Blackwell Publishing Journal Backfiles 1879-2005
Reactive oxygen species (ROS) play a major role in recruiting and activating inflammatory cells, inducing angiogenesis, fibroblast proliferation, and collagen synthesis, all processes essential to wound healing. However, the same mediators have been implicated in pulmonary and hepatic fibrosis, vascular occlusion, and necrotic tissue damage. We have previously shown that hyperbaric oxygen caused a prolonged elevation of VEGF and delayed wound healing in a rat model of tissue ischemia. In this study we examine the effect of the ROS scavenger, n-acetylcysteine (NAC), on ischemic wound healing. NAC is a virtually nontoxic free radical scavenger that has been used in many experimental studies to block ROS-mediated signaling.Methods: Male Sprague-Dawley rats underwent creation of the ischemic flap previously validated by this laboratory. This model provides two ischemic and two nonischemic excisional wounds. Rats were treated daily with HBO for 90 minutes at 2.4 atm, HBO plus 150 mg/kg NAC intraperitoneal, or control (neither HBO nor NAC). Wounds were analyzed for surface area, lactate, and VEGF.Results: The HBO/NAC-treated animals had markedly impaired healing of their ischemic wounds at day 7 (0.105 ± .005 cm vs. 0.068 ± .002 cm for ctl and 0.064 ± .006 for HBO) and a twofold elevation of VEGF (120 pg/mg protein vs. 60 pg/mg protein). Lactate levels were not altered by NAC treatment and non-ischemic wounds showed no difference in healing, lactate, or VEGF.Conclusion: Reactive oxygen species are required for wound healing. Our initial hypothesis was that the delay in wound closure with HBO treatment was due to excess ROS and that NAC would improve healing. The finding of elevated VEGF and delayed wound healing in the presence of a potent free radical scavenger suggests that blocking ROS signaling prevents the normal mitogenic response to VEGF. Additional studies to examine the VEGF receptor and tyrosine kinase activation will further elucidate the mechanism of ROS signaling in response to HBO treatment.
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