The VICC.ORG Directory of Doctors, Healthcare Providers & Researchers
Brian W. Christman, M.D.
Professor of Medicine
Vice-Chair, Dept. of Medicine
Chief, Medical Service, VA TN Valley Health System
VICC Member
Researcher
Contact Information:
Vanderbilt University Medical Center
T-1219 Medical Center North
Nashville, TN 37232-2650
615-327-5349
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.
Publications
- Robbins, IM, Hemnes, AR, Gibbs, JS, Christman, BW, Howard, L, Meehan, S, Cabrita, I, Gonzalez, R, Oyler, T, Zhao, L, Du, RH, Mendes, LA, Wilkins, MR Safety of sapropterin dihydrochloride (6r-bh4) in patients with pulmonary hypertension. Exp Lung Res, 37(1), 26-34, 2011.
- Lee, HJ, Joo, M, Abdolrasulnia, R, Young, DG, Choi, I, Ware, LB, Blackwell, TS, Christman, BW Peptidylarginine deiminase 2 suppresses inhibitory {kappa}B kinase activity in lipopolysaccharide-stimulated RAW 264.7 macrophages. J Biol Chem, 285(51), 39655-62, 2010.
- Robbins, IM, Kawut, SM, Yung, D, Reilly, MP, Lloyd, W, Cunningham, G, Loscalzo, J, Kimmel, SE, Christman, BW, Barst, RJ A study of aspirin and clopidogrel in idiopathic pulmonary arterial hypertension. Eur Respir J, 27(3), 578-84, 2006.
- Smith, HA, Canter, JA, Christian, KG, Drinkwater, DC, Scholl, FG, Christman, BW, Rice, GD, Barr, FE, Summar, ML Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg, 132(1), 58-65, 2006.
- Siore, AM, Parker, RE, Stecenko, AA, Cuppels, C, McKean, M, Christman, BW, Cruz-Gervis, R, Brigham, KL Endotoxin-induced acute lung injury requires interaction with the liver. Am J Physiol Lung Cell Mol Physiol, 289(5), L769-76, 2005.
- Robbins, IM, Morrow, JD, Christman, BW Oxidant stress but not thromboxane decreases with epoprostenol therapy. Free Radic Biol Med, 38(5), 568-74, 2005.
- Wong, F, Bernardi, M, Balk, R, Christman, B, Moreau, R, Garcia-Tsao, G, Patch, D, Soriano, G, Hoefs, J, Navasa, M, , Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club. Gut, 54(5), 718-25, 2005.
- Kallianpur, AR, Hall, LD, Yadav, M, Byrne, DW, Speroff, T, Dittus, RS, Haines, JL, Christman, BW, Summar, ML The hemochromatosis C282Y allele: a risk factor for hepatic veno-occlusive disease after hematopoietic stem cell transplantation. Bone Marrow Transplant, 35(12), 1155-64, 2005.
- Summar, ML, Barr, F, Dawling, S, Smith, W, Lee, B, Singh, RH, Rhead, WJ, Sniderman King, L, Christman, BW Unmasked adult-onset urea cycle disorders in the critical care setting. Crit Care Clin, 21(4 Suppl), S1-8, 2005.
- Humbert, M, Morrell, NW, Archer, SL, Stenmark, KR, MacLean, MR, Lang, IM, Christman, BW, Weir, EK, Eickelberg, O, Voelkel, NF, Rabinovitch, M Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol, 43(12 Suppl S), 13S-24S, 2004.
- Summar, ML, Hall, L, Christman, B, Barr, F, Smith, H, Kallianpur, A, Brown, N, Yadav, M, Willis, A, Eeds, A, Cermak, E, Summar, S, Wilson, A, Arvin, M, Putnam, A, Wills, M, Cunningham, G Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Mol Genet Metab, 81 Suppl 1S12-9, 2004.
- Chen, Jian-xiong, Lawrence, Mayme Lee, Cunningham, Gary, Christman, Brian W, Meyrick, Barbara HSP90 and Akt modulate Ang-1-induced angiogenesis via NO in coronary artery endothelium. J Appl Physiol, 96(2), 612-20, 2004.
- Kallianpur, Asha R, Hall, Lynn D, Yadav, Meeta, Christman, Brian W, Dittus, Robert S, Haines, Jonathan L, Parl, Fritz F, Summar, Marshall L Increased prevalence of the HFE C282Y hemochromatosis allele in women with breast cancer. Cancer Epidemiol Biomarkers Prev, 13(2), 205-12, 2004.
