Principal Investigator:

Patrick M. Kochanek, MD

Con-Investigators and Collaborators:

Valerian Kagan, PhD, Hulya Bayir, MD, Timothy Billiar, MD, C. Edward Dixon, PhD, Robert S.B. Clark, MD, and Larry Jenkins, PhD

Inducible nitric oxide synthase (iNOS) is a NOS isoform that is involved in the inflammatory response. iNOS may govern key mechanisms in the evolution of injury, protection and repair, including vascular regulation, inflammation, cytoprotection, cytotoxicity, and regeneration. In traumatic brain injury (TBI), iNOS is expressed in a variety of cell types in the peri-trauma region. Recently, our work has focused on examination of one of the putative beneficial aspects of iNOS-derived NO formation -- i.e., the role of S-nitrosylation. Our hypothesis is that early after injury that iNOS is detrimental, but in the subacute periods after injury, iNOS serves as endogenous neuroprotectants -- via S-nitrosylation. Our studies are being carried out in both the iNOS knockout (ko) and corresponding wild-type (wt) mouse –in which we are currently studying the time course of both protein nitration and S-nitrosylation after injury—and the consequences of this pathway on putative neuroprotective mechanisms. In a preliminary report (Bayir et al, Crit Care Med 30:Vol 12 Suppl, A13) similarly, we have been studying S-nitrosylation in human head injury by examining ventricular cerebrospinal fluid. In a recent report (Bayir et al, J Cereb Blood Flow Metab, 23, 51-61, 2003), we demonstrated significant increases in CSF nitrosothiols—particularly S-nitrosoalbumin—after severe TBI in infants and children. In future studies in our experimental mouse TBI model, we plan to use proteomics to evaluate the specific proteins nitrosylated after injury in iNOS ko and wt. We also plan to evaluate the effect of iNOS inhibitors on S-nitrosylation and study the effect of S-nitrosoalbumin supplementation in our model.