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The critical link between intracellular responses and innate autoimmunity in ischemia-reperfusion injury.
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Zhang, Ming
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2012-03-14
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Doctoral Dissertation
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Reperfusion of ischemic tissue leads to acute ischemia/reperfusion (I/R) injury. Two theories have been suggested for the mechanism of I/R injury. One involves intracellular responses to ischemia, e.g. generation of reactive oxygen species (ROS), while the other involves extrinsic acute inflammation, e.g. natural IgM-mediated innate autoimmune attack. Whether the ROS-mediated mechanism plays a role in the natural IgM-mediated mechanism is still unknown. We studied this important question by using transgenic (TG) mice overexpressing an antioxidant enzyme, superoxide dismutase (SOD), in a murine model of intestinal I/R. If the intracellular response contributes to the extrinsic inflammation, we predicted that inhibiting the ROS mechanism would protect animals from natural IgM-mediated I/R injury. Our results showed that SOD1 TG mice have a significant reduction in intestinal I/R injury compared to wild-type (WT) littermates. In addition, IgM-mediated inflammatory response is blocked in SOD1 TG mice. We further explored whether cell membrane damage is the critical link between the generation of intracellular ROS and the exposure of self-antigens triggering the innate autoimmune response. A cell membrane stabilizer was applied to WT mice prior to I/R surgery, and the mice had a significantly reduced I/R injury along with blocked IgM-mediated complement activation. We also tested this stabilizer in a hypoxia model of human coronary artery endothelial cells (hCAECs). Our results showed that under hypoxia conditions, human IgM and C3 deposited on hCAECs, suggesting activation of complements similar to that in the animal I/R model. Treatment with trehalose before hypoxia treatment blocked IgM-mediated complement activation. In summary, our current study identified a critical link between the intracellular response to I/R injury and the first step in the innate autoimmune response.
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Lee, H. (2012). The critical link between intracellular responses and innate autoimmunity in ischemia-reperfusion injury. [Doctoral dissertation, SUNY Downstate Health Sciences University]. SUNY Open Access Repository. https://soar.suny.edu/handle/20.500.12648/15980
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Doctoral Dissertation