The present hypothesis is that toxic 02 metabolites derive from xanthine oxidase (XO) in EC contribute to lung EC injury and acute edematous lung injury due to hyperopia. Xo derived 02 metabolites directly alter EC permeability barrier function, inactivate EC associated antiproteases and increase neutrophil adherence and injury. The premliminary data supports this premise. After treatment with neutrophil elastase, hyperopia pretreated, XO depleted EC monolayers leaked less albumin than XO replete EC monolayers. Before and after perfusion with neutrophil elastase, lungs isolated from XO depleted rats exposed to hyperopia leaked less ficoll than XO replete lungs. XO depleted gerbils also survived and had less brain swelling than XO replete gerbils after temporary unilateral carotid occlusion. Finally, addition of normal neutrophils (cut not 02 metabolite deficient chronic granulomatous disease (CGD) neutrophils) worsened injury in ischemic but not non-ischemic isolated perfused kidneys. The immediate specific aims now are to determine if treatment with XO inhibitors (tungsten or allopurinol) alters XO activities (by HPLC) permeability injury (albumin leak), 02 metabolite production ( by GSH/GSSG, DMTU dioxide formation, aminothiazole inactivated catalase), EC associated antiprotease activities, susceptibility to neutrophilelastse, neutrophil adherence (111 in labeled neutrophils) and/or neutrophil injury to EC or lungs isolated from rats exposed to hyperopia. The contribution of 02 metabolite scavengers, oxidizable or non-oxidizable elastase inhibitors, normal and CGD neutrophils. The significance of these studies is to improve understanding of mechanisms responsible for ARDS by identifying the contribution of 02 metabolites derived form XO in EC. The new information will be relevant to the pathogenesis of numerous disorders, such as oxygen toxicity, ARDS, shock, hypoxia and ischemia reperfusion insults.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL040784-01
Application #
3900802
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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