- Richard, C, Gao, J, LaFleur, B, Christman, BW, Anderson, J, Brown, N, Reese, J Patency of the preterm fetal ductus arteriosus is regulated by endothelial nitric oxide synthase and is independent of vasa vasorum in the mouse. Am J Physiol Regul Integr Comp Physiol, 287(3), R652-60, 2004.
- Summar, Marshall L, Gainer, James V, Pretorius, Mias, Malave, Hector, Harris, Stephanie, Hall, Lynn D, Weisberg, Alec, Vaughan, Douglas E, Christman, Brian W, Brown, Nancy J Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function. Hypertension, 43(2), 186-91, 2004.
- Chen, Daohong, Balyakina, Elena V, Lawrence, Mayme, Christman, Brian W, Meyrick, Barbara Cyclooxygenase is regulated by ET-1 and MAPKs in peripheral lung microvascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol, 284(4), L614-21, 2003.
- Barr, FE, Beverley, H, VanHook, K, Cermak, E, Christian, K, Drinkwater, D, Dyer, K, Raggio, NT, Moore, JH, Christman, B, Summar, M Effect of cardiopulmonary bypass on urea cycle intermediates and nitric oxide levels after congenital heart surgery. J Pediatr, 142(1), 26-30, 2003.
- Chen, Jian-Xiong, Berry, Leonard C, Christman, Brian W, Meyrick, Barbara Glutathione mediates LPS-stimulated COX-2 expression via early transient p42/44 MAPK activation. J Cell Physiol, 197(1), 86-93, 2003.
- Langleben, David, Christman, Brian W, Barst, Robyn J, Dias, Virgil C, Galiè, Nazzareno, Higenbottam, Timothy W, Kneussl, Meinhard, Korducki, Larry, Naeije, Robert, Riedel, Axel, Simonneau, Gerald, Hirsch, Andrew M, Rich, Stuart, Robbins, Ivan M, Oudiz, Ronald, McGoon, Michael D, Badesch, David B, Levy, Robert D, Mehta, Sanjay, Seeger, Werner, Solèr, Markus Effects of the thromboxane synthetase inhibitor and receptor antagonist terbogrel in patients with primary pulmonary hypertension. Am Heart J, 143(5), E4, 2002.
- Klings, E S, Christman, B W, McClung, J, Stucchi, A F, McMahon, L, Brauer, M, Farber, H W Increased F2 isoprostanes in the acute chest syndrome of sickle cell disease as a marker of oxidative stress. Am J Respir Crit Care Med, 164(7), 1248-52, 2001.
- Robbins, I M, Barst, R J, Rubin, L J, Gaine, S P, Price, P V, Morrow, J D, Christman, B W Increased levels of prostaglandin D(2) suggest macrophage activation in patients with primary pulmonary hypertension. Chest, 120(5), 1639-44, 2001.
- Chen, J X, Berry, L C, Christman, B W, Tanner, M, Myers, P R, Meyrick, B O NO regulates LPS-stimulated cyclooxygenase gene expression and activity in pulmonary artery endothelium. Am J Physiol Lung Cell Mol Physiol, 280(3), L450-7, 2001.
- Pearson, D L, Dawling, S, Walsh, W F, Haines, J L, Christman, B W, Bazyk, A, Scott, N, Summar, M L Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med, 344(24), 1832-8, 2001.
- Blackwell, T S, Christman, J W, Hagan, T, Price, P, Edens, T, Morris, P E, Wolff, S N, Goodman, S A, Christman, B W Oxidative stress and NF-kappaB activation: correlation in patients following allogeneic bone marrow transplantation. Antioxid Redox Signal, 2(1), 93-102, 2001.
- Dworski, R, Sheller, JR, Christman, BW Quantitative analysis of cyclooxygenase metabolites of arachidonic Acid. Methods Mol Med, 56411-22, 2001.
- Dworski, R, Christman, BW, Sheller, JR Quantitative analysis of f(2) isoprostanes. Methods Mol Med, 56423-30, 2001.
- Collins, B J, Blum, M G, Parker, R E, Chang, A C, Blair, K S, Zorn, G L, Christman, B W, Pierson, R N Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection. J Appl Physiol, 90(6), 2257-68, 2001.
- Mangialardi, R J, Martin, G S, Bernard, G R, Wheeler, A P, Christman, B W, Dupont, W D, Higgins, S B, Swindell, B B Hypoproteinemia predicts acute respiratory distress syndrome development, weight gain, and death in patients with sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med, 28(9), 3137-45, 2000.
- Haselton, D J, Klekamp, J G, Christman, B W, Barr, F E Use of high-dose corticosteroids and high-frequency oscillatory ventilation for treatment of a child with diffuse alveolar hemorrhage after bone marrow transplantation: case report and review of the literature. Crit Care Med, 28(1), 245-8, 2000.
