Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity. A likely mediator of both good and bad events after TBI is inducible nitric oxide synthase (iNOS). iNOS is expressed in neutrophils (PMNs), macrophages (macs), and other cell types in brain after TBI and produces large amounts of NO for sustained periods. iNOS activity appears to be detrimental early after TBI but beneficial chronically. Early after injury, the detrimental effects of iNOS are likely mediated by protein nitration. Interaction of NO with either myeloperoxidase (MPO) or superoxide anion in leukocytes may play an important role. Later after TBI, iNOS may confer benefit through a number of mechanisms including 1) NO-mediated nitrosylation reactions, such as nitrosylation of caspases, 2) NO-mediated antioxidant effects including termination of lipid peroxidation, 3) NO-mediated increases in CBF, and 4) other repair mechanisms. The overall HYPOTHESIS that will be tested is that iNOS is expressed after TBI and has powerful endogenous detrimental and beneficial effects that are governed by the timing, cellular localization, and level of oxidative stress in the injured tissue.
Five specific aims are proposed including 1) Further explore the temporal profile of nitration and nitrosylation after TBI. The contribution of blood (PMN, mac<|>) vs resident (brain) iNOS to increases in 3NT and RSNO will also be explored using reciprocal iNOS bone marrow chimeras, 2) Explore the link between iNOS and MPO in mediating early detrimental effects after experimental TBI, 3) Explore the specific targets for post-translational modification of proteins by nitrosylation, 4) Explore the contribution of iNOS to the recovery of CBF after TBI in mice, and 5) Link bench to bedside confirming these mechanisms and providing a means to monitor the clinical effect of therapies that influence nitrosative stress after severe TBI in humans. The ability to selectively modulate iNOS at the appropriate time after injury could lead to targeted therapies in patients after severe TBI.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS030318-16
Application #
7657394
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
16
Fiscal Year
2008
Total Cost
$148,749
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Markos, Steven M; Failla, Michelle D; Ritter, Anne C et al. (2017) Genetic Variation in the Vesicular Monoamine Transporter: Preliminary Associations With Cognitive Outcomes After Severe Traumatic Brain Injury. J Head Trauma Rehabil 32:E24-E34
Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E (2017) Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders. Ageing Res Rev 34:51-63
Jackson, Edwin K; Kotermanski, Shawn E; Menshikova, Elizabeth V et al. (2017) Adenosine production by brain cells. J Neurochem 141:676-693
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Santarsieri, M; Kumar, R G; Kochanek, P M et al. (2015) Variable neuroendocrine-immune dysfunction in individuals with unfavorable outcome after severe traumatic brain injury. Brain Behav Immun 45:15-27
Janata, Andreas; Magnet, Ingrid A M; Uray, Thomas et al. (2014) Regional TNF? mapping in the brain reveals the striatum as a neuroinflammatory target after ventricular fibrillation cardiac arrest in rats. Resuscitation 85:694-701
Santarsieri, Martina; Niyonkuru, Christian; McCullough, Emily H et al. (2014) Cerebrospinal fluid cortisol and progesterone profiles and outcomes prognostication after severe traumatic brain injury. J Neurotrauma 31:699-712
Gandy, Sam; Ikonomovic, Milos D; Mitsis, Effie et al. (2014) Chronic traumatic encephalopathy: clinical-biomarker correlations and current concepts in pathogenesis. Mol Neurodegener 9:37
Alexander, Sheila A; Ren, Dianxu; Gunn, Scott R et al. (2014) Interleukin 6 and apolipoprotein E as predictors of acute brain dysfunction and survival in critical care patients. Am J Crit Care 23:49-57
Yan, Hong Q; Shin, Samuel S; Ma, Xiecheng et al. (2014) Differential effect of traumatic brain injury on the nuclear factor of activated T Cells C3 and C4 isoforms in the rat hippocampus. Brain Res 1548:63-72

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