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Dr. John Repine's Laboratory

Investigating Inflammation, Oxidative Stress and Antioxidant Deficiency


Repine lab

Under the direction of John E. Repine, MD, the Webb-Waring Center Division of Experimental Research is focused on finding better ways to diagnose, treat, and prevent inflammation, antioxidant deficiency, and oxidative stress related diseases and aging.  These investigations target a number of important interrelated health and disease concerns including the following:

  1. The Acute Respiratory Distress Syndrome (ARDS).  ARDS is a highly fatal disease (approximately 40% death rate) that occurs for unknown reasons following infection, trauma, pancreatitis, multiple transfusions, and multiple other common predisposing insults.  ARDS kills more Americans (estimated at 80,000/year) each year than breast cancer and AIDS combined.  ARDS also takes the lives of many young soldiers, first-responders, and victims of terrorist attacks. ARDS is the common disorder that frequently afflicts patients in Intensive Care Units. ARDS patients develop diffuse lung edema caused by inflammation and oxidative stress.  We are presently pursuing a number of novel approaches (some patent protected) for predicting and preventing ARDS. Our primary goal is to discover ways to prospectively identify susceptible individuals so that ARDS can be treated and, hopefully, prevented before it becomes established and so deadly and disabling. Our research focuses primarily on the contributing roles of inflammatory macrophages, neutrophils, and oxidative stress.  In addition, the mechanisms responsible for ARDS development appear similar to mechanisms that contribute to Traumatic Brain Injury (TBI) and Post-Traumatic Stress Disorder (PTSD) that is also being investigated in parallel.  These investigations are all being propelled by use of a remarkable ARDS resistant rat that was discovered and developed here.

  2. Aging and the Metabolic Syndrome. Aging and the metabolic syndrome has become another focus of our research. This emphasis developed in part because during our studies of hyperoxia induced ARDS, we serendipitously discovered a single rat that uncharacteristically survived indefinitely in hyperoxia while all of the other rats died. By breeding this unique hyperoxia tolerant rat and its tolerant offspring, we created a new strain of rats that survive indefinitely in hyperoxia.  Amazingly, tolerant rats also resist ARDS, diabetes (they have lower blood glucose and insulin levels), obesity, and fatty liver development. Tolerant rats also are more active, have a greater exercise capacity, and live longer than control rats.  Tolerant rats seem to be the antithesis of individuals with metabolic syndrome with type 2 diabetes who develop abdominal obesity, hypertension, abnormal blood lipid levels, premature cardiovascular disease.  Accordingly, we are presently seeking the mechanism that underlies the remarkable protected phenotype of tolerant rats. This unexpected “experiment of nature” offers the opportunity to create unanticipated new insights regarding the causes and treatment of aging and age-related disorders.  In particular, we seek to find new ways to treat and prevent diabetes, metabolic syndrome, and the aging and aging related challenges that are increasingly impacting the health and wellness of more and more individuals worldwide.

  3. Age-Related Macular Degeneration (AMD) and Dry Eye.  AMD is the leading cause of blindness in the elderly.  It is a very common and devastating disorder that may afflict as many as 8% of individuals who are 70 years of age or older. AMD starts as a dry form that then unpredictably changes to a more severe wet form. There is no known effective treatment for dry ARDS.  We are developing a new approach that has the potential of reducing dry AMD and hopefully preventing it from evolving into wet AMD.  We are also working on way to prevent dry eye which is contributed to by eye inflammation and oxidative stress caused by environmental exposures, drugs, ocular disorders, and aging.

