Ischemia is an important cause of human disease. However, therapy is complicated by toxic O2 metabolite generation during reperfusion which aggravates injury from ischemia. Ischemia-reperfusion (I/R) injury of the lung may increase damage from pulmonary embolism and other ischemic events and is impeding progress in lung embolism and other ischemic events an is impeding progress in lung transplantation. My hypothesis is that (1) endogenous lung antioxidants are impaired during ischemia and (2) that impaired lung antioxidants increase susceptibility to reperfusion injury. Background evidence indicates that (1) oxidants generated during reperfusion contribute to tissue injury, (2) alterations in endogenous antioxidant levels may affect susceptibility to oxidant injury, (3) exogenous antioxidants reduce I/R injury, and (4) ischemia decreases endogenous antioxidants (GSH and SOD) in a variety of organs. Our preliminary data supports this hypothesis by showing that endotoxin, which causes antioxidant increase in rats during hyperoxia exposure, decreases susceptibility of isolated lungs and hearts to I/R. Immediate goals are to use the isolated lung model to determine (1) if pulmonary antioxidants decrease during I/R, (2) if O2 metabolite scavengers or xanthine oxidase I/R and (3) if increasing or decreasing endogenous antioxidants alters susceptibility to I/R injury. The significance is to advance understanding of the mechanisms of pulmonary I/R injury and to develop a rational basis for more urgently needed effective therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002369-05
Application #
2209983
Study Section
Research Manpower Review Committee (MR)
Project Start
1990-08-01
Project End
1995-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
5
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Beehler, C J; Ely, M E; Rutledge, K S et al. (1994) Toxic effects of dimethylthiourea in rats. J Lab Clin Med 123:73-80
Beehler, C J; Simchuk, M L; McCord, J M et al. (1992) Effects of dimethylthiourea in hyperoxic injury. J Lab Clin Med 119:508-13