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Histone Deacetylase Inhibitors Attenuate Acute Lung Injury During Cecal Ligation and Puncture-Induced Polymicrobial Sepsis

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Abstract

Background

The histone deacetylase (HDAC) inhibitors have emerged as the useful reagents that epigenetically modulate the expression of various genes. In the present study, the effects of HDAC inhibitors on the expression of inflammation-related genes and lung injury during sepsis were investigated.

Methods

Mice were pretreated with two structurally unrelated HDAC inhibitors, Trichostatin A (TSA) and sodium butyrate (SB). Thirty minutes later, mice underwent cecal ligation and puncture (CLP)-induced sepsis. Lung injury and the expression of inflammation-related molecules were determined. In addition, survival was assessed post-CLP.

Results

Our results indicated that administration of TSA or SB alleviated sepsis-induced lung injury. This was accompanied by reduced neutrophil infiltration, decreased intercellular adhesion molecule-1 (ICAM-1) and E-selectin expression in lung tissue, and lower interleukin-6 (IL-6) level in plasma. In addition, treatment with HDAC inhibitors significantly prolonged the survival time of CLP mice.

Conclusions

These data indicated that the HDAC inhibitors, based on modulating the key enzymes linked to acetylation modification, effectively attenuate intrapulmonary inflammatory response, thus significantly alleviating lung injury during sepsis.

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References

  1. Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342:1334–1349

    Article  CAS  PubMed  Google Scholar 

  2. Phua J, Badia JR, Adhikari NK et al (2009) Has mortality from acute respiratory distress syndrome decreased over time?: a systematic review. Am J Respir Crit Care Med 179:220–227

    Article  PubMed  Google Scholar 

  3. Balibrea JL, Arias-Díaz J (2003) Acute respiratory distress syndrome in the septic surgical patient. World J Surg 27:1275–1284

    Article  PubMed  Google Scholar 

  4. Abraham E, Singer M (2007) Mechanisms of sepsis-induced organ dysfunction. Crit Care Med 35:2408–2416

    Article  PubMed  Google Scholar 

  5. Kawai T, Akira S (2008) Toll-like receptor and RIG-I-like receptor signaling. Ann N Y Acad Sci 1143:1–20

    Article  CAS  PubMed  Google Scholar 

  6. Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol 8:349–361

    Article  CAS  PubMed  Google Scholar 

  7. Berger SL (2007) The complex language of chromatin regulation during transcription. Nature 447:407–412

    Article  CAS  PubMed  Google Scholar 

  8. Ito T (2007) Role of histone modification in chromatin dynamics. J Biochem 141:609–614

    Article  CAS  PubMed  Google Scholar 

  9. Berger SL (2002) Histone modifications in transcriptional regulation. Curr Opin Genet Dev 12:142–148

    Article  CAS  PubMed  Google Scholar 

  10. Yang XJ, Seto E (2007) HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26:5310–5318

    Article  CAS  PubMed  Google Scholar 

  11. Pan LN, Lu J, Huang B (2007) HDAC inhibitors: a potential new category of anti-tumor agents. Cell Mol Immunol 4:337–343

    CAS  PubMed  Google Scholar 

  12. Mehnert JM, Kelly WK (2007) Histone deacetylase inhibitors: biology and mechanism of action. Cancer J 13:23–29

    Article  CAS  PubMed  Google Scholar 

  13. Leoni F, Fossati G, Lewis EC et al (2005) The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med 11:1–15

    Article  CAS  PubMed  Google Scholar 

  14. Choi JH, Oh SW, Kang MS et al (2005) Trichostatin A attenuates airway inflammation in mouse asthma model. Clin Exp Allergy 35:89–96

    Article  CAS  PubMed  Google Scholar 

  15. Glauben R, Batra A, Fedke I et al (2006) Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol 176:5015–5022

    CAS  PubMed  Google Scholar 

  16. Lin HS, Hu CY, Chan HY et al (2007) Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol 150:862–872

    Article  CAS  PubMed  Google Scholar 

  17. Han SB, Lee JK (2009) Anti-inflammatory effect of Trichostatin-A on murine bone marrow-derived macrophages. Arch Pharm Res 32:613–624

    Article  CAS  PubMed  Google Scholar 

  18. Iwata K, Tomita K, Sano H et al (2002) Trichostatin A, a histone deacetylase inhibitor, down-regulates interleukin-12 transcription in SV-40-transformed lung epithelial cells. Cell Immunol 218:26–33

    Article  CAS  PubMed  Google Scholar 

  19. Li Y, Liu B, Zhao H et al (2009) Protective effect of suberoylanilide hydroxamic acid against LPS-induced septic shock in rodents. Shock 32:517–523

    Article  PubMed  CAS  Google Scholar 

  20. Sailhamer EA, Li Y, Smith EJ et al (2008) Acetylation: a novel method for modulation of the immune response following trauma/hemorrhage and inflammatory second hit in animals and humans. Surgery 144:204–216