- Arons, M M, Wheeler, A P, Bernard, G R, Christman, B W, Russell, J A, Schein, R, Summer, W R, Steinberg, K P, Fulkerson, W, Wright, P, Dupont, W D, Swindell, B B Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med, 27(4), 699-707, 1999.
- Costa, F, Sulur, P, Angel, M, Cavalcante, J, Haile, V, Christman, B, Biaggioni, I Intravascular source of adenosine during forearm ischemia in humans: implications for reactive hyperemia. Hypertension, 33(6), 1453-7, 1999.
- Martin, G S, Christman, B W, Standaert, S M Rapidly fatal infection with Ehrlichia chaffeensis. N Engl J Med, 341(10), 763-4, 1999.
- Robbins, I M, Christman, B W, Newman, J H, Matlock, R, Loyd, J E A survey of diagnostic practices and the use of epoprostenol in patients with primary pulmonary hypertension. Chest, 114(5), 1269-75, 1998.
- Robbins, I M, Cuiper, L L, Stein, C M, Wood, A J, He, H B, Parker, R, Christman, B W Angiotensin II mediates systemic rebound hypertension after cessation of prostacyclin infusion in sheep. J Appl Physiol, 85(2), 731-7, 1998.
- Carpenter, C T, Price, P V, Christman, B W Exhaled breath condensate isoprostanes are elevated in patients with acute lung injury or ARDS. Chest, 114(6), 1653-9, 1998.
- Becker, P M, Sanders, S P, Price, P, Christman, B W F2-isoprostane generation in isolated ferret lungs after oxidant injury or ventilated ischemia. Free Radic Biol Med, 25(6), 703-11, 1998.
- Christman, B W Lipid mediator dysregulation in primary pulmonary hypertension. Chest, 114(3 Suppl), 205S-207S, 1998.
- Alexander, J S, Patton, W F, Christman, B W, Cuiper, L L, Haselton, F R Platelet-derived lysophosphatidic acid decreases endothelial permeability in vitro. Am J Physiol, 274(1 Pt 2), H115-22, 1998.
- Tchekneva, E, Quertermous, T, Christman, B W, Lawrence, M L, Meyrick, B Regional variability in preproEndothelin-1 gene expression in sheep pulmonary artery and lung during the onset of air-induced chronic pulmonary hypertension. Participation Of arterial smooth muscle cells. J Clin Invest, 101(6), 1389-97, 1998.
- He, H, Stein, CM, Christman, B, Wood, AJ Determination of catecholamines in sheep plasma by high-performance liquid chromatography with electrochemical detection: comparison of deoxyepinephrine and 3,4-dihydroxybenzylamine as internal standard. J Chromatogr B Biomed Sci Appl, 701(1), 115-9, 1997.
- Bernard, G R, Wheeler, A P, Russell, J A, Schein, R, Summer, W R, Steinberg, K P, Fulkerson, W J, Wright, P E, Christman, B W, Dupont, W D, Higgins, S B, Swindell, B B The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med, 336(13), 912-8, 1997.
- Blackwell, T S, Blackwell, T R, Holden, E P, Christman, B W, Christman, J W In vivo antioxidant treatment suppresses nuclear factor-kappa B activation and neutrophilic lung inflammation. J Immunol, 157(4), 1630-7, 1996.
- Cuiper, L L, Price, P V, Christman, B W Systemic and pulmonary hypertension after abrupt cessation of prostacyclin: role of thromboxane A2. J Appl Physiol, 80(1), 191-7, 1996.
- Meyrick, B, Berry, L C, Christman, B W Response of cultured human pulmonary artery endothelial cells to endotoxin. Am J Physiol, 268(2 Pt 1), L239-44, 1995.
- Conary, J T, Parker, R E, Christman, B W, Faulks, R D, King, G A, Meyrick, B O, Brigham, K L Protection of rabbit lungs from endotoxin injury by in vivo hyperexpression of the prostaglandin G/H synthase gene. J Clin Invest, 93(4), 1834-40, 1994.
- Biggs, V J, Dummer, S, Holsinger, F C, Loyd, J E, Christman, B W, Frist, W H Successful treatment of invasive bronchial aspergillosis after single-lung transplantation. Clin Infect Dis, 18(1), 123-4, 1994.
- Christman, B W, Bernard, G R Antilipid mediator and antioxidant therapy in adult respiratory distress syndrome. New Horiz, 1(4), 623-30, 1993.
