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

Elizabeth A. Sailhamer, Yongqing Li, Eleanor J. Smith, Baoling Liu, Fahad Shuja, Chad P. Soupir, Marc A. DeMoya, George C. Velmahos, Hasan B. Alam*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)303-311
Number of pages9
JournalCytokine
Volume49
Issue number3
DOIs
StatePublished - Mar 2010
Externally publishedYes

Keywords

  • Hemorrhagic shock
  • Histone acetylation
  • Histone deacetylase inhibitor
  • Hypoxia
  • Inflammation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Biochemistry
  • Hematology
  • Molecular Biology

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