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    Role of Interleukin-1beta and neutrophil activation during acetaminophen overdose

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    Williams_ku_0099D_12294_DATA_1.pdf (6.189Mb)
    Issue Date
    2012-08-31
    Author
    Williams, Clarence David
    Publisher
    University of Kansas
    Format
    180 pages
    Type
    Dissertation
    Degree Level
    Ph.D.
    Discipline
    Pharmacology, Toxicology & Therapeutics
    Rights
    This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.
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    Abstract
    Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US. APAP is metabolized to a reactive metabolite that causes hepatotoxicity in a dose-dependent manner. A series of cascading intracellular events lead to cellular necrosis; this necrosis initiates a sterile inflammatory response which includes the production of multiple cytokines and chemokines that in turn recruit innate immune cells into the liver. Many of the inflammatory or corresponding anti-inflammatory mediators that are produced in this process have been linked to alterations in the subsequent injury as well as the injury resolution. This dissertation focuses on one particular inflammatory mediator, interleukin-1â (IL-1â), and its ability to modulate neutrophil priming, activation and hepatic recruitment. We show that mature IL-1â is produced during APAP overdose in a caspase dependent manner (Nalp3 inflammasome) which can be inhibited in vivo by a pan-caspase inhibitor, and that IL-1â is capable of activating neutrophils in vivo. However, the limited amount of IL-1â produced during APAP overdose is insufficient to activate or recruit neutrophils into the liver. In confirmation of these findings, genetic elimination of the components of the Nalp3 inflammasome or the IL-1 receptor does not alter APAP-induced injury or neutrophil recruitment. It has previously been shown that neutrophils do not participate in APAP-induced injury. This has been demonstrated in various ways, however, controversy arose when pretreatment of mice with neutropenia-inducing antibody resulted in protection from APAP toxicity. To further clarify this matter, CD18-deficient mice were subjected to APAP overdose, and in agreement with previous findings these mice were not protected from APAP overdose. Next we functionally characterized neutrophils during APAP overdose to further confirm that neutrophils do not participate in exacerbation of injury. Interestingly, during injury resolution neutrophils become activated especially in peripheral blood but did not have enhanced reactive oxygen priming in the liver. These findings were confirmed with NADPH oxidase deficient mice which had no alteration in injury resolution. Interestingly, these data were very similar to neutrophil function in human APAP overdose patients. These data indicate that activation of neutrophils might be critical for maintaining host defense during hepatic impairment. As a whole, this dissertation shows IL-1â is a minor participant in the sterile inflammatory response following APAP overdose, but this response is critical for neutrophil activation and eventual injury resolution.
    URI
    http://hdl.handle.net/1808/10290
    Collections
    • Dissertations [4472]
    • Pharmacy Dissertations and Theses [118]

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    785-864-8983
    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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