Hypoxic “second hit” in leukocytes from trauma patients: Modulation of the immune response by histone deacetylase inhibition

Introduction: Histone deacetylase inhibitors (HDACI), can improve survival after lethal hemorrhagic shock, and modulate the inflammatory response after hemorrhage/lipopolysaccharide (LPS). The current experiments were designed to study the effects of HDACI after hemorrhage and severe hypoxia. Methods: Splenic leukocytes from trauma and non-trauma patients (n = 4–5/group) were exposed to severe hypoxia with/without suberoylanilide hydroxamic acid (SAHA, 400 nM) for 8 h. Cytokines were measured by ELISA and RT-PCR, and hypoxia inducible factor (HIF)-1a and heme oxygenase (HO)-1 by Western blot. Results: After hemorrhage and hypoxia, SAHA increased IL-1b gene (4.7 ± 1.2-fold) and protein expression (2.1 ± 0.6-fold) in trauma splenic leukocytes. It also reduced IL-10 gene expression (0.6 ± 0.2-fold), but did not alter TNFa or IL-6 levels. This unexpected pro-inflammatory response may be due to a decrease in HIF-1a and HO-1 protein levels. Conclusions: In this model of severe hypoxia, treatment with SAHA increased the inflammatory response in trauma leukocytes, possibly through inhibition of the HIF-1/HO-1 pathway. Splenic leukocytes from non-trauma patients were variably affected by SAHA. Taken in context with the known anti-inflammatory properties of HDACI after hemorrhage/LPS, these findings suggest that the immune-modulating functions of HDACI are dependent on the type and severity of both the priming injury and subsequent insult.