    Article  PubMed  Google Scholar 

  21. Caldwell CC, Martignoni A, Leonis MA et al (2008) Ron receptor tyrosine kinase-dependent hepatic neutrophil recruitment and survival benefit in a murine model of bacterial peritonitis. Crit Care Med 36:1585–1593

    Article  CAS  PubMed  Google Scholar 

  22. Rittirsch D, Huber-Lang MS, Flierl MA et al (2009) Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc 4:31–36

    Article  CAS  PubMed  Google Scholar 

  23. van Griensven M, Probst C, Müller K et al (2006) Leukocyte-endothelial interactions via ICAM-1 are detrimental in polymicrobial sepsis. Shock 25:254–259

    Article  PubMed  CAS  Google Scholar 

  24. Rossi B, Constantin G (2008) Anti-selectin therapy for the treatment of inflammatory diseases. Inflamm Allergy Drug Targets 7:85–93

    Article  CAS  PubMed  Google Scholar 

  25. Yang XJ, Seto E (2008) Lysine acetylation: codified crosstalk with other posttranslational modifications. Mol Cell 31:449–461

    Article  CAS  PubMed  Google Scholar 

  26. Halili MA, Andrews MR, Sweet MJ et al (2009) Histone deacetylase inhibitors in inflammatory disease. Curr Top Med Chem 9:309–319

    Article  CAS  PubMed  Google Scholar 

  27. Blanchard F, Chipoy C (2005) Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases? Drug Discov Today 10:197–204

    Article  CAS  PubMed  Google Scholar 

  28. Wagner JG, Roth RA (2000) Neutrophil migration mechanisms, with an emphasis on the pulmonary vasculature. Pharmacol Rev 52:349–374

    CAS  PubMed  Google Scholar 

  29. Zemans RL, Colgan SP, Downey GP (2009) Transepithelial migration of neutrophils: mechanisms and implications for acute lung injury. Am J Respir Cell Mol Biol 40:519–535

    Article  CAS  PubMed  Google Scholar 

  30. Reutershan J, Ley K (2004) Bench-to-bedside review: acute respiratory distress syndrome—how neutrophils migrate into the lung. Crit Care 8:453–461

    Article  PubMed  Google Scholar 

  31. Calandra T, Gerain J, Heumann D et al (1991) High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. Am J Med 91:23–29

    Article  CAS  PubMed  Google Scholar 

  32. Gårdlund B, Sjölin J, Nilsson A et al (1995) Plasma levels of cytokines in primary septic shock in humans: correlation with disease severity. J Infect Dis 172:296–301

    PubMed  Google Scholar 

  33. Damas P, Ledoux D, Nys M et al (1992) Cytokine serum level during severe sepsis in human IL-6 as a marker of severity. Ann Surg 215:356–362

    Article  CAS  PubMed  Google Scholar 

  34. Cao W, Bao C, Padalko E et al (2008) Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. J Exp Med 205:1491–1503

    Article  CAS  PubMed  Google Scholar 

  35. Chen Lf, Fischle W, Verdin E et al (2001) Duration of nuclear NF-kappaB action regulated by reversible acetylation. Science 293:1653–1657

    Article  CAS  Google Scholar 

  36. Chen LF, Greene WC (2003) Regulation of distinct biological activities of the NF-kappaB transcription factor complex by acetylation. J Mol Med 81:549–557

    Article  CAS  PubMed  Google Scholar 

  37. Batta K, Das C, Gadad S et al (2007) Reversible acetylation of nonhistone proteins: role in cellular function and disease. Subcell Biochem 41:193–212

    Article  PubMed  Google Scholar 

  38. Das C, Kundu TK (2005) Transcriptional regulation by the acetylation of nonhistone proteins in humans—a new target for therapeutics. IUBMB Life 57:137–149

    Article  CAS  PubMed  Google Scholar 

  39. Esmon CT (2004) Why do animal models (sometimes) fail to mimic human sepsis? Crit Care Med 32:S219–S222

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (Nos. 30772088 and 30900651) and the Chongqing Municipal Education Commission (No. KJ090304).

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Authors and Affiliations

  1. Department of Pathophysiology, Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China

    Li Zhang

  2. Department of Anesthesiology, Second Affiliated Hospital, Wenzhou Medical College, Wenzhou, China

    Shengwei Jin

  3. Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing, China

    Changdong Wang

  4. Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China

    Rong Jiang

  5. Department of Pharmacology, Chongqing Medical University, 400016, Chongqing, China

    Jingyuan Wan

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  1. Li Zhang
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  2. Shengwei Jin
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  3. Changdong Wang
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Correspondence to Jingyuan Wan.

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Zhang, L., Jin, S., Wang, C. et al. Histone Deacetylase Inhibitors Attenuate Acute Lung Injury During Cecal Ligation and Puncture-Induced Polymicrobial Sepsis. World J Surg 34, 1676–1683 (2010). https://doi.org/10.1007/s00268-010-0493-5

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