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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center


Brian W. Christman, M.D.

Professor of Medicine (Allergy, Pulmonary, and Critical Care)
Vice-Chair, Department of Medicine
Chief, Medical Service, VA TN Valley Health System

Contact Information:

Vanderbilt University Medical Center
T-1219 Medical Center North
Nashville, TN 37232-2650

Research Specialty

Role of urea/nitric oxide synthase cycle during inflammation

Research Description

Our research efforts are currently funded via two NIH grants: (1) PO1HL066196 (Program Project Grant-- Liver-lung interaction in the pathogenesis of lung inflammation, and (2) R01CA092313-- Chemotherapy Toxicity Reduction via Urea Cycle Support. By way of background, the hepatic urea cycle is the primary end pathway of nitrogen catabolism. This cycle fixes ammonia and generates urea. A key intermediate in the cycle is arginine, the substrate for NO generation via the actions of nitric oxide synthase. NOS, when provided with sufficient cofactors (NADPH, tetrahydrobiopterin, oxygen) and substrate, exists in a homodimeric form and produces mainly NO. During periods of substrate limitation or cofactor oxidation, "uncoupled NOS" generates large quantities of superoxide anion. In work supported by our PPG, we have found that mice with partial deficiency of proximal urea cycle enzymes experience increased post-endotoxin in vivo lipid peroxidation, as assessed by GC/MS measurement of isoprostanes and isofurans. This can be ameliorated by manipulation of NOS cofactors and substrate provision. In parallel studies supported by the NCI, we are engaged in a Phase II clinical trial of providing urea cycle intermediates to patients receiving escalated dose chemotherapy and stem cell transplant. This is aimed at reducing regimen related toxicity. . . . .

Clinical Interest

Special interest in problems of lung disease associated with hepatic dysfunction, connective tissue disease-related lung dysfunction, bronchiolar diseases after HSCT, and pulmonary vascular disease. Also actively involved in care of patients with acute respiratory distress syndrome.

Clinical Research Description

We have found that escalated dose chemotherapy causes urea cycle dysfunction, decreased NO synthesis, and venocclusive disease in the liver. We are conducting a Phase II NIH sponsored clinical trial to determine if urea cycle support, by substrate provision, can limit tissue injury and in vivo oxidant stress after stem cell transplant.