title: Protective effect of suberoylanilide hydroxamic acid against LPS-induced septic shock in rodents.
abstract: We have recently found that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, improves survival in a lethal model of hemorrhagic shock in rats. The purpose of the present study was to determine whether SAHA treatment would prevent LPS-induced septic shock and improve the survival in a murine model. C57BL/6J mice were randomly divided into two groups. Experimental mice were given intraperitoneal SAHA (50 mg/kg) in vehicle dimethyl sulfoxide fluid (n = 10). The control mice (n = 10) received vehicle dimethyl sulfoxide only. They were injected with LPS (20 mg/kg, i.p.) 2 h later, and the animals from the treatment group were given a second dose of SAHA. Survival was monitored during the next 7 days. In a parallel study, mice treated with or without SAHA were subjected to LPS insult while normal (sham) mice serviced as controls. 1) Lungs were harvested at 3 and 48 h for analysis of gene expression and pathologic changes, respectively; 2) spleens were isolated for analysis of neutrophilic cell population. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA on LPS-induced inflammation in vitro. All mice in the control group that were subjected to LPS challenge died in less than 48 h. However, SAHA-treated animals displayed a significantly higher 1-week survival rate (87.5%) compared with the control group (0%). Moreover, LPS insult decreased the acetylation of histone proteins (H2A, H2B, and H3), elevated the levels of TNF-alpha in vivo (circulation) and in vitro (culture medium), increased the neutrophilic cell population in the spleen, enhanced the expression of TNF-alpha and IL-1beta genes in lung tissue, and augmented the pulmonary neutrophil infiltration. In contrast, SAHA treatment markedly attenuated all of these LPS-induced alterations. We report for the first time that administration of SAHA (50 mg/kg) significantly attenuates a variety of inflammatory markers and improves long-term survival after a lethal LPS insult.
authors.affiliation: Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Li
authors.forename: Baoling
authors.initials: B
authors.lastname: Liu
authors.forename: Hang
authors.initials: H
authors.lastname: Zhao
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Sailhamer
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Fukudome
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhang
authors.forename: Tareq
authors.initials: T
authors.lastname: Kheirbek
authors.forename: Robert A
authors.initials: RA
authors.lastname: Finkelstein
authors.forename: George C
authors.initials: GC
authors.lastname: Velmahos
authors.forename: Marc
authors.initials: M
authors.lastname: deMoya
authors.forename: Charles A
authors.initials: CA
authors.lastname: Hales
authors.forename: Hasan B
authors.initials: HB
authors.lastname: Alam
mesh_terms: D000107:Acetylation / Q000187:drug effects; D055371:Acute Lung Injury; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012772:Shock, Septic / Q000139:chemically induced* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D000077337:Vorinostat; D009195:Peroxidase