Yongqing Li, T. Zhao, Baoling Liu
Feb 1, 2015
Citations
2
Influential Citations
57
Citations
Quality indicators
Journal
Journal of Trauma and Acute Care Surgery
Abstract
BACKGROUND We recently demonstrated that suberoylanilide hydroxamic acid, a broad-spectrum histone deacetylase (HDAC) inhibitor that inhibits HDACs 1, 2, 3, and 6, improves survival in a mouse model of cecal ligation and puncture (CLP)–induced lethal sepsis. The current study was undertaken to determine the effect of selective inhibition of HDAC isoform on survival, key cytokine production, organ injury, bacteria clearance, and cell apoptosis. METHODS In Experiment 1, C57BL/6J mice were subjected to CLP and, 1 hour later, given intraperitoneal injections of (1) Tubastatin A (inhibitor of HDAC6) dissolved in dimethyl sulfoxide (DMSO), (2) MS-275 (inhibitor of HDACs 1, 2, and 3) in DMSO, and (3) DMSO only. Survival was monitored for 10 days. In Experiment 2, 1 hour after CLP, animals were treated with DMSO vehicle or Tubastatin A. Sham-operated animals served as control. Peritoneal fluid and blood samples were collected for measurement of cytokines at 24 hours or 48 hours. Blood at 48 hours was also used to determine bacteria load. Liver was harvested to evaluate acute liver injury. In Experiment 3, Primary splenocytes were used to assess cytokine responses and phagocytosis. Macrophages were cultured and harvested 3 hours and 6 hours after lipopolysaccharide stimulation in the absence or presence of Tubastatin A to analyze cell apoptosis. RESULTS Animals treated with Tubastatin A, but not MS-275, displayed a significant improvement in survival. Moreover, Tubastatin A significantly inhibited cytokine production in peritoneal fluid and plasma as well as in supernatant from splenocytes stimulated with lipopolysaccharide. Tubastatin A significantly attenuated acute liver injury, increased blood bacteria clearance and splenocyte phagocytosis, and decreased macrophage apoptosis. CONCLUSION HDAC6 inhibition significantly improves survival, reduces “cytokine storm,” attenuates acute livery injury, increases bacteria clearance and immune cell phagocytosis, and inhibits macrophage apoptosis in a lethal mouse CLP model.