Global Gene Dysregulation Due To High Oxidative Stress Leads To Chronic Wound Initiaton
Jane H. Kim, Sandeep Dhall, Manuela Martins-Green.
University of California, Riverside, Riverside, CA, USA.
Wound healing involves a series of sequential processes that are regulated in a temporal and spatial manner leading to successful tissue repair after injury. Chronic wounds develop as a result of defective regulation of one or more of these complex processes, but how these processes are affected during chronicity initiation is still not known. We used a diabetic mouse model of chronic wound to study gene regulation during initiation of chronicity. Cutaneous tissue was collected between 24 hours and 5 days post-wounding from mice treated with vehicle or inhibitors for the antioxidant enzymes, catalase and glutathione peroxidase, to increase the oxidative stress (OS) in the wound and stimulate chronicity. RNAseq was performed and the data processed and analyzed via systempipeR and biomaRt. Within 24 hours, over 2000 genes are differentially expressed in chronic wounds. Most are up-regulated and they include transcription factors from the Fox, Hox, Grh and AP-2 families, chromatin remodeling factors such as SNF/SWI and histone acetyltransferases (HATs). Gene ontology analysis shows that these genes stimulate biological processes such as membrane and cytoskeleton organization, cell death, cell proliferation, differentiation, adhesion, migration, inflammation and angiogenesis, all of which are critical for proper granulation tissue formation and wound closure. In contrast, most genes are significantly downregulated by Day 5, indicating that the wound is in disarray and cannot proceed to proper healing. These results suggest that high OS levels stimulate large-scale transcription activation early in the healing process, leading to turning on processes that should not occur early after injury whereas these processes are not turned on later when they are needed for proper healing. In conclusion, understanding the effects of high levels of OS shortly after debridement of human wounds, could lead to the development of treatments that can reverse the course of non-healing to healing.
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