Plastic Surgery Research Council
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PSRC 60th Annual Meeting

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Influence of MAPK Signaling on Ischemic Wound Healing in the Elderly
Ran Ito, MD, Qixu Zhang, MD, PhD.
MD Anderson Cancer Center, Houston, TX, USA.

Purpose: The majority of chronic wounds occurs in people over age 60 and is increasing at a rate of approximately 10% per year. However, there is still no effective treatment method for such wounds because the mechanism has not been fully elucidated. We have found both high ROS production and MMPs expression in the ischemic wound of young animal, which correlated with high levels of MAPKs. The present study aimed to test the hypothesis that the ROS/MAPK/MMPs signaling axis plays an important role in pathobiological process of chronic wound in elderly by using small interference RNA (siRNA) approach in a novel ischemic wound model. Methods: The delayed wound healing model based on an axial ischemic flap on the abdomen was created in 12 month-old male Fischer 344 rats. 80 µg DY547 labeled Non-targeting control siRNA and SMARTpool AP-1-siRNA was administered to ischemic wound tissue by injecting into superficial inferior epigastric artery (SIEA) of the animal for both control and experimental group respectively. The closure of the wounds was monitored and the wound tissue was analyzed on days 7 &14 respectively (n=6). Results: The ischemic wounds showed significantly impaired closure compared to the normal acute wounds. 3-nitrotyrosine, a marker of oxidative stress, is markedly increased in ischemic wounds. IL-1, HIF-1α and VEGF receptor 2 were significantly decreased in ischemic wound tissue. The MMP9 and Cleaved Caspase 3 protein were increased dramatically, correlated with more collagen degradation. These data of control group suggested severe oxidative stress with excessive collage breakdown and increased apoptosis leading to wound closure impairment. The fluorescently labeled siRNA was successfully delivered and detected in the wound tissue. AP-1 siRNA treatment significantly improved ischemic wound healing and reversed the effects of oxidative stress on such wounds (Figure 1). Conclusions: Specific agents can be selectively and accurately delivered to the wounds via an arterial pedicle in the novel model, enhancing the ability to study wound healing mechanisms. Blockage of ROS/MAPK/MMPs signaling axis with MAPKs- siRNA could be an important therapeutic approach for chronic non-healing wounds.


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