Abstract 15722: Epigenetic Modifiers Attenuate Inflammation and Improve Survival in Sepsis
BACKGROUND and OBJECTIVE: Sepsis is a systemic inflammatory disorder, and its progression to septic shock is a serious clinical problem with very high mortality of 40%. We investigated whether epigenetic modifiers trichostatin A (TSA, a histone deacetylase inhibitor) and 5-aza-2-deoxycytidine (Aza, a DNA methyl transferase inhibitor) would protect against lipopolysaccharide (LPS)-induced acute lung injury in mice.
METHODS: Acute lung injury was induced in C57BL/6J mice by intraperitoneal injection of LPS (40 mg/kg). One hour after LPS administration, the mice received vehicle or TSA (1 ug/g) or Aza (1 ug/g) or TSA+Aza. Survival was monitored for 6 days and histological changes and gene expression were evaluated in the lung. LPS-induced inflammation and the effects of TSA and Aza were assed in vitro in mouse macrophage (RAW264.7) cells. Endothelial junctional barrier function was determined by measuring real-time changes in transendothelial electrical resistance (TER) in endothelial cells and pulmonary endothelial permeability was measured by capillary filtration coefficient (Kf,c) in lung tissue.
RESULTS: All mice in the control group subjected to LPS died in less than 19h (0% survival), while TSA+Aza-treated animals displayed a strikingly higher survival rate (80%). LPS challenge increased the levels of TNF-alpha and IL-6 in vivo (blood and gene expression in lung tissue) and in vitro (culture medium), and augmented pulmonary neutrophil infiltration. Treatment with TSA+Aza led to significant attenuation of LPS-induced lung histopathological changes, and increased levels of anti-inflammatory cytokine IL-10 in blood as well as the gene expression in lung tissues than either alone. TSA+Aza treatment ameliorated LPS-induced endothelial barrier disruption and prevented pulmonary microvascular permeability in lung injury.
CONCLUSION: Our results show, for the first time, that combined administration of TSA and Aza significantly attenuates inflammation and improves long-term survival after LPS-induced sepsis and acute lung injury. We conclude that epigenetic modifiers (TSA and Aza) have great potential as novel therapeutic agent against sepsis and associated pulmonary injury.
- © 2011 by American Heart Association, Inc.