Associate Chief of Staff (ACOS) for Research and Development, MVAHS Professor of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Miami Miller School of Medicine Contact Information Location: Research Service (151) 1201 N.W. 16th Street, Miami, FL 33125 Office Phone: 305-575-3548 Lab Phone: 305-575-3941 or 305-575-3971 Fax: 305-575-3126 or 305-575-7146 Email: rjackson2@med.miami.edu or robert.jackson4@va.gov Affiliations Miami VA Research Service and Pulmonary Section Division of Pulmonary, Critical Care and Sleep Medicine University of Miami School of Medicine Education A.B. Magna cum Laude Boston University (Combined 6-year program in liberal arts and medicine), 1973 M.D., Boston University School of Medicine, 1976 Post-Graduate Training Program Affiliations Residency in Medicine, University of Miami Hospitals, 1976-1979 Fellowship in Pulmonary Disease, University of Miami Hospitals, 1979-1981 Post-doctoral Research Associate, Institute for Environmental Medicine, University of Pennsylvania School of Medicine, 1981-1983 Sabbatical in molecular biology, Duke University Medical Center, 1991-1992 Certifications 1979 American Board of Internal Medicine Candidate number 071394 1982 A.B.I.M., Pulmonary Disease 1988-1998 A.B.I.M, Critical Care Medicine 1998-2008 A.B.I.M., Critical Care Medicine Description of Research Expertise Research Interests Pulmonary oxygen toxicity/oxidant injury, Hypoxic cellular physiology and metabolism, Alveolar epithelial cell biology, Oxidant stress as a mechanism in interstitial lung disease
Our laboratory and clinical research programs focus on redox signaling and antioxidant defense mechanisms in lung epithelial cells and on oxidant stress in idiopathic pulmonary fibrosis. Projects investigate both basic mechanisms by which lung epithelial cells respond to oxidant stress and clinical aspects of reactive oxygen species production during exercise. This combination has allowed an integrated approach that extends basic mechanistic studies typically done in cell culture directly to a translational context. A major area of interest has been to understand how hypoxia modulates redox signaling in the lung epithelium. Recently, we found that hypoxia decreases cellular glutathione content and appears to decrease the effect of N-acetylcysteine on repletion of GSH. We discovered that hypoxia decreases two key enzyme activities that regulate GSH synthesis, glutamate cysteine ligase (GCL) (E.C. 6.3.2.2) and glutathione synthase (GS) (E.C. 6.3.2.3). No hypoxia dependent change occurs in GCL or GS protein expression on western blots. When epithelial cells are transfected with an adenoviral vector that causes over expression of human catalase protein (Ad.Cat or Ad.mCat), GCL and GS activities do not decrease in hypoxia. Inhibition of p38MAPK (using SB203580) or ERK (PD98059) prevents the hypoxia-dependent decrease in GCL and GS activity. To seek in vivo correlation, we assayed total glutathione in lungs and livers from MK2-/- (homozygous knockout) mice. MK2-/- mice are presumably unable to phosphorylate Hsp27 normally, because of absent kinase (MK2) activity. Liver GSH content (expressed per mg protein) was 20% less in MK2-/- mice than in non transgenic Black 6 controls. Down regulation of lung GSH content in hypoxia depends on peroxide tone of the cell and the p38MAPK system. Such studies demonstrate that cellular antioxidant defenses in hypoxia are regulated in a complex way by the MAPK system (in press, 2009). A second major focus of interest is to determine how oxidant stress relates to hypoxia and exercise tolerance in IPF patients. We investigated whether markers of systemic oxidant stress were detectable in 29 typical IPF patients, and whether these increased after low level exercise. We obtained resting plasma for measurement of amino terminal pro brain natriuretic peptide (NT-pro BNP), and plasma and urine samples for isoprostanes and total nitrite. Total antioxidant capacity (TAC) was measured in plasma, and H2O2 was measured in urine. Subjects exercised at ~50 watts on a semi recumbent bicycle until limited by dyspnea. Samples were obtained immediately after exercise for measurement of the same variables. SaO2 decreased and lactate concentration increased significantly after exercise. Plasma and urine samples were also obtained at rest from 6 normal individuals over 40 years of age to establish comparison values for NT-proBNP, nitrite, H2O2 and TAC assays. Plasma NT-proBNP was high at rest and after exercise, suggesting pulmonary arterial hypertension. IPF plasma isoprostanes at rest clearly exceeded the normals, but they did not increase after exercise. IPF urine isoprostanes increased significantly after exercise (P=0.047 by signed rank test). Plasma TAC decreased significantly after exercise (P<0.001 by signed rank test). Neither plasma nor urine nitrite changed significantly after exercise. H2O2 concentration was quite high after exercise in some IPF subjects’ urine, but it did not increase significantly. These studies demonstrate that hypoxia and oxidant stress both occur after low level exercise in IPF patients. They lead us to test the hypothesis that oxidant stress due to cellular hypoxia is a major factor that limits exercise tolerance in IPF and other lung diseases (submitted, 2009). Representative Publication Jackson, R. and R. Garcia-Rojas. Kinase activity, Hsp27 phosphorylation and epithelial cell glutathione. Exp Lung Research 34: 245-262, 2008. Etanercept for idiopathic pulmonary fibrosis: Lessons on clinical trial design. Jackson, R., and C. Fell. Am J Resp Crit Care Med 178: 3889-893, 2008. Jackson, R., C. Ramos, M. Glassberg, P. Bejarano, O. Gomez-Marin. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis: a randomized controlled trial. In press, LUNG, 2009. Jackson, R., C. Ramos, C. Gupta, O. Gomez-Marin. Exercise decreases plasma antioxidant capacity and increases urinary isoprostanes in IPF. Submitted, 2009. Jackson, R. and Gupta, C. Hypoxia and kinase activity regulate lung epithelial cellular glutathione. In press, Exp Lung Research 35: xxx-xxx, 2009. tp://sfvafre.org/investigators.php |
