SPM Biodegradation: A Novel Mechanism for Impaired Healing of Chronic Wounds in Aging

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ABSTRACT As stated in “PA-16-231 Non-healing Ulcerative Wounds in Aging (R21)”, “diabetic ulcers occur more commonly in the elderly... few studies have explored how aging impacts these (wound healing) processes and this gap in our understanding limits the applicability of novel therapies”. Impeded resolution of chronic inflammation contributes largely to the impairment of healing by the combination of aging and diabetes. Resolving chronic inflammation is pivotal in overcoming this impairment, and is attributable to specialized pro- resolving lipid mediators (SPMs). Our long-term goal is to delineate the mechanisms of healing impaired by diabetes and aging and develop better modalities for effective treatment of chronic wounds in the elderly. SPMs are endogenously made enzymatically from polyunsaturated fatty acids. SPMs in normally healing skin- wounds include SPM1 (i.e., 14S,21R-dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid) and neuroprotectin D1 (NPD1). SPM1 and NPD1 can potently resolve chronic inflammation and restoring the healing of diabetic wounds. Chronic wounds of diabetic or aged humans and mice are SPM1 and NPD1 deficient and contain higher levels of SPM1 and NPD1 biodegradation products, compared to normally healing wounds, suggesting that the SPM deficiency is an important contributor to the healing impairment. Our pilot study found that SPM1 and NPD1 were converted to the degradation products by 15-hydroxyprostaglandin dehydrogenase (PGDH, the key endogenous enzyme that degrade hydroxyl-containing lipid mediators). Thus we hypothesize that the exacerbated biodegradation of wound SPMs is at least partially responsible for the healing impairment in diabetic wounds in the elderly. This will be tested in an established aged diabetic db/db mouse model of splinted excisional wounds. We will also use PGDH knockout and inhibition, and our unique aqueous chiral (ac) LC-UV-MS/MS lipidomics platform. Aim 1. Test the prediction that the biodegradation deactivates endogenous SPMs in healing the wounds of aged diabetic mice. 1A) Determine the time course of degradation of wound SPMs. We will establish the temporal profiles of biodegradants of wound SPMs of aged diabetic mice using acLC-UV-MS/MS. 1B) Test whether or not the SPM1 and NPD1 biodegradants are able to promote wound healing in mice. Aim 2. Test the prediction that suppressing the key enzymatic pathway for SPM biodegradation restores the wound healing in aged diabetic mice. We will determine the healing and inflammation resolution of wounds: 2A) of the aged diabetic mice with the key biodegradation enzyme PGDH blocked by inhibitors; and 2B) of mice with PGDH knocked out to verify the results from 2A. Overall impact: This project will define novel mechanisms and explore the therapeutic potential of suppressing the degradation of SPMs, in restoring the healing of diabetic wound in aging. These studies will fill the clinically significant gap of basic scientific knowledge about diabetic wounds in aging, lipid mediator biology, and pharmacology associated with SPMs. The proposed novel mechanism is highly translational.