Article Text
Abstract
Background Isoform-specific histone deacetylase inhibitors (HDACIs) MC1568 and ACY1083 are comparable to the non-selective HDACI valproic acid (VPA) in improving survival in rodents undergoing lethal hemorrhage. However, the organ-specific properties of isoform-specific HDACIs have not been fully evaluated. Also, whether they can act synergistically is not known. We hypothesized that isoform-specific HDACIs are superior to VPA in attenuating intestinal injury and act synergistically when coadministered.
Methods Sprague Dawley rats were hemorrhaged (40% of total blood volume) and randomized to receive (n=4 per group) (1) MC1568 (5 mg/kg), (2) ACY1083 (30 mg/kg), (3) MC1568+ACY1083 (combination: 5 mg/kg + 30 mg/kg, respectively), (4) VPA (250 mg/kg), or (5) normal saline (NS; vehicle; 250 μL). Animals were observed for 3 hours, after which blood samples were collected and samples of the ileum were harvested. Expression of interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and cytokine-induced neutrophil chemoattractant 1 (CINC-1) was assessed in the tissues using enzyme-linked immunosorbent assay. Intestinal cleaved caspase 3 (c-caspase 3) levels were assessed as a marker of apoptosis, and histologic sections of the ileum were examined for signs of bowel injury. Levels of IL-1β and TNF-α were also measured in the serum as global markers of inflammation.
Results Treatments with MC1568, ACY1083, MC1568+ACY1083, and VPA were associated with decreased IL-1β levels in the intestine and serum compared with NS. IL-1β and TNF-α levels were significantly lower in the ACY1083 group compared with the VPA group. CINC-1 levels were significantly lower in the isoform-specific HDACI groups compared with the NS; however, no significant differences were seen with VPA. All treatment groups had a lower expression of intestinal c-caspase 3 compared with NS. Furthermore, MC1568 and ACY1083 groups had lower apoptosis compared with the VPA group. Bowel injury scores were significantly lower in the isoform-specific HDACI groups compared with the NS group; however, the attenuation in the VPA-treated animals did not reach statistical significance.
Discussion Isoform-specific HDACIs provide superior intestinal protection compared with VPA in a rodent model of hemorrhagic shock.
Level of evidence Preclinical study.
- hemorrhagic shock
- histone deacetylase inhibitors
- intestine
- inflammation
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Footnotes
Presented at American College of Surgeons – Michigan Chapter (2019)
Contributors UFB and HBA conceived the study. UFB, PC, and RGK performed the animal experiments. UFB and BL performed the tissue analyses. JD graded the histology slides. UFB wrote the initial draft of the article, which was revised by AMW, RGK, PC, JZ, JD, BEB, ZW, BL, and YL. HBA performed the final review and critical revision of the article, and he also obtained funding for this work.
Funding This study was funded by NIH RO1 GM084127 (HBA).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the University of Michigan Institutional Animal Care and Use Committee.
Provenance and peer review Not commissioned; externally peer reviewed.