Principal Investigator:

Patrick M. Kochanek, MD

Co-Investigators:

Hulya Bayir, MD, Timothy Carlos, MD, Rosemary Hoffman, PhD and Larry Jenkins, PhD

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 (macφs), 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, macφ) 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.