- Kuratomi, Y, Lefferts, P L, Christman, B W, Parker, R E, Smith, W G, Mueller, R A, Snapper, J R Effect of a 5-lipoxygenase inhibitor on endotoxin-induced pulmonary dysfunction in awake sheep. J Appl Physiol, 74(2), 596-605, 1993.
- Brigham, KL, Meyrick, B, Christman, B, Conary, JT, King, G, Berry, LC, Magnuson, MA Expression of human growth hormone fusion genes in cultured lung endothelial cells and in the lungs of mice. Am J Respir Cell Mol Biol, 8(2), 209-13, 1993.
- Christman, B W, Christman, J W, Dworski, R, Blair, I A, Prakash, C Prostaglandin E2 limits arachidonic acid availability and inhibits leukotriene B4 synthesis in rat alveolar macrophages by a nonphospholipase A2 mechanism. J Immunol, 151(4), 2096-104, 1993.
- Christman, B W, McPherson, C D, Newman, J H, King, G A, Bernard, G R, Groves, B M, Loyd, J E An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension. N Engl J Med, 327(2), 70-5, 1992.
- Trochtenberg, D S, Lefferts, P L, King, G A, Hwang, Y S, Christman, B W, Snapper, J R Effects of thromboxane synthase and cyclooxygenase inhibition on PAF-induced changes in lung function and arachidonic acid metabolism. Prostaglandins, 44(6), 555-77, 1992.
- Christman, B W, Gay, J C, Christman, J W, Prakash, C, Blair, I A Analysis of effector cell-derived lyso platelet activating factor by electron capture negative ion mass spectrometry. Biol Mass Spectrom, 20(9), 545-52, 1991.
- Meyrick, B, Christman, B, Jesmok, G Effects of recombinant tumor necrosis factor-alpha on cultured pulmonary artery and lung microvascular endothelial monolayers. Am J Pathol, 138(1), 93-101, 1991.
- Christman, J W, Christman, B W, Shepherd, V L, Rinaldo, J E Regulation of alveolar macrophage production of chemoattractants by leukotriene B4 and prostaglandin E2. Am J Respir Cell Mol Biol, 5(3), 297-304, 1991.
- Christman, B W, Lefferts, P L, Blair, I A, Snapper, J R Effect of platelet-activating factor receptor antagonism on endotoxin-induced lung dysfunction in awake sheep. Am Rev Respir Dis, 142(6 Pt 1), 1272-8, 1990.
- Schapira, M, Christman, B W Neutralization of heparin by protamine. Time for a change?. Circulation, 82(5), 1877-9, 1990.
- Takahashi, K, Schreiner, G F, Yamashita, K, Christman, B W, Blair, I, Badr, K F Predominant functional roles for thromboxane A2 and prostaglandin E2 during late nephrotoxic serum glomerulonephritis in the rat. J Clin Invest, 85(6), 1974-82, 1990.
- Christman, B W, Blair, I A Analysis of platelet activating factor in human saliva by gas chromatography/mass spectrometry. Biomed Environ Mass Spectrom, 18(4), 258-64, 1989.
- Brigham, KL, Meyrick, B, Christman, B, Berry, LC, King, G Expression of a prokaryotic gene in cultured lung endothelial cells after lipofection with a plasmid vector. Am J Respir Cell Mol Biol, 1(2), 95-100, 1989.
- Brigham, KL, Meyrick, B, Christman, B, Magnuson, M, King, G, Berry, LC In vivo transfection of murine lungs with a functioning prokaryotic gene using a liposome vehicle. Am J Med Sci, 298(4), 278-81, 1989.
- Coggeshall, J W, Christman, B W, Lefferts, P L, Serafin, W E, Blair, I A, Butterfield, M J, Snapper, J R Effect of inhibition of 5-lipoxygenase metabolism of arachidonic acid on response to endotoxemia in sheep. J Appl Physiol, 65(3), 1351-9, 1988.
- Christman, B W, Lefferts, P L, King, G A, Snapper, J R Role of circulating platelets and granulocytes in PAF-induced pulmonary dysfunction in awake sheep. J Appl Physiol, 64(5), 2033-41, 1988.
- Christman, B W, Lefferts, P L, Snapper, J R Effect of platelet-activating factor on aerosol histamine responsiveness in awake sheep. Am Rev Respir Dis, 135(6), 1267-70, 1987.
- Snapper, J R, Coggeshall, J W, Serafin, W E, Phillips, M A, Lefferts, P L, Christman, B W Role of leukotrienes in an animal model of the adult respiratory distress syndrome. Adv Prostaglandin Thromboxane Leukot Res, 17B1043-6, 1987.
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