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
Specialized Center (P50)
Project #
5P50NS030318-15
Application #
7551871
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
15
Fiscal Year
2007
Total Cost
$153,208
Indirect Cost

  Institution

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

  Publications

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
Osier, Nicole D; Bales, James W; Pugh, Bunny et al. (2017) Variation in PPP3CC Genotype Is Associated with Long-Term Recovery after Severe Brain Injury. J Neurotrauma 34:86-96
Jackson, Edwin K; Kotermanski, Shawn E; Menshikova, Elizabeth V et al. (2017) Adenosine production by brain cells. J Neurochem 141:676-693
Willyerd, F Anthony; Empey, Philip E; Philbrick, Ashley et al. (2016) Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans. J Neurotrauma 33:226-31
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
Drabek, Tomas; Janata, Andreas; Wilson, Caleb D et al. (2014) Minocycline attenuates brain tissue levels of TNF-? produced by neurons after prolonged hypothermic cardiac arrest in rats. Resuscitation 85:284-91
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
Conley, Yvette P; Okonkwo, David O; Deslouches, Sandra et al. (2014) Mitochondrial polymorphisms impact outcomes after severe traumatic brain injury. J Neurotrauma 31:34-41
Abrahamson, Eric E; Foley, Lesley M; Dekosky, Steven T et al. (2013) Cerebral blood flow changes after brain injury in human amyloid-beta knock-in mice. J Cereb Blood Flow Metab 33:826-33
Cousar, J'mir L; Conley, Yvette P; Willyerd, F Anthony et al. (2013) Influence of ATP-binding cassette polymorphisms on neurological outcome after traumatic brain injury. Neurocrit Care 19:192-8

Showing the most recent 10 out of 116 publications