Document Detail


Identification of citrullinated histone H3 as a potential serum protein biomarker in a lethal model of lipopolysaccharide-induced shock.
MedLine Citation:
PMID:  21878229     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Circulating proteins may serve as biomarkers for the early diagnosis and treatment of shock. We have recently demonstrated that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, significantly improves survival in a rodent model of lipopolysaccharide (LPS)-induced septic shock. Preliminary proteomic data showed that LPS-induced shock altered a number of proteins in circulation, including histone H3 (H3) and citrullinated histone H3 (Cit H3). The present study was designed to confirm these findings and to test whether the pro-survival phenotype could be detected by an early alteration in serum biomarkers.
METHODS: Three experiments were performed. In experiment I, Western blotting was performed on serum samples from male C57B1/6J mice (n = 9, 3/group) that belonged to the following groups: (a) LPS (20 mg/kg)-induced septic shock, (b) SAHA-treated septic shock, and (c) sham (no LPS, no SAHA). In experiment II, HL-60 granulocytes were cultured and treated with LPS (100 ng/m1) in the absence or presence of SAHA (10 μmol/L). Sham (no LPS, no SAHA) granulocytes served as controls. The medium and cells were harvested at 3 hours, and proteins were measured with Western blots. In experiment III, a large dose (LD, 35 mg/kg) or small dose (SD, 10 mg/kg) of LPS was injected intraperitoneally into the C57B1/6J mice (n = 10 per group). Blood was collected at 3 hours, and serum proteins were determined by Western blots or enzyme-linked immunosorbent assay (ELISA). All of the Western blots were performed with antibodies against H3, Cit H3, and acetylated H3 (Ac H3). ELISA was performed with antibody against tumor necrosis factor (TNF)-α. Survival rates were recorded over 7 days.
RESULTS: In experiment I, intraperitoneal (IP) injection of LPS (20 mg/kg) significantly increased serum levels of H3, which was prevented by SAHA treatment. In experiment II, LPS (100 ng/mL) induced expression and secretion of Cit H3 and H3 proteins in neutrophilic HL-60 cells, which was decreased by SAHA treatment. In experiment III, administration of LPS (LD) caused a rise in serum H3 and Cit H3 but not Ac H3 at 3 hours, and all of these animals died within 23 hours (100% mortality). Decreasing the dose of LPS (SD) significantly reduced the mortality rate (10% mortality) as well as the circulating levels of Cit H3 (non detectable) and H3. An increase in serum TNF-α was found in both LPS (LD) and (SD) groups, but in a non-dose-dependent fashion.
CONCLUSION: Our results reveal for the first time that Cit H3 is released into circulation during the early stages of LPS-induced shock. Moreover, serum levels of Cit H3 are significantly associated with severity of LPS-induced shock. Therefore, Cit H3 could serve as a potential protein biomarker for early diagnosis of septic shock, and for predicting its lethality.
Authors:
Yongqing Li; Baoling Liu; Eugene Y Fukudome; Jenifer Lu; Wei Chong; Guang Jin; Zhengcai Liu; George C Velmahos; Marc Demoya; David R King; Hasan B Alam
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Surgery     Volume:  150     ISSN:  1532-7361     ISO Abbreviation:  Surgery     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-31     Completed Date:  2011-11-01     Revised Date:  2013-06-27    
Medline Journal Info:
Nlm Unique ID:  0417347     Medline TA:  Surgery     Country:  United States    
Other Details:
Languages:  eng     Pagination:  442-51     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 Mosby, Inc. All rights reserved.
Affiliation:
Department of Surgery, Division of Trauma, Emergency Surgery and Surgical Critical Care, Massachusetts General Hospital/ Harvard Medical School, Boston, MA, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Markers / blood
Blotting, Western
Citrulline / analogs & derivatives,  blood
Disease Models, Animal
Histone Deacetylase Inhibitors / therapeutic use
Histones / blood*,  metabolism
Hydroxamic Acids / therapeutic use
Lipopolysaccharides
Male
Mice
Mice, Inbred C57BL
Random Allocation
Sensitivity and Specificity
Shock, Hemorrhagic / blood*,  chemically induced,  diagnosis*,  drug therapy
Survival Rate
Tumor Necrosis Factor-alpha / blood
Grant Support
ID/Acronym/Agency:
R01 GM084127/GM/NIGMS NIH HHS; R01 GM084127-01A1/GM/NIGMS NIH HHS; R01 GM084127-02/GM/NIGMS NIH HHS; R01 GM084127-03/GM/NIGMS NIH HHS; R01 GM084127-04/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Histone Deacetylase Inhibitors; 0/Histones; 0/Hydroxamic Acids; 0/Lipopolysaccharides; 0/Tumor Necrosis Factor-alpha; 149647-78-9/vorinostat; 372-75-8/Citrulline
Comments/Corrections

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