 15, 16 .…”

Selective histone deacetylase 6 inhibition prolongs survival in a lethal two-hit model

“…A phase I dose optimization clinical trial is currently underway in healthy volunteers and trauma patients (ClinicalTrials.gov Identifier: NCT01951560) to identify the maximum safe dose. Another potential approach is to use isoform selective HDACI instead that have shown promising results [21–23] and may have better safety profiles.…”