The lungs are constantly subjected to both self-generated and exogenous sources of oxidant stress. This oxidant stresses often mediated by reactive species have in unpaired electrons, termed free radicals. The important contribution which the free radical nitric oxide (NO) plays in vasoregulation, cell-mediated immunity and neurotransmission has been revealed in he last few years. During this time it was generally accepted that superoxide (Ox) """"""""inactivate"""""""" the vasoactive action of NO. We have observed that the product of this reaction, peroxynitrite (ONOO) is actually a potent oxidant and can mediate many of the cell-mediated immunity and toxic reactions previously ascribed to NO and O2. Importantly, ONOO is also a source of hydroxyl radical (OH), the most reactive molecule in biology. There are a number of significant clinical conditions where the excess production of O2 and NO may contribute to tissue injury, including sepsis, reperfusion injury, acute inflammation, hyperoxia and smoke inhalation. We have hypothesized that pulmonary reactions of O2 and NO yield potent secondary oxidants, which then mediate diverse pulmonary pathological processes. These oxidants include ONOO and its decomposition product, OH. This hypothesis will be addressed by interrelated experimental aims spanning from biochemical and cellular constructs of pulmonary free radical reaction to a model of lung transplantation. We propose to define regulatory mechanisms for lung cell production of ONOO and then assess the contribution of O2 and NO- derived reactive species to oxidant lung injury associated with lung transplantation and inhalation of NO gas. These proposed experiments will reveal more detailed information about the pathologic roles of O2 and NO and permit detection of tissue ONOO production especially as related to defining mechanisms of sepsis-induced lung injury and the loss of pulmonary function and viability during lung transplantation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL051245-01
Application #
2227877
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1994-02-01
Project End
1999-01-31
Budget Start
1994-02-01
Budget End
1995-01-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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