Oxidative Stress and Macrophage Dysfunction

  • Asmis, Reto (PI)
  • Van Zant, Gary (CoI)

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Macrophages orchestrate complex processes such as cell proliferation, angiogenesis and tissue regeneration through the coordinated release of chemoattractants, cytokines, growth factors, proteases and extracellular matrix molecules. These cellular processes are sensitive to thiol oxidation and changes in the cellular redox state. Both atherosclerosis and diabetes appear to be associated with macrophage dysfunction as macrophages isolated from either atherosclerosis-susceptible mice or diabetic mice show different morphology and altered cytokine and chemokine responses compared to macrophages from healthy control mice. The mechanisms underlying macrophage dysfunction in vivo are unclear, but our preliminary data show that chronic oxidative stress in mice promotes macrophage dysfunction and impaired wound healing. We found that oxidative stress was also significantly increased in macrophages from diabetic Leprdb mice compared to strain-matched control mice. More importantly, macrophages from diabetic Leprdb mice showed the same abnormal cytokine and growth factor responses we observed in our mouse model of chronic oxidative stress. Our studies in cultured primary macrophages show that oxidative stress-induced cell injury involves the loss of glutathione reductase activity, accumulation of oxidized glutathione, a decreased glutathione/glutathione disulfide ratio and increased protein-S-glutathiolation. Based on these observations we hypothesize that preventing the accumulation of GSSG in macrophages will prevent macrophage dysfunction and improve wound healing in oxidatively-stressed mice. To test our hypothesis we propose the following specific aims: Aim 1: To determine the role of altering the GSH/GSSG ratio in regulating cytokine and growth factor responses in macrophages from oxidatively stressed mice. Aim 2: To determine whether increasing glutathione reductase activity improves macrophage function and wound healing in diabetic Leprdb mice.
Effective start/end date7/1/046/30/06


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