Oxidative stress has been suggested to play an important role in a wide variety of disease processes including hyperoxia- induced lung and retinal injury and the normalaging process. We have reported the discovery of novel bioactive prostaglandin F,-like compounds, termed F2-isoprostanes (F2-IsoPs) that are produced in vivo non-enzymatically by free radical induced peroxidation of arachidonic acid (AA) and that similar compounds are also produced in the brain from oxidation of docosahexaenoic acid (DHA). Measurement of these compounds has proven to be a major advance in our ability to assess oxidative stress status in vivo. We have also shown that compounds that have E-, D-, A-, and J-type rings and highly reactive isolevuglandins (IsoLGs) are products of IsoP pathway. We have recently discovered a series of novel lipid peroxidation products that we speculate contain a furan ring (IsoFs). These compounds will be structurally characterized and their mechanism(s) of formation will be determined using a number of analytical approaches utilizingmass spectrometry. In the presence of high oxygen tension, we have found that the formation of IsoFs is highly favored over the IsoPs. Thus, studies are proposed to utilize measurements of IsoFs to investigate the role of free radicals in hyperoxia-induced pathologies. New IsoPs and IsoFs will also be synthesized and tested for bioactivity. We have obtained evidence that the formation of IsoPs is increased dramatically in aged rats. This will be further characterized and correlated with other products of oxidation and antioxidant defenses in rats. We will also explore the hypothesisthat this phenomenon may be the cause of multi-organ failure in the elderly. Studies are also planned to further characterize the spectrum of IsoP-like and related compounds that can be formed from oxidation of DHA. Studies are also planned to explore the biochemistry and pathobiology of IsoLGs, focusing on their preferential adduction to membrane proteins with attendant alteration in the function of receptors and ion channels. We will also explore whetherthese compounds, which are initially formed esterified inphospholipids, are substrates for platelet activating factor acetyl hydrolase. Finally, we will test the hypothesis that free radicals and IsoPs play an important role in the renal failure that ensues in glactosamine treated rats, an animal model of the hepatorenal syndrome.
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