Elizabeth Sailhammer, MD, MMSc, Yongqing Li, MD, PhD, Baoling Liu, MD, H. Zhao, PhD, George C. Velmahos, MD, Hasan B. Alam, MD
Massachusetts General Hospital- Division of Division of Trauma, Emergency Surgery and Surgical Critical Care; Boston, MA
PURPOSE OF STUDY
Lipopolysaccharide (LPS) and trauma-induced heat shock protein 60 (HSP60) can bind to toll-like receptor 4 (TLR-4), which in turn recruits MyD88 adaptor for downstream expression of many inflammatory cytokines. We have recently found that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lethal model of hemorrhagic shock in rodents. The purpose of the present study was to determine whether SAHA would improve survival in an LPS model of septic shock.
METHODS USED:
C57B1/6J mice were given intraperitoneal (ip) SAHA (50 mg/kg). Untreated mice (Control) and MyD88 knockout mice (MyD88-/-) received vehicle agent only (n=8/group). The animals were then injected with LPS (20 mg/kg, ip), and treated animals were given a second dose of SAHA. All animals were observed until death. In a parallel study, lungs were harvested from normal and LPS- injected mice (with or without SAHA treatment) after 3 hours.
SUMMARY OF RESULTS:
Animals treated with SAHA displayed significantly higher long-term survival (87.5%), compared to control (0%) and MyD88-/- (50%) mice after LPS-induced septic shock. The lung tissue from LPS-stimulated mice demonstrated neutrophilic granulocyte infiltration and increased mRNA expression of IL-1ß and TNF-a, which were markedly attenuated by SAHA. This corresponded to hyperacetylation of histone protein (H3 at lysine 9) after treatment with SAHA.
CONCLUSIONS:
We report for first time that SAHA improves survival from LPS-induced septic shock in rodents. This appears to be independent of the TLR-4 receptor. SAHA attenuates LPS-induced gene expression of pro-inflammatory cytokines (IL-1ß and TNF-a) and granulocyte infiltration in the lung, through hyperacetylation of histone protein.