Dr. Richard Bowen, DMV, Colorado State University, Fort Collins, Colorado

Robert Scheinman, PhD, SOP, CU Anschutz

Oscar Reiss, PhD, Retired, CU Anschutz

John J. Hall, PhD, NIST-University of Colorado, Boulder

Jun Ye, PhD, NIST-University of Colorado, Boulder

Thomas Meersman, PhD, University of Notthingham, England

  1. Repine, J.E., White, J.G., Clawson, C.C. and Holmes, B.M.:  Effects of phorbol myristate acetate on the metabolism and ultrastructure of neutrophils in chronic granulomatous disease. J. Clin. Invest. 54:83-90, 1974 (PMID: 4366245).
  2. Repine, J.E., Eaton, J.W., Anders, M.W., Hoidal, J.R. and Fox, R.B.:  Generation of hydroxyl radical by enzymes, chemicals, and human phagocytes in vitro:  Detection using the anti-inflammatory agent - Dimethyl sulfoxide.  J. Clin. Invest. 64:1642-1651, 1979 (PMID: 500830).
  3. Repine, J.E., Pfenninger, O.W., Talmage, D.W., Berger, E.M. and Pettijohn, D.E.:  Dimethyl sulfoxide prevents DNA nicking mediated by ionizing radiation or iron/hydrogen peroxide-generated hydroxyl radical.  Proc. Natl. Acad. Sci. (USA) 78:1001-1003, 1981 (PMID: 6940118).
  4. Repine, J.E., Fox, R.B. and Berger, E.M.:  Hydrogen peroxide kills Staphylococcus aureus by reacting with staphylococcal iron to form hydroxyl radical.  J. Biol. Chem. 256:7094 7096, 1981 (PMID: 6265438).
  5. Tate, R.M., Morris, H.G., Schroeder, W.R. and Repine, J.E.: Oxygen metabolites stimulate thromboxane production and vasoconstriction in isolated saline-perfused rabbit lungs. J. Clin. Invest. 74:608-613, 1984 (PMID: 6547730).
  6. Toth, K.M., Clifford, D.P., Berger, E.M., White, C.W. and Repine, J.E.:  Intact human erythrocytes prevent hydrogen peroxide mediated damage to isolated perfused rat lungs and cultured bovine pulmonary artery endothelial cells. J. Clin. Invest. 74:292-295, 1984 (PMID: 6330176).
  7. White, C.W., Ghezzi, P., Dinarello, C.A., Caldwell, S.A., McMurtry, I.J. and Repine, J.E.:  Recombinant tumor necrosis factor/cachectin and interleukin 1 pretreatment decreases lung oxidized glutathione accumulation, lung injury and mortality in rats exposed to hyperoxia.  J. Clin. Invest. 79:1868 1873, 1987 (PMID: 3495553).
  8. Curtis, W.E., Muldrow, M.E., Parker, N.B., Barkley, R., Linas, S.L. and Repine, J.E.:  N,N' Dimethyl-thiourea dioxide formation from N,N' dimethylthiourea reflects hydrogen peroxide concentrations in simple biological systems.  Proc. Natl. Acad. Sci. (USA) 85:3422  3425, 1988 (PMID: 3130627).
  9. Brown, J.M., Terada, L.S., Grosso, M.A., Whitmann, G.J., Velasco, S.E., Patt, A., Harken, A.H. and Repine, J.E.:  Xanthine oxidase produces hydrogen peroxide which contributes to reperfusion injury of ischemic isolated perfused rat hearts.  J. Clin. Invest. 81: 1297 1301, 1988 (PMID: 3127425).
  10. Patt, A., Harken, A.H., Burton, L.K., Rodell, T.C., Piermattei, D., Schorr, W.J., Parker, N.B., Berger, E.M., Horesh, I.R., Linas, S.L., Cheronis, J.C. and Repine, J.E.:  Xanthine oxidase derived hydrogen peroxide contributes to ischemia reperfusion induced edema in gerbil brains.  J. Clin. Invest. 81:1556 1562, 1988 (PMID: 3130395).
  11. Adler, K.B., Holden-Stauffer, W.J. and Repine, J.E.:  Oxygen metabolites stimulate release of high molecular weight glycoconjugates by cell and organ cultures of rodent respiratory epithelium via an arachidonic acid-dependent mechanism.  J. Clin. Invest. 85:75-85, 1990 (PMID: 2153154).
  12. Guidot, D.M., McCord, J.M., Wright, R.M. and Repine, J.E.:  Absence of electron transport (Rho O state) restores growth of a manganese superoxide dismutase deficient Saccharomyces cerevisiae in hyperoxia: evidence for electron transport as a major source of superoxide generation in vivo.  J. Biol. Chem. 268: 26699 26703, 1993 (PMID: 8253804).
  13. Guidot, D.M., Repine, M.J., Westcott, J.Y. and Repine, J.E.:  Intrinsic 5 lipoxygenase activity is required for neutrophil responsivity.  Proc. Natl. Acad. Sci. (USA) 91:8156-8159, 1994 (PMID: 8058773).
  14. Abraham, E., Bursten, S., Shenkar, R., Allbee, J., Tudor, R., Woodson, P., Guidot, D.M., Rice, G.,Singer, J.W. and Repine, J.E.:  Phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury  following hemorrhage.  J. Exp. Med. 181:569-575, 1995 (PMID: 7836912).
  15. Cleveland, Z.I., Pavlovskaya, G.E., Elkins, N.D., Stupic, K.F., Repine, J.E. and Meersman, T.:  Hyperpolarized 83Kr MRI of lungs.  J. Mag. Reson. 195:232-237, 2008 (PMID: 18948043).
  16. Repine, J.E., Reiss, O.K., Elkins, N., Chughtai, A.R. and Smith, D.M. Effects of fine carbonaceous particles containing high and low unpaired electron spin densities on lungs of female mice. Trans. Res. 152:185-193, 2008 (PMID: 18940721).