Background: We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, before a lethal dose of lipopolysaccharide (LPS) improves survival in mice. The purpose of the present study was to determine whether SAHA treatment would attenuate LPS-induced shock and improve survival when given postinsult in a rodent model.
Methods: C57BL/6J mice were intraperitoneally (IP) injected with LPS (30 mg/kg), and 2 hours later randomized into 2 groups: (1) vehicle animals (n = 10) received dimethyl sulfoxide (DMSO) solution only; and (2) SAHA animals (n = 10) were given SAHA (50 mg/kg, IP) in DMSO solution. Survival was monitored over the next 7 days. In a second study, LPS-injected mice were treated with either DMSO or SAHA as described, and normal (sham) animals served as controls. Lungs were harvested at 4, 6, and 8 hours after LPS injection for analysis of gene expression. In addition, RAW264.7 mouse macrophages were cultured to assess the effects of SAHA post-treatment on LPS-induced inflammation using enzyme-linked immunosorbent assay.
Results: All LPS-injected mice that received the vehicle agent alone died within 24 hours, whereas the SAHA-treated animals displayed a significant improvement in 1 week survival (80% vs 0%; P < .001). LPS insult significantly enhanced gene expression of MyD88, tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, and was associated with an increased protein secretion of TNF-alpha and IL-6 into the cell culture medium. In contrast, SAHA treatment significantly attenuated all of these LPS-related alterations.
Conclusion: We report for the first time that administration of SAHA (50 mg/kg IP) after a lethal dose of LPS significantly improves long-term survival, and attenuates expression of the proinflammatory mediators TNF-alpha and IL-6. Furthermore, our data suggest that the anti-inflammatory effects of SAHA may be due to downregulation of the MyD88-dependent pathway, and decreased expression of associated proinflammatory genes.
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