Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 307, Issue 11, Pages C1058-C1067Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00270.2014
Keywords
pro-healing and neurotrophic function; anti-inflammatory and pro-resolving mediators; diabetic wound healing; macrophage
Categories
Funding
- National Institutes of Health [R01-DK-087800, P30-GM-103340, 1P01 GM-095467]
- Research to Prevent Blindness New York
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK087800] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P30GM103340, P01GM095467] Funding Source: NIH RePORTER
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Dysfunction of macrophages (M Phi s) in diabetic wounds impairs the healing. M Phi s produce anti-inflammatory and pro-resolving neuroprotectin/protectin D1 (NPD1/ PD1, 10R, 17S-dihydroxy-docosa-4Z, 7Z, 11E, 13E, 15Z, 19Z-hexaenoic acid); however, little is known about endogenous NPD1 biosynthesis by M Phi s and the actions of NPD1 on diabetic M Phi functions in diabetic wound healing. We used an excisional skin wound model of diabetic mice, M Phi depletion, M Phi s isolated from diabetic mice, and mass spectrometry-based targeted lipidomics to study the time course progression of NPD1 levels in wounds, the roles of M Phi s in NPD1 biosynthesis, and NPD1 action on diabetic M Phi inflammatory activities. We also investigated the healing, innervation, chronic inflammation, and oxidative stress in diabetic wounds treated with NPD1 or NPD1-modulated M Phi s from diabetic mice. Injury induced endogenous NPD1 biosynthesis in wounds, but diabetes impeded NPD1 formation. NPD1 was mainly produced by M Phi s. NPD1 enhanced wound healing and innervation in diabetic mice and promoted M Phi s functions that accelerated these processes. The underlying mechanisms for these actions of NPD1 or NPD1-modulated M Phi s involved 1) attenuating M Phi inflammatory activities and chronic inflammation and oxidative stress after acute inflammation in diabetic wound, and 2) increasing M Phi production of IL10 and hepatocyte growth factor. Taken together, NPD1 appears to be a M Phi s-produced factor that accelerates diabetic wound healing and promotes M Phi pro-healing functions in diabetic wounds. Decreased NPD1 production in diabetic wound is associated with impaired healing. This study identifies a new molecular target that might be useful in development of more effective therapeutics based on NPD1 and syngeneic diabetic M Phi s for treatment of diabetic wounds.
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