Risk factors for ARDS often include conditions which compromise intestinal perfusion and viability (sepsis, shock, multiple organ failure). Since intestines have high concentrations of potential toxins, we hypothesize that intestinal ischemia/reperfusion (I/R) injury causes acute edematous lung injury (ARDS) by a mechanism involving release of XO into the circulation. Our preliminary data supports our premise. First, circulating XO increases after reperfusion of the ischemic rat and canine intestines and plasma XO levels are higher in humans with ARDS than controls. Second, lung neutrophil sequestration occurs in the lungs of rats subjected to intestinal I/R. Similarly, increases in O2 metabolite release and neutrophil adherence to cultured endothelial cells (EC) are both decreased by XO inhibition. Third, skin burn increases blood XO levels and damages lungs in vivo and isolated blood-perfused lungs in untreated controls but not rats treated with XO inhibitors and O2 metabolite scavengers. My immediate specific objectives are to determine the contribution of XO- derived O2 metabolites to acute edematous lung injury following intestinal I/R and to relate this injury to changes in circulating XO and antiprotease levels, lung neutrophil accumulation and activation in parallel in vivo, isolated lung and in vitro test systems. The significance of this project is to provide new information about the mechanisms by which blood-borne mediators are formed and contribute to lung injury. The approach may reveal common mechanisms which unify acute lung injury from diverse causes, further targeting treatment. Lance S. Terada, M.D. is a broad certified internist and is committed to a career in academic medicine and research. He has complete his training in clinical pulmonary medicine and has spent the last 15 months investigating basic mechanisms of oxidant injury under John E. Repine, M.D. Dr. Repine has extensive experience in training young investigator and has a well equipped laboratory.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002375-04
Application #
3082736
Study Section
Research Manpower Review Committee (MR)
Project Start
1990-04-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Terada, L S (1996) Hypoxia-reoxygenation increases O2-. efflux which injures endothelial cells by an extracellular mechanism. Am J Physiol 270:H945-50
Moores, H K; Beehler, C J; Hanley, M E et al. (1994) Xanthine oxidase promotes neutrophil sequestration but not injury in hyperoxic lungs. J Appl Physiol 76:941-5
Terada, L S (1994) Suppression of rabbit myocardial xanthine dehydrogenase activity by an endogenous compound. J Mol Cell Cardiol 26:125-32
Terada, L S; Arnold, P D (1993) Xanthine oxidase does not mediate the antiproliferative effects of interferon-gamma in human umbilical vein endothelial cells. J Interferon Res 13:419-22
Terada, L S; Dormish, J J; Shanley, P F et al. (1992) Circulating xanthine oxidase mediates lung neutrophil sequestration after intestinal ischemia-reperfusion. Am J Physiol 263:L394-401
Terada, L S; Guidot, D M; Leff, J A et al. (1992) Hypoxia injures endothelial cells by increasing endogenous xanthine oxidase activity. Proc Natl Acad Sci U S A 89:3362-6
Terada, L S; Willingham, I R; Guidot, D M et al. (1992) Tungsten treatment prevents tumor necrosis factor-induced injury of brain endothelial cells. Inflammation 16:13-9
Terada, L S; Rubinstein, J D; Lesnefsky, E J et al. (1991) Existence and participation of xanthine oxidase in reperfusion injury of ischemic rabbit myocardium. Am J Physiol 260:H805-10
Terada, L S; Willingham, I R; Rosandich, M E et al. (1991) Generation of superoxide anion by brain endothelial cell xanthine oxidase. J Cell Physiol 148:191-6
Terada, L S; Leff, J A; Guidot, D M et al. (1991) Inactivation of xanthine oxidase by hydrogen peroxide involves site-directed hydroxyl radical formation. Free Radic Biol Med 10:61-8