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.
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.
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.