Oxidative Stress and MMP's

Massachusetts General Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

Oxidative stress is an important factor in the activation of matrix metalloproteinases (MMPs) which disrupt the blood brain barrier and contribute to edema and hemorrhage after acute infarction. Currently, there is very limited data available on oxidative stress after stroke in humans, and no studies have examined the interaction between oxidative stress and MMPs. Levels of oxidative stress markers and MMPs may help predict stroke outcome and, more importantly, may be targets for therapeutic intervention. Establishing the correlation between brain and blood levels is critical for the development of novel therapeutic strategies. We will use a rat model of stroke to investigate the correlation between brain and plasma marker levels, determine the impact of reperfusion on marker levels, and determine the association between F2- isoprostane (F2isoP), a direct marker of non-enzymatic oxidation of membrane phospholipids, and MMPs. In humans, we have designed a translational study measuring F2isoP, the Oxygen Radical Absorbance Capacity Assay (ORAC), a functional assay of antioxidant capacity, and MMP9 in 630 ischemic stroke patients presenting within 9 hours of stroke onset over a 4.5-year period. Using an animal model, we will compare cellular and mitochondria! oxidative stress and MMP9 activation in rats exposed to tPA, hyperoxia, neither, or both. Project #1, a study of normobaric oxygen (NBO), provides a unique opportunity to address concerns about oxidative stress with high dose oxygen therapy in humans. This will have important implications for clinical trials involving oxygen. We will measure free radicals in patients enrolled in the NBO (n=192) study in order to determine the effect of NBO on levels of free radical, 8-hydroxy-2'deoxyguanosine (8OHdG), and explore our hypothesis that this treatment will reduce oxidative stress, levels of MMP9, and infarct volume. Our Specific Aims are: (1) To elucidate the effect of cerebral ischemia on brain and peripheral levels of F2isoP, MMP9, and MMP2, (2) To determine whether acute measurements of peripheral F2isoP and MMP9 improve prediction of ischemic stroke outcome in humans, (3) To determine whether hyperoxia therapy has a direct beneficial effect on oxidative stress in the brain, and (4) To explore predictors of oxidative stress and gelatinase levels, quantifying the contributions of oxidative stress, hemorrhage, infarction volume, tPA, inflammation, and reperfusion.