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

Abstract

Introduction Hemorrhagic shock (HS) followed by a subsequent insult (“second hit”) often initiates an exaggerated systemic inflammatory response and multiple organ failure. We have previously demonstrated that valproic acid, a pan histone deacetylase (HDAC) inhibitor, could improve survival in a rodent “two-hit” model. In present study, our goal was to determine whether selective inhibition of histone deacetylase 6 with Tubstatin A (Tub-A) could prolong survival in a 2-hit model where HS was followed by sepsis from cecal ligation and puncture (CLP). Methods C57Bl/6J mice were subjected to sublethal HS (30% blood loss) and then randomly divided into 2 groups (n=13/group): Tub-A group (treatment) and vehicle group (control). The Tub-A group was given an intraperitoneal injection of Tub-A (70mg/kg) dissolved in dimethyl sulfoxide (DMSO). The vehicle group was injected with 1 μl/g DMSO. After 24 h, all mice were subjected CLP followed immediately by another dose of Tub-A or DMSO. Survival was monitored for 10 days. In a parallel study, peritoneal irrigation fluid and liver tissue from Tub-A or DMSO treated mice were collected 3h after CLP. Enzyme-linked immunosorbent assay was performed to quantify activity of the myeloperoxidase (MPO) and concentrations of tumor necrosis factor-alpha (TNF-α) and interleukin -6 (IL-6) in the peritoneal irrigation fluid. RNA was isolated from the liver tissue and real-time PCR was performed to measure relative mRNA levels of TNF-α and IL-6. Results Treatment with Tub-A significantly improved survival compared to the control (69.2% vs. 15.4%). In addition, Tub-A significantly suppressed MPO activity (169.9 ± 8.4 ng/ml vs. 70.4 ± 17.4ng/ml; p < 0.01), and reduced levels of cytokines TNF-α and IL-6 in the peritoneal fluid (TNF-α: 105.7 ± 4.7 pg/ml vs. 7.4 ± 2.4 pg/ml; IL-6: 907.4 ± 2.3 pg/ml vs. 483.6 ± 1.6 pg/ml; p < 0.01) compared to vehicle control. Gene expression measured by real-time PCR confirmed that Tub-A inhibits transcription of TNF-α and IL-6. Conclusion Tubastatin A treatment significantly improves survival, attenuates inflammation and down-regulates TNF-α and IL-6 gene expression in a rodent two-hit 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.…”

Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

“…HDAC6 inhibition resulted in prolonged survival in murine models of hemorrhagic shock and sepsis (8,10,28). However, molecular mechanisms of the protective effects observed by HDAC6 inhibition in those models have yet to be determined.…”

Targeted inhibition of histone deacetylase 6 in inflammatory diseases

“…Improper activation of HDAC6 has been observed in a variety of diseases, including cancer and neurodegenerative disorders, and small molecule drugs targeting HDAC6 are under active investigation as therapeutic agents . Recent studies have implicated HDAC6 in the pathogenesis of a variety of inflammatory diseases, and HDAC6 inhibition has been suggested as a potential therapeutic strategy . In this review, we analyze the molecular mechanisms and pathological functions of HDAC6 in inflammation, and discuss the potential value of HDAC6 as a therapeutic target in the setting of inflammatory diseases.…”

“…[13][14][15][16][17][18] Recent studies have implicated HDAC6 in the pathogenesis of a variety of inflammatory diseases, and HDAC6 inhibition has been suggested as a potential therapeutic strategy. [19][20][21][22][23] In this review, we analyze the molecular mechanisms and pathological functions of HDAC6 in inflammation, and discuss the potential value of HDAC6 as a therapeutic target in the setting of inflammatory diseases.…”