Hypoxic "second hit" in leukocytes from trauma patients: Modulation of the immune response by histone deacetylase inhibition.
BACKGROUND
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 8h. 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.
Sailhamer
Elizabeth A
EA
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Li
Yongqing
Y
Smith
Eleanor J
EJ
Liu
Baoling
B
Shuja
Fahad
F
Soupir
Chad P
CP
DeMoya
Marc A
MA
Velmahos
George C
GC
Alam
Hasan B
HB
D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006657:Histones / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D055633:Immune System Phenomena / Q000502:physiology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D012771:Shock, Hemorrhagic / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000293:injuries / Q000601:surgery; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014947:Wounds and Injuries / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000601:surgery
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D051547:Heme Oxygenase-1