Acetylation: a novel method for modulation of the immune response following trauma/hemorrhage and inflammatory second hit in animals and humans.

Abstract

BACKGROUND:

Hemorrhage induces an imbalance in histone acetyl transferase/histone deacetylase (HAT/HDAC) ratio. Correction of this imbalance with histone deacetylase inhibitors (HDACI) improves survival. We aimed to identify whether this was due to modulation of the post-shock immune response.

METHODS:

We established a "two-hit" model in which rats (n=11; 5-6/group) and humans (n=10; 5/group) sustained trauma/hemorrhage, followed by exposure of splenic leukocytes to lipopolysaccharide (LPS, 10 ng/mL) for 8 or 24 hours. The leukocytes were treated with: No treatment, SAHA (suberoylanilide hydroxamic acid, HDACI, 400 nM), or Garcinol (HAT inhibitor, 20 microM).

RESULTS:

Hemorrhage in the animals produced severe shock and a pro-inflammatory state. SAHA reduced TNFa secretion in the hemorrhaged leukocytes after LPS "second-hit" (34.0%, P = .003), whereas it increased transcript levels of TNFa and IL-1b (2.1+/-0.3 and 5.1+/- 2.2 fold respectively, P < .05). Leukocytes from trauma patients displayed 2 distinct responses to SAHA after LPS "second-hit," with markedly increased or decreased cytokine levels.

CONCLUSIONS:

SAHA normalizes TNFa levels following hemorrhage and LPS "second hit" in the rats, whereas trauma patients respond to SAHA in 2 distinct patterns, with either marked attenuation or exaggeration of inflammatory cytokines. Cytokine levels were independent of gene expression, implicating acetylation of non-nuclear proteins as the dominant regulatory mechanism.

• Authors: Elizabeth A Sailhamer, Yongqing Li, Eleanor J Smith, Fahad Shuja, Christian Shults, Baoling Liu, Chad Soupir, Marc deMoya, George Velmahos, Hasan B Alam
• Journal: Surgery (Surgery) Vol. 144 Issue 2 Pg. 204-16 (Aug 2008) ISSN: 1532-7361 [Electronic] United States
• PMID: 18656627 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Interleukin-1beta
• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• Vorinostat
• Histone Acetyltransferases
• Histone Deacetylases

Topics

• Abdominal Injuries (metabolism)
• Acetylation
• Adult
• Animals
• Cell Culture Techniques
• Female
• Hemorrhage (metabolism, physiopathology)
• Histone Acetyltransferases (metabolism)
• Histone Deacetylase Inhibitors
• Histone Deacetylases (metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Inflammation
• Interleukin-1beta (blood, genetics)
• Leukocytes (metabolism)
• Lipopolysaccharides (pharmacology)
• Male
• Rats
• Rats, Inbred WKY
• Shock, Hemorrhagic (complications, immunology, metabolism, therapy)
• Spleen (metabolism)
• Splenectomy
• Systemic Inflammatory Response Syndrome (etiology, metabolism)
• Transcriptional Activation
• Tumor Necrosis Factor-alpha (blood, genetics)
• Vorinostat