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The Role of IRAK-1 in the Regulation of Free Radicals and Oxidative Stress during Endotoxemia

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dc.contributor.authorSingh, Neerajen
dc.contributor.committeechairLi, Liwuen
dc.contributor.committeememberLeRoith, Tanyaen
dc.contributor.committeememberMisra, Hara P.en
dc.contributor.committeememberMahaney, James E.en
dc.contributor.committeememberYuan, Lijuanen
dc.contributor.departmentVeterinary Medical Sciencesen
dc.date.accessioned2017-04-06T15:43:09Zen
dc.date.adate2010-07-30en
dc.date.available2017-04-06T15:43:09Zen
dc.date.issued2010-07-14en
dc.date.rdate2016-10-18en
dc.date.sdate2010-07-26en
dc.description.abstractOxidative stress plays a vital role in the pathogenesis of many chronic and acute inflammatory diseases. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are two key mediators that are known to induce cellular and tissue oxidative stress. The generation of ROS and RNS is mediated by innate immune signaling processes. Lipopolysaccharide (LPS), a major inflammatory signal, is known to be a potent inducer of ROS/RNS. Thus, strategies that may block LPS-mediated generation of free radicals may hold promise in treating various inflammatory disease processes. However, the molecular mechanisms underlying LPS-mediated ROS/RNS production are not fully defined. Interleukin-1 Receptor associated kinase (IRAK-1), an intracellular kinase downstream of Toll-like Receptor 4 (TLR4) has been shown to contribute to the inflammatory cascade associated with LPS-TLR4 signaling pathway. However, its role in ROS production has not been defined. Therefore, we tested the hypothesis that IRAK-1 plays an important role in regulating ROS/RNS production. Both in vitro and in vivo studies were conducted to investigate the role of IRAK-1 in modulating free radicals as well as oxidative stress. In vitro studies demonstrate that IRAK-1 is a critical molecule involved in the induction of ROS/RNS. IRAK-1 deletion ablated free radical production following LPS challenge in a variety of cell types including macrophages, fibroblasts and microglia. Mechanistically, we observed that IRAK-1 is required for optimal expression and activity of NADPH oxidase subunits and iNOS. IRAK-1 deletion reduced LPS-triggered p47phox membrane translocation, suppressed NOX-1 expression and protein levels as well as hampered Rac1 activation. On the other hand, IRAK-1 deletion sustained antioxidative enzyme activity and levels in IRAK-1-/- macrophages and fibroblasts. In terms of the in vivo physiological consequences, IRAK-1-/- mice exhibited attenuated lipid peroxidation in vital organs, attenuated histopathological lesions in liver and kidney, and reduced endotoxemia-associated mortality. Taken together, IRAK-1 may, at least in part, serve as an important therapeutic target in the treatment of various inflammatory disease processes.en
dc.description.degreePh. D.en
dc.identifier.otheretd-07262010-131201en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-07262010-131201/en
dc.identifier.urihttp://hdl.handle.net/10919/77145en
dc.language.isoen_USen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectAll-trans Retinoic Aciden
dc.subjectFree radicalsen
dc.subjectMacrophagesen
dc.subjectIRAK-1en
dc.subjectLipopolysaccharideen
dc.subjectSepsisen
dc.subjectNADPH oxidaseen
dc.subjectiNOSen
dc.titleThe Role of IRAK-1 in the Regulation of Free Radicals and Oxidative Stress during Endotoxemiaen
dc.typeDissertationen
dc.type.dcmitypeTexten
thesis.degree.disciplineVeterinary Medical Sciencesen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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