| Creating a Pro-survival and Anti-inflammatory Phenotype by Modulation of Acetylation in Models of Hemorrhagic and Septic Shock. | |
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MedLine Citation:
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PMID: 22127890 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Shock, regardless of etiology, is characterized by decreased tissue perfusion resulting in cell death, organ dysfunction, and poor survival. Current therapies largely focus on restoring tissue perfusion through resuscitation but have failed to address the specific cellular dysfunction caused by shock. Acetylation is rapidly emerging as a key mechanism that regulates the expression of numerous genes (epigenetic modulation through activation of nuclear histone proteins), as well as functions of multiple cytoplasmic proteins involved in key cellular functions such as cell survival, repair/healing, signaling, and proliferation. Cellular acetylation can be increased immediately through the administration of histone deacetylase inhibitors (HDACI). A series of studies have been performed using: (1) cultured cells; (2) single-organ ischemia-reperfusion injury models; (3) rodent models of lethal septic and hemorrhagic shock; (4) swine models of lethal hemorrhagic shock and multi-organ trauma; and (5) tissues from severely injured trauma patients, to fully characterize the changes in acetylation that occur following lethal insults and in response to treatment with HDACI. These data demonstrate that: (1) shock causes a decrease in acetylation of nuclear and cytoplasmic proteins; (2) hypoacetylation can be rapidly reversed through the administration of HDACI; (3) normalization of acetylation prevents cell death, decreases inflammation, attenuates activation of pro-apoptotic pathways, and augments pro-survival pathways; (4) the effect of HDACI significantly improves survival in lethal models of septic shock, hemorrhagic shock, and complex poly-trauma without need for conventional fluid resuscitation or blood transfusion; and (5) improvement in survival is not due to better resuscitation but due to an enhanced ability of cells to tolerate lethal insults.As different models of hemorrhagic or septic shock have specific strengths and limitations, this chapter will summarize our attempts to create "pro-survival and anti-inflammatory phenotype" in various models of hemorrhagic shock and septic shock. |
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Authors:
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Yongqing Li; Hasan B Alam |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Advances in experimental medicine and biology Volume: 710 ISSN: 0065-2598 ISO Abbreviation: Adv. Exp. Med. Biol. Publication Date: 2012 |
Date Detail:
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Created Date: 2011-11-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0121103 Medline TA: Adv Exp Med Biol Country: United States |
Other Details:
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Languages: eng Pagination: 107-33 Citation Subset: IM |
Affiliation:
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